JPH11236386A - Production of 3-cephem compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a 3-cephem compound having a wide range of antimicrobial spectra from a raw material that is readily available from inexpensive penicillin by allowing a β-lactam halide to react with an organic halide in the presence of a specific metal and a specific metal compound through simplified operations under industrially advantageous conditions. SOLUTION: A compound of formula I (R<1> is H, amino group or the like; R<2> is H, a halogen or the like; R<3> is H, a carboxylic group-protecting group; R<4> is an aryl, a nitrogen-containing aromatic heterocyclic ring; m is 0-2; X is a halogen; Y is a halogen, an eliminable group) is allowed to react with an organic halide of the formula: R<5> -CH2 X (R<5> is a 1-alkenyl, an aryl) in the presence of at least equimolar amount of a metal having the standard oxidation- reduction potential of -0.3 (V/SCE) and a metal compound having a higher standard oxidation-reduction potential than this metal to prepare the objective compound of formula II. In a preferred embodiment, manganese is used as the metal and a nickel compound is employed as the metal compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 3-cephem compound. The 3-cephem compound obtained by the method of the present invention is an antibacterial agent having a broad antibacterial spectrum (for example, Japanese Patent Application Laid-Open Nos.
No. 31482).

[0002]

2. Description of the Related Art JP-A-48-19593 discloses a 3-halogenomethylcephalosporin compound derived from a 3-halogenomethylcephalosporin compound.
A method for synthesizing a 3-substituted allylcephem compound by coupling a phosphoranylideneethylcephalosporin compound with a carbonyl compound is shown. In this reaction, it is necessary to once pass through a phosphoranilideneethylcephalosporin compound, which is not an industrially useful method. Further, a coupling reaction between 3-trifluoromethanesulfonyloxycephem (4) or 3-chloromethylcephem (5) and an organotin compound using a palladium catalyst has been reported (Journal of Organic Chemistry, 55, p5833-5847). , 19
90).

[0003]

Embedded image (In the formula, R ¹ , R ² and R ³ are the same as described below.)

[0004]

Embedded image (In the formula, R ¹ , R ² and R ³ are the same as described below.)

However, these production methods require not only the use of stoichiometric amounts of industrial tin compounds which are industrially difficult to use, the use of expensive palladium catalysts, but also the synthesis of compound (4). In this case, there is a problem that trifluoromethanesulfonic anhydride, which is industrially difficult to handle, must be used. A method using an allenyl β-lactam compound has also been reported as a method for producing a 3-cephem compound using penicillin as a starting material (JP-A-7-133279). Need to handle
There are disadvantages as an industrially advantageous production method.

[0006]

An object of the present invention is to provide a 3-cephem compound having a broader antibacterial spectrum than a halogenated β-lactam compound which can be easily derived in a short reaction step using inexpensive penicillin as a starting material. Is to provide a novel technique which can be easily produced by a simple reaction operation under industrially advantageous reaction conditions.

[0007]

According to the present invention, there is provided a compound represented by the general formula (1):
In the presence of a metal compound having at least an equimolar amount of a metal having a standard oxidation-reduction potential of -0.3 (V / SCE) or less and a standard oxidation-reduction potential higher than the metal. The present invention relates to a method for producing a 3-cephem compound, characterized by reacting with an organic halide compound represented by the general formula (2) to obtain a 3-cephem compound represented by the general formula (3).

[0008]

Embedded image (Wherein R ¹ represents a hydrogen atom, a halogen atom, an amino group, or a protected amino group. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group, a lower alkyl group, a hydroxyl group or a protected amino group. A lower alkyl group, a hydroxyl group, or a protected hydroxyl group which may have a hydroxyl group as a substituent, R ³ represents a hydrogen atom or a carboxylic acid protecting group, and R ⁴ may have a substituent. Represents an aryl group or a nitrogen-containing aromatic heterocyclic group which may have a substituent, m represents 0 to 2, X represents a halogen atom, and Y represents a halogen atom or a leaving group.

R ⁵ —CH ₂ X (2) (wherein R ⁵ represents a 1-alkenyl group which may have a substituent or an aryl group which may have a substituent.
X represents a halogen atom. )

[0010]

Embedded image (In the formula, R ¹ , R ² , R ³ , and R ⁵ are the same as described above.)

The inventor of the present invention has selected, instead of using a compound which is essentially difficult to synthesize as a starting material, a halogenated β-lactam compound which can be easily derived from penicillin as a starting material, and reduction, elimination, and addition of a halogen atom. An epoch-making production method in which a series of cyclization reactions proceed simultaneously has been found. In this method, instead of using an unstable compound such as an allenyl β-lactam compound as a starting material, a stable halogenated β
A standard oxidation-reduction potential of -0.3 using a lactam compound
(V / SCE) Reduction by reacting with an organic halide compound represented by the general formula (2) in the presence of a metal compound having at least equimolar amount of the following metal and a standard oxidation-reduction potential higher than the metal. A series of reactions including elimination, addition, and cyclization reactions proceeded simultaneously, and an excellent reaction mode in which the desired 3-cephem compound can be produced in one step was found, thereby completing the present invention. V / SCE indicates an oxidation-reduction potential based on a standard caramel electrode.

According to the method of the present invention, the objective 3 represented by the general formula (3) can be stably obtained in a simple operation and in one step.
-Cephem compounds can be prepared. In addition, the desired cephem compound can be produced in high yield and high purity. Compound (1) has both a cis-form and a trans-form based on a carbon-carbon double bond, and both are included in the present invention.

Each group shown in the present specification is specifically as follows. Examples of the halogen atom include fluorine, chlorine, bromine, and iodine. As the lower alkyl group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-
Linear or branched C ₁ such as butyl, tert-butyl, etc.
It can be exemplified -C ₄ alkyl group. Examples of the aryl group include phenyl, tolyl, and naphthyl.

Further, as the protected amino group represented by R ¹ , “Proective Gr.” By Theodora W. Greene.
oups in Organic Synthesis, 1981 by John Wi
ley & Sons. Inc. "(hereinafter simply referred to as" literature "), in addition to various groups described in Chapter 7 (p. 218 to 287), phenoxyacetamide, p-methylphenoxyacetamide, p-methoxyphenoxyacetamide,
p-chlorophenoxyacetamide, p-bromophenoxyacetamide, phenylacetamide, p-methylphenylacetamide, p-methoxyphenylacetamide, p-chlorophenylacetamide, p-bromophenylacetamide, phenylmonochloroacetamide, phenyldichloroacetamide, phenylhydroxyacetamide, Phenylacetoxyacetamide, α
-Oxophenylacetamide, thienylacetamide, benzamide, p-methylbenzamide, pt-
Butylbenzamide, p-methoxybenzamide, p-
Chlorobenzamide, p-bromobenzamide, phenylglycylamido and amino-protected phenylglycylamido, p-hydroxyphenylglycylamido and one or both of amino- and hydroxyl-protected
Amides such as p-hydroxyphenylglycylamide,
Examples include imides such as phthalimide and nitrophthalimide. Examples of the protecting group for the amino group of phenylglycylamido and p-hydroxyphenylglycylamido include the groups described in Chapter 7 (p. 218 to 287) of the above document. Examples of the protecting group for the hydroxyl group of p-hydroxyphenylglycylamido include the groups described in Chapter 2 (p10-72) of the above-mentioned document.

The lower alkoxy group represented by R ² includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-
Examples thereof include linear or branched C ₁ -C ₄ alkoxy groups such as butoxy and tert-butoxy. As the lower acyl represented by R ^2, for example, it can be exemplified formyl, acetyl, propionyl, butyryl, straight-chain or branched C ₁ -C ₄ acyl group such as isobutyryl. Examples of the protected hydroxyl group of a lower alkyl group having a hydroxyl group or a protected hydroxyl group represented by R ² as a substituent, and the protected hydroxyl group of a protected hydroxyl group represented by R ² are described in Chapter 2 (p10 to p. 72) can be exemplified. R
^The above-mentioned substituted lower alkyl group represented by ² may be substituted one or more times on the same or different carbons with the same or different kinds of substituents selected from a hydroxyl group or the protected hydroxyl group shown above. .

Examples of the carboxylic acid protecting group represented by R ³ include various groups described in Chapter 5 (p. 152 to 192) of the above-mentioned document, as well as a benzyl group, a p-methoxybenzyl group and a p-nitrobenzyl group. Group, diphenylmethyl group, trichloroethyl group, tert-butyl group and the like. Examples of the nitrogen-containing aromatic heterocyclic group of the nitrogen-containing aromatic heterocyclic group which may have a substituent represented by R ⁴ include thiazol-2-yl, thiadiazol-2-yl, and benzothiazol-2-yl Oxazol-2-yl, benzoxazol-2-yl, imidazol-2-yl, benzimidazol-2-yl, pyrimidyl, pyridyl groups and the like.

The types of substituents which may be substituted on the aryl group or nitrogen-containing aromatic heterocyclic group represented by R ⁴ include a halogen atom, a hydroxyl group, a nitro group, a cyano group, an aryl group, a lower alkyl group, An amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a mercapto group, an alkylthio group or an arylthio group represented by a group R ⁶ S- (R ⁶ is a lower alkyl group or an aryl group), a formyloxy group, a group R An acyloxy group represented by ⁶ COO- (R ⁶ is as defined above), a formyl group, an acyl group represented by a group R ⁶ CO- (R ⁶ is as defined above), a group R ⁶ O- (R ⁶ is alkoxy group or an aryloxy group represented by the same) to the carboxyl group, an alkoxycarbonyl group or the group R ⁶ OCO- (R ⁶ is represented by the same) in said aryloxycarbonyl group There can be exemplified. The aryl group or the nitrogen-containing aromatic heterocyclic group for R ⁴ may be substituted with one or more substituents of the same or different types selected from the above substituents.

The 1-alkenyl group represented by R ⁵ includes, for example, vinyl, 1-methylvinyl, allenyl, 1-alkenyl.
Propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-
Butenyl, 1,2-dimethyl-1-butenyl, 1,3-dimethyl-1-butenyl, 2,3-dimethyl-1-butenyl, styryl and the like can be exemplified. Examples of the substituent which may be substituted on the 1-alkenyl group or the aryl group represented by R ⁵ include all the substituents which may be substituted on the aryl group or the nitrogen-containing aromatic heterocyclic group described in the above R ⁴ . Can be used. The 1-alkenyl group or the aryl group for R ⁵ may be substituted with one or more same or different kinds of substituents selected from the above substituents.

Examples of the halogen atom represented by X and Y include fluorine, chlorine, bromine and iodine. As the leaving group represented by Y, a lower alkylsulfonyloxy group optionally having a substituent (for example, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a trichloromethanesulfonyloxy group), an aromatic sulfonyloxy group ( For example, benzenesulfonyloxy group, toluenesulfonyloxy group), halogenated sulfonyloxy group (for example, fluorosulfonyloxy group), lower alkylphosphoryloxy group (for example, trimethylphosphoryloxy group, triethylphosphoryloxy group, tributylphosphoryloxy group), aromatic Examples thereof include a phosphoryloxy group (for example, a triphenylphosphoryloxy group and a tolylphosphoryloxy group).

The halogenated β-lactam compound represented by the general formula (1), which is a starting material of the present invention, is described, for example, in JP-A-8-245573 (USSN 08 / 732,44).
It can be manufactured by the method shown in 3). That is, in the compound represented by the general formula (1),
By substituting the hydroxyl group with a halogen atom or a leaving group, a halogenated β-lactam compound represented by the general formula (1) is obtained. In the present invention, the halogenated β-lactam compound represented by the general formula (1) is prepared by converting a standard oxidation-reduction potential into at least equimolar amount of a metal having a standard oxidation-reduction potential of −0.3 (V / SCE) or less and a standard By reacting with an organic halide compound represented by the general formula (2) in the presence of a metal compound having an oxidation-reduction potential, a cephem compound represented by the general formula (3) is obtained. The amount of the organic halide compound represented by the general formula (2) is determined by the general formula (1)
It is preferred to use 1 to 10 mol, preferably 1 to 4 mol, per 1 mol of the compound.

The standard oxidation-reduction potential is -0.3 (V / SC)
E) Examples of the following metals include magnesium, aluminum, manganese, zinc, iron, nickel, tin, and lead, but manganese is preferred. The shape of these metals is not particularly limited, and a wide range of forms such as powdery, plate-like, foil-like, lump-like, and needle-like can be used as appropriate, but it is more preferable to use powdery metal or foil-like metal. Good. The particle size of the powdered metal can be appropriately used in a wide range, but it is preferable to use one having a mesh size of about 10 to 300 mesh. The amount of these metals to be used is generally 1 to 50 mol, preferably 1 to 10 mol, per 1 mol of the compound of the general formula (1).

The metal compound having a higher standard oxidation-reduction potential than the above-mentioned metal includes a lead compound (for example, lead fluoride,
Inorganic salt lead such as lead chloride, lead bromide, lead iodide, lead nitrate, lead sulfate, lead perchlorate, lead borate, lead carbonate, lead phosphate, etc., lead acetate,
Fatty acid lead such as lead oxalate and lead stearate, lead oxide, lead hydroxide, etc., copper compounds (for example, copper fluoride, copper chloride, copper bromide, copper iodide, copper nitrate, copper sulfate, copper perchlorate) Inorganic salts such as copper carbonate, copper acetate, fatty acid copper such as copper oxalate, copper oxide,
Copper hydroxide, etc.), titanium compounds (eg, titanium fluoride, titanium chloride, titanium bromide, titanium iodide, titanium nitrate, titanium sulfate, etc.), bismuth compounds (eg, bismuth fluoride,
Bismuth chloride, bismuth bromide, bismuth iodide, bismuth nitrate, bismuth sulfate, bismuth oxide, etc., nickel compounds [for example, nickel fluoride, nickel chloride, nickel bromide, nickel iodide, nickel nitrate, nickel sulfate, perchloric acid] Nickel, fatty acid nickel such as nickel acetate,

Tetraethylammonium tetrachloronickelate (II), tetraethylammonium tetrabromonickelate (II), hexaamminenickel chloride (I
I), hexaammine nickel bromide (II), dinitrotetraammine nickel (II), tris (ethylenediamine) nickel (II) chloride, tris (ethylenediamine) nickel (II) sulfate, dinitrobis (ethylenediamine) nickel (II), perchlorine Bis (N, N-dimethylethylenediamine) nickel (II), dichloro (bipyridyl) nickel (II), dibromo (bipyridyl) nickel (II), chloro (cyclopentadienyl) (triphenylphosphine) nickel (II), Nickel (II) complexes such as dichloro (triphenylphosphine) nickel (II) and dibromo (triphenylphosphine) nickel (II), tetrakis (triphenylphosphine) nickel (0), tris (triphenylphosphine) nickel (0) , Nickel (0) acetyl Tonato, nickel (0) nickel and the like hexafluoroacetylacetonato (0) complexes, etc.], and others. These metal compounds may be used alone or in combination of two or more.
In particular, when a nickel compound is used, the reaction yield is remarkably improved.

In these metal compounds, one kind of the metal compound is usually 0.0001 to 1 mol of the compound of the general formula (1).
５5 mol, preferably 0.001-2 mol. Therefore, for example, when two or more metal compounds are used in combination, it is preferable to use two or more metal compounds in the above-mentioned amounts. Specific examples of the combination of a metal having a standard oxidation-reduction potential of -0.3 (V / SCE) or less and a metal compound having a standard oxidation-reduction potential higher than the metal include, for example, an Al / Pb compound and an Al
/ Bi compound, Mn / Al compound, Mn / Ni compound, Mn /
Pb compound, Zn / Pb compound, Zn / Ni compound, Mg / B
i compound, Mg / Bi compound, Mg / Cu compound, Sn / Ti
Compound, Sn / Bi compound, Sn / Sb compound, Al / Pb /
Combinations of Ni compounds and the like are more preferable, and combinations of Mn / Ni compounds and Al / Pb / Ni compounds are more preferable.

Additives can be added to make the reaction proceed efficiently. As additives, Lewis acids such as aluminum compounds (for example, aluminum halides such as aluminum fluoride, aluminum chloride, aluminum bromide, and aluminum iodide, aluminum nitrate, aluminum sulfate, and the like), silylating agents (for example, trimethylsilyl chloride, O, N-bistrimethylsilylacetamide, bistrimethylsilylurea, hexamethyldisilazane, hexamethyldisilane, etc., carboxylic acid halides (acetic chloride, chloroacetic chloride, acetoxyacetic chloride, acetoacetic chloride, acetic bromide, formic chloride, formic bromide) Carboxylic acid halides which may have a substituent such as, for example, propanoic chloride), lower alkyl carbonate halides (such as ethyl chlorocarbonate), carboxylic anhydrides (such as acetic anhydride and trifluoroacetic anhydride) ), Sulfonic acid halides (lower alkylsulfonyl chloride such as methanesulfonyl chloride, arylsulfonyl chloride optionally having a substituent such as benzenesulfonyl chloride, halogeno sulfonyl chloride such as fluorosulfonyl chloride, etc.),
Sulfonic anhydrides (optionally having a substituent such as lower alkylsulfonic anhydride, benzenesulfonic anhydride, etc., which may have a substituent such as methanesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.) A good arylsulfonic anhydride). These may be used alone or as a mixture of two or more kinds. In particular, 0.5 mol of an aluminum halide compound such as aluminum chloride or aluminum bromide is used per 1 mol of the compound of the general formula (1). When ~ 2 mol is used, the reaction is remarkably improved.

Examples of the solvent include amides such as dimethylacetamide, dimethylformamide, 1-methyl-2-pyrrolidinone, hexamethylphosphoric triamide, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile and the like. Nitriles, dimethyl sulfoxide and the like, tetrahydrofuran and the like may be used alone or as a mixture of two or more,
In addition, the above-mentioned solvent is mainly used, and other ordinary solvents such as lower solvents such as methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, and ethyl propionate. Lower alkyl esters of alkyl carboxylic acids, diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve, ethers such as dimethoxyethane, tetrahydrofuran, cyclic ethers such as dioxane, benzene, Substituted or unsubstituted aromatic hydrocarbons such as toluene, xylene, chlorobenzene, and anisole; hydrocarbons such as pentane, hexane, heptane, and octane; cyclopentane, cyclohexane, and cyclohexane May heptane, cycloalkanes such as cyclooctane, dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride, also possible to use a mixed solvent in combination with halogenated hydrocarbons such as carbon tetrachloride. As a particularly preferred solvent, a mixed solvent containing dimethylformamide, 1-methyl-2-pyrrolidinone, and dimethylsulfoxide as main solvents is used.

The amount of these solvents to be used is about 0.5 to 200 liters, preferably about 1 to 50 liters per kg of the compound of the formula (1). The reaction is usually
The reaction is performed at a temperature in the range of 10 to 80C, preferably 0 to 50C. The reaction of the present invention suitably proceeds even at a reaction temperature near room temperature. The compound of the general formula (3) obtained by the present invention is
After completion of the reaction, it can be obtained as a substantially pure product by performing a normal extraction operation or crystallization operation, but it can be purified by other methods such as chromatography.

[0028]

The present invention will be described in detail below with reference to examples. Example 1 Manganese powder 71 mg, aluminum chloride 17.9 mg,
4 mg of dichloro (bipyridyl) nickel (II) was weighed, and the compound (1a) of the general formula (1) dissolved in 2 ml of 1-methyl-2-pyrrolidinone (R ¹ = phenylacetamide, R ² = H, R ³ = p-methoxybenzyl,
100 mg of R ⁴ = phenyl, m = 2, X = Cl, Y = para-toluenesulfonyloxy) and 24 mg of the compound (2a) of the general formula (2) (R ⁵ = —CH ＝ CH ₂ , X = Br) are added. . After stirring for 2 hours at room temperature, ethyl acetate, 5%
The mixture is extracted by adding hydrochloric acid, and the organic layer is washed with water and brine.
The organic layer is dried over sodium sulfate, and the concentrated residue obtained by evaporating the solvent under reduced pressure is purified by a silica gel column (toluene / ethyl acetate = 2/1) to obtain a compound (3a) of the general formula (3) (R ¹ = Phenylacetamide, R ² = H, R ³
= _{^{P-methoxybenzyl, R 5 = -CH = CH 2}} ) 48
mg (90% yield).

¹ H NMR (200 MHz, CDCl ₃ ) δ
2.88 (dd, J = 7.3, 13.9 Hz, 1H), 3.
25 (d, J = 18.3 Hz, 1H), 3.39 (d, J =
18.3Hz, 1H), 3.36 (dd, J = 5.4, 13.
9Hz, 1H), 3.58 (d, J = 17.0, 1H),
3.68 (d, J = 17.0 Hz, 1H), 3.79 (s, 3
H), 4.90 (d, J = 4.8 Hz, 1H), 5.05 (d
d, J = 1.2, 16.0 Hz, 1H), 5.12 (d, J =
1.2 Hz, 1 H), 5.17 (s, 2 H), 5.75 (dd
d, J = 5.3, 5.4, 7.3, 1H), 5.76 (dd,
J = 4.8, 9.0 Hz, 1H), 6.16 (d, J = 9.0
Hz, 1H), 6.85 to 7.40 (m, 9H)

Example 2 In Example 1, the reaction was carried out in the same manner as in Example 1 except for aluminum chloride, to obtain compound (3a) (26 mg, 54% yield). Example 3 In Example 1, the reaction was carried out in the same manner as in Example 1 except that N, N-dimethylformamide was used instead of 1-methyl-2-pyrrolidinone, whereby 79% of the compound (3a) was obtained.

Examples 4 to 9 In Example 1, the reaction was carried out in the same manner as in Example 1 using the compound (1a) and the compound of the general formula (2) having a substituent shown in Table 1 as R ^5. Corresponding compound of general formula (3) (R ¹ = phenylacetamide, R ² = H, R ³ = p-
Methoxybenzyl, R ⁵ is Table 1) were obtained.

[0032]

[Table 1]

Example 10 Manganese powder 71 mg, aluminum chloride 17.9 mg,
Weigh 4 mg of dichloro (bipyridyl) nickel (II),
100 mg of the compound (1a) of the general formula (1) dissolved in 2 ml of 1-methyl-2-pyrrolidinone and 30 mg of benzyl bromide [the compound of the general formula (2), R ⁵ = Ph, X = Br]
Add. After stirring and reacting at room temperature for 2 hours, ethyl acetate,
The mixture is extracted by adding 5% hydrochloric acid, and the organic layer is washed with water and brine. The organic layer is dried over sodium sulfate, and the concentrated residue obtained by evaporating the solvent under reduced pressure is purified by a silica gel column (toluene / ethyl acetate = 2/1) to obtain a compound (3f) of the general formula (3) (R ¹ = Phenylacetamide, R ² = H,
R ³ = p-methoxybenzyl, R ⁵ = Ph) was obtained 48 mg (90% yield).

¹ H NMR (200 MHz, CDCl ₃ )
δ 2.99 (dd, J = 14.3, 7.3 Hz, 1
H), 3.26 (d, J = 18.3 Hz, 1H), 3.42
(D, J = 18.3 Hz, 1H), 3.50 (dd, J = 1
4.3, 6.3 Hz, 1H), 3.62 (s, 2H), 3.7
7 (s, 3H), 4.91 (d, J = 4.8 Hz, 1H),
5.28 (s, 2H), 5.75 (dd, J = 9.0, 4.8)
Hz, 1H), 6.34 (d, J = 9.0 Hz, 1H), 6.
01 to 6.45 (m, 2H), 6.84 to 7.40 (m, 1
4H)

Examples 11 to 14 In Example 11, the reaction was carried out in the same manner as in Example 10 except that the compound (1a) and the compound of the general formula (2) having a substituent shown in Table 2 as R ⁵ were used. The corresponding compound of general formula (3) (R ¹ = phenylacetamide, R ² = H, R ³ = p
- methoxybenzyl, R ⁵ is Table 2) were obtained.

[0036]

[Table 2]

Examples 15 to 18 In Example 1, the compound represented by the general formula (1) was used in place of the compound (1a).
Compound (1j) (R ¹ = phenylacetamide, R ² =
H, R ³ = diphenylmethyl, R ⁴ = phenyl, m = 2,
X = Cl, Y = para-toluenesulfonyloxy) and the same reaction as in Example 1 yields the corresponding compound of general formula (3) (R ¹ = phenylacetamide, R ² =
H, R ³ = diphenylmethyl, R ⁵ = see Table 3).

[0038]

[Table 3]

Examples 19 to 22 In Example 1, compound (1) was replaced with a compound of the general formula (1)
Compound (1n) (R ¹ = phenylacetamide, R ² =
H, R ³ = p-methoxybenzyl, R ⁴ = 2-benzothiazolyl, m = 2, X = Cl, Y = para-toluenesulfonyloxy), the same reaction as in Example 1 was carried out to obtain the corresponding general formula. The compound (3) (R ¹ = phenylacetamide, R ² = H, R ³ = diphenylmethyl, R ⁵ =
Ref) was obtained.

[0040]

[Table 4]

Compound A described in JP-A-1-313482 useful as an antibacterial agent from compound (3) of the present invention
[7- [D-2-amino- (4-hydroxyphenyl)
A synthetic route to [acetamido] -3- (2-propenyl) -3-cephemu-4-carboxylic acid] is shown below.

[0042]

Embedded image

[0043]

According to the present invention, an intermediate of a cephalosporin antibacterial agent having a broad antibacterial spectrum can be obtained from a halogenated β-lactam compound which can be easily derived in a short reaction step using inexpensive penicillin as a starting material. The 3-cephem compound useful as a compound can be easily produced by a simple reaction operation and industrially advantageous reaction conditions.

Claims (2)

[Claims]) 1. A halogenated β- represented by the general formula (1)
The lactam compound is prepared by standard oxidation-reduction potential of -0.3 (V / S
CE) reacting with an organic halide compound represented by the general formula (2) in the presence of a metal compound having at least an equimolar amount of the following metal and a standard oxidation-reduction potential higher than the metal; A method for producing a 3-cephem compound, which comprises obtaining the 3-cephem compound represented by the formula (I). Embedded image (Wherein R ¹ represents a hydrogen atom, a halogen atom, an amino group, or a protected amino group. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group, a lower alkyl group, a hydroxyl group or a protected amino group. A lower alkyl group, a hydroxyl group, or a protected hydroxyl group which may have a hydroxyl group as a substituent, R ³ represents a hydrogen atom or a carboxylic acid protecting group, and R ⁴ may have a substituent. Represents an aryl group or a nitrogen-containing aromatic heterocyclic group which may have a substituent, m represents 0 to 2, X represents a halogen atom, Y represents a halogen atom or a leaving group. ^5- CH ₂ X (2) (wherein, R ⁵ represents a 1-alkenyl group which may have a substituent or an aryl group which may have a substituent.
X represents a halogen atom. ) (In the formula, R ¹ , R ² , R ³ , and R ⁵ are the same as described above.) 2. A standard oxidation-reduction potential of -0.3 (V / SC)
E) The method according to claim 1, wherein manganese is used as the following metal and a nickel compound is used as the metal compound having a higher standard oxidation-reduction potential than the metal.