JPH08245634A - Cephem compound and its production - Google Patents

Abstract

PURPOSE: To readily obtain the subject high-purity compound having antimicrobial activities in high yield by carrying out the Diels-Alder reaction of a specific starting substance with a dienophile. CONSTITUTION: This compound of formula I [R<1> is a (protected)amino or H; R<2> is H, a halogen, a lower alkoxy, a lower acyl or a (substituted)lower alkyl; R<3> is H or a protecting group of a carboxylic acid; Ra , Rb and Rc are each H, a (substituted)lower alkyl or an aryl; X and Y are each O, C or S]. The compound of formula I is obtained by reacting a compound of formula II with a dienophile of the formula Xa ...Ya [Xa and Ya are each O, a (substituted)C or a (substituted)S; Xa and Ya are bound through double (triple) bond] (e.g. acrolein) in a solvent, e.g. methane chloride at 10-90 deg.C temperature. Furthermore, the compound of formula II is preferably prepared by reacting a 3- sulfonyloxycephem compound of formula III with an organotin compound of formula IV in the presence of metallic copper or a copper compound (e.g. copper chloride).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a tricyclic β-lactam compound represented by the general formula (1) and a process for producing the same. The compound of the present invention is a novel compound which has not been published in the literature and exhibits antibacterial activity and is useful in the medical field.

[0002]

BACKGROUND OF THE INVENTION Many cephem compounds are known, but the tricyclic β-lactam compound represented by the general formula (1) and the method for producing these compounds are not known. Also,
As a method for producing the synthetic intermediate represented by the general formula (2),
Conventionally, a reaction using an organic copper compound (alkenyl cuprate reagent) prepared from various copper salts and an alkenyllithium reagent as shown in formula (A) is known. For example, J. Org. Chem., 58, 2296 (1993), T
etrahedron Lett. 31, 3389 (1990), Tet
rahedron Lett. 33, 3565 (1992) and the like. Formula (A)

[0003]

Embedded image However, since it is necessary to carry out a reaction at an extremely low temperature of about −78 ° C., and the product is obtained as a mixture of Δ3 olefin and Δ2 olefin which is difficult to separate, it has a problem that it is very practical. is not.

[0004]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a cephem compound having more excellent antibacterial activity and effective as a medicine, and a method for producing the same.

[0005]

The present invention relates to a cephem compound represented by the general formula (1) and a method for producing the same.

[0006]

[Chemical 6] [In the formula, R ¹ represents an amino group, a protected amino group or a hydrogen atom. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group or a lower alkyl group having a hydroxyl group or a protected hydroxyl group as a substituent. R ³
Represents a hydrogen atom or a carboxylic acid protecting group. Ra, Rb, R
c represents a hydrogen atom or a lower alkyl group or aryl group which may have a substituent. X and Y each represent an oxygen atom, a carbon atom having a substituent or a nitrogen atom having a substituent, and X and Y are bonded by a single bond or a double bond. ]

The cephem compound represented by the general formula (1) of the present invention is produced, for example, by reacting the cephem compound represented by the general formula (2) with the dienophile represented by the general formula (3). can do.

[0008]

[Chemical 7] [In the formula, R ¹ represents an amino group, a protected amino group or a hydrogen atom. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group or a lower alkyl group having a hydroxyl group or a protected hydroxyl group as a substituent. R ³
Represents a hydrogen atom or a carboxylic acid protecting group. Ra, Rb, R
c represents a hydrogen atom or a lower alkyl group or aryl group which may have a substituent. ]

Xa ... Ya (3) [In the formula, Xa and Ya each represent an oxygen atom, a carbon atom which may have a substituent or a nitrogen atom which may have a substituent, and Xa and Ya are double bonds or They are linked by triple bonds. ]

Further, the cephem compound represented by the general formula (2), which is the starting material of the present invention, is, for example, the general formula (4)
It can be produced by reacting a 3-sulfonyloxycephem compound represented by the formula (3) with an organotin compound represented by the general formula (5) in the presence of metallic copper or a copper compound.

[0011]

Embedded image [Wherein R ¹ , R ² and R ³ are the same as above. R ⁴ represents a halogen atom or an aliphatic hydrocarbon group which may have a substituent, an alicyclic hydrocarbon group or an aromatic hydrocarbon group. ]

[0012]

[Chemical 9] [In the formula, R ⁵ represents an aliphatic hydrocarbon group which may have a substituent, an alicyclic hydrocarbon group or an aromatic hydrocarbon. R
a, Rb and Rc represent a hydrogen atom or a lower alkyl group or aryl group which may have a substituent. ]

The compound of the general formula (2) containing no olefin isomer can be obtained by the method for producing the compound of the general formula (2). Each group shown in the present specification is more specifically as follows. Examples of the protected amino group represented by R ¹ include Protective Group in Organic Synthesis (Protective Gro).
ups in Organic Synthesis, Theodora W. Greene
In addition to various groups described in Chapter 7 (pages 218 to 287) of 1981, hereinafter simply referred to as "references", phenoxyacetamide, p-methylphenoxyacetamide, p-methoxyphenoxyacetamide, p.
-Chlorophenoxyacetamide, p-bromophenoxyacetamide, phenylacetamide, p-methylphenylacetamide, p-methoxyphenylacetamide, p-chlorophenylacetamide, p-bromophenylacetamide, phenylmonochloroacetamide,
Phenyldichloroacetamide, phenylhydroxyacetamide, thienylacetamide, phenylacetoxyacetamide, α-oxophenylacetamide, benzamide, p-methylbenzamide, p-methoxybenzamide, p-chlorobenzamide, p-bromobenzamide, phenylglycylamide and amino groups Protected phenylglycylamide, p-hydroxyphenylglycylamide, amides such as p-hydroxyphenylglycylamide having one or both amino groups and hydroxyl groups protected, and imides such as phthalimide and nitrophthalimide. It can be illustrated. Examples of the protecting group for the amino group of phenylglycylamide and p-hydroxyphenylglycylamide include various groups described in Chapter 7 (pages 218 to 287) of the above-mentioned document. Further, as a protective group for the hydroxyl group of p-hydroxyphenylglycylamide,
The various groups described in Chapter 2 (pages 10 to 72) of the above literature can be exemplified.

The halogen atom represented by R ² is, for example,
Atoms such as fluorine, chlorine, bromine and iodine can be mentioned. Examples of the lower alkoxy group represented by R ² include linear or branched C ₁ -C such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. The alkoxy group of ₄ can be illustrated. Examples of the lower acyl group represented by R ² include linear or branched C such as formyl, acetyl, propionyl, butyryl and isobutyryl.
An acyl group having ₁ -C ₄ can be exemplified.

The protected hydroxyl group of a lower alkyl group having a hydroxyl group represented by R ² or a protected hydroxyl group as a substituent and the protected group of a protected hydroxyl group represented by R ² are described in Chapter 2 of the above-mentioned document. Examples thereof include the groups described in (Pages 10 to 72). The substituted lower alkyl group represented by R ² is the same or different kind of substituent selected from a hydroxyl group or a protected hydroxyl group shown above, and may be substituted on the same or different carbons by one or more. Good. Examples of the lower alkyl group include linear or branched C ₁ -C ₄ alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. be able to.

Examples of the protecting group for carboxylic acid represented by R ³ include allyl group, benzyl group, p-methoxybenzyl group, in addition to various groups shown in Chapter 5 (pages 152 to 192) of the above-mentioned document. , P-nitrobenzyl group, diphenylmethyl group, trichloromethyl group, tert-butyl group and the like. Examples of the type of halogen atom represented by R ⁴ include fluorine, chlorine, bromine and iodine, but fluorine and chlorine are preferably used.

As the aliphatic, alicyclic or aromatic hydrocarbon group which may have a substituent represented by R ⁴ ,
Aliphatic hydrocarbon groups such as C _{1 to} C ₄ linear or branched alkyl groups (eg, methyl group, ethyl group, etc.), alkenyl groups (eg, allyl group, butenyl group, etc.), C _{3 to} C ₈
Examples thereof include alicyclic hydrocarbon groups such as cycloalkyl groups (eg, cyclopentyl group, cyclohexyl group) and aromatic hydrocarbon groups such as phenyl group and naphthyl group. Examples of the kind of the substituent which may be substituted on these hydrocarbon groups include a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like), a C _{1 to} C ₄ straight chain or a branched chain. -Like alkoxy group (eg, methoxy group, ethoxy group, etc.), C ₁ -C ₄ linear or branched alkylthio group (eg, methylthio group, ethylthio group, etc.), C ₁ -C ₄
A straight chain or branched chain alkyl group (for example, a methyl group,
An ethyl group), an amino group, an amino group having one or two C _{1 to} C ₄ linear or branched alkyl groups as a substituent (for example, a methylamino group, a diethylamino group, etc.),
An acyloxy group represented by a hydroxyl group, R'COO- (R 'is a phenyl group, a tolyl group or a C _{1 to} C ₄ linear or branched alkyl group) (for example, a phenylcarbonyloxy group, an acetyloxy group, etc.) , R'CO- (R 'is the same as above), such as an acyl group (eg, phenylcarbonyl group, acetyl group, etc.), nitro group, cyano group, phenyl group and the like. These substituents may be substituted on the hydrocarbon group represented by R ⁴ by 1 to 5, especially 1 to 3, the same or different types. As R ⁴ , methyl, ethyl, trifluoromethyl, tolyl or phenyl is preferably used.

The aliphatic, alicyclic or aromatic hydrocarbon group which may have a substituent represented by R ⁵ is:
Aliphatic hydrocarbons such as C _{1 to} C ₄ linear or branched alkyl groups (eg, methyl group, ethyl group, n-propyl, n-butyl, etc.), alkenyl groups (eg, allyl group, butenyl group, etc.) Groups, alicyclic hydrocarbon groups such as C _{3 to} C ₈ cycloalkyl groups (eg, cyclopentyl group, cycloaxyl group, etc.), aromatic hydrocarbon groups such as phenyl group, naphthyl group, etc. As the kind of the substituent which may be substituted on these hydrocarbon groups, the substituent which may be substituted on the above R ⁴ is used as it is. These substituents are R
^The hydrocarbon group represented by 5 may be substituted with 1 to 5, especially 1 to 3, the same or different types. As R ⁵ , methyl, ethyl, n-propyl, n-butyl, tolyl or phenyl is preferably used.

The lower alkyl group and aryl group which may have a substituent represented by Ra, Rb and Rc include C ₁
To C ₄ linear or branched alkyl groups (eg, methyl group, ethyl group, etc.), alkenyl groups (eg, allyl group, butenyl group, etc.), and other aliphatic hydrocarbon groups, C ₃ -C ₈ cycloalkyl Examples thereof include alicyclic hydrocarbon groups such as groups (eg, cyclopentyl group, cyclohexyl group, etc.), aromatic hydrocarbon groups such as phenyl group, naphthyl group, etc. As the kind of the substituent which may be substituted on these hydrocarbon groups, the substituent which may be substituted on the above R ⁴ is used as it is.

In the compound of the general formula (3), Xa, Ya
Each represents an oxygen atom, a carbon atom having a substituent or a nitrogen atom having a substituent, and Xa and Ya are bonded by a double bond or a triple bond. As a combination of (Xa, Ya), when Xa and Ya (Xa, Ya) are linked by a double bond, (C = C), (N = O), (O = N),
A combination of (N = N) can be shown. Also Xa
And Ya (Xa, Ya) are bound by a triple bond, a combination of (C≡C), (C≡N) and (N≡C) can be shown.

The types of substituents which may be substituted on Xa and Ya include, in addition to the substituents which may be substituted on R ⁴ described above,
Formyl group, a carboxyl group, an alkoxycarbonyl group R'OCO- (e.g. methoxycarbonyl group, ethoxycarbonyl group, etc.), COCl, COAr, Ar, CH 2 O
H, CH ₂ Cl, CH ₂ NH ₂ , CH ₂ CN, CH ₂ COOH
(Ar is an aryl group) and the like. One or two of these substituents may be substituted on the same Xa and Ya. Specific compounds of the general formula (3) include, for example, acrolein, methylacrolein, 3-vinyl-3-cephem, 3-vinyl-2-cephem, diethylazodicarboxylate, nitrosobenzene, acetylenedicarboxylic acid dimethyl ester and the like. Can be mentioned.

The 3-sulfonyloxycephem compound represented by the general formula (4) used in the present invention is a known compound. Org. Chem., 54, 4962
(1989) and Recent Advances in the Chemistry
It is easily produced according to the method described in of β-Lactam Antibiotics (1988). That is, the β-lactam compound represented by the general formula (6) in an inert solvent,
The compound of the general formula (4) can be obtained by reacting with a sulfonyl halide or a sulfonic anhydride in the presence of a base.

[0023]

[Chemical 10] [In the formula, R ¹ , R ² and R ³ are the same as defined above. ]

Specifically, this reaction is carried out in a suitable solvent. Examples of the solvent that can be used include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol, methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, propione. Methyl acid, lower alkyl esters of lower carboxylic acids such as ethyl propionate, ketones such as acetone, methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone, diethyl ketone, etc.,
Diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve, ethers such as dimethoxyethane, cyclic ethers such as tetrahydrofuran, dioxane, dioxolane, acetonitrile, propionitrile, butyronitrile, iso Nitriles such as butyronitrile, valeronitrile, benzene,
Toluene, xylene, chlorobenzene, substituted or unsubstituted aromatic hydrocarbons such as anisole, dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride, carbon tetrachloride, halogenated hydrocarbons such as freons, pentane,
Aliphatic hydrocarbons such as hexane, heptane, and octane;
Examples thereof include cycloalkanes such as cyclopentane, cyclohexane, cycloheptane, and cyclooctane, amides such as dimethylformamide and dimethylacetamide, and dimethyl sulfoxide. These may be used alone or in combination of two or more. Further, these organic solvents may contain water as needed. These solvents are generally used in an amount of about 10 to 200 liters, preferably about 20 to 100 liters, per 1 kg of the compound of the general formula (6). The reaction temperature of the above reaction is usually about −78 to 60 ° C., preferably −40 to 30.
It is about ℃. Examples of the type of base used include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, lithium hydrogen carbonate and lithium carbonate, triethylamine, diisopropylamine, ethyldiisopropylamine, tributylamine, 1,5-diazabicyclo [ 4.3.0] Nonene-5 (DBN), 1,
8-diazabicyclo [5.4.0] undecene-7 (DB
U) 1,4-diazabicyclo [2.2.2] octane (Dabco), N-methylpiperidine, 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N, N
Examples thereof include organic bases such as -dimethylaniline and N, N-dimethylaminopyridine. These amines are used alone or as a mixture of two or more kinds. The amount of the base used in the above reaction is usually 1 to 10 equivalents with respect to the β-lactam compound represented by the general formula (6), but if necessary, β-lactam compound represented by the general formula (6) is further used. It is advisable to add more base until the lactam compound is gone. The 3-sulfonylcephem compound represented by the general formula (4) can be isolated by an ordinary purification method, but can be used as it is in the next reaction.

The type of sulfonyl halide used includes halogenated sulfonyl halides such as fluorosulfonyl chloride, lower alkylsulfonyl halides such as methanesulfonyl chloride, methanesulfonyl bromide, trifluoromethanesulfonyl chloride, and ethanesulfonyl chloride, benzenesulfonyl chloride, and chloride. Examples thereof include arylsulfonyl halides such as toluenesulfonyl, and preferably methanesulfonyl chloride, methanesulfonyl bromide, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, and toluenesulfonyltoluenesulfonic acid bromide are preferably used. Examples of the sulfonic acid anhydride used include lower alkyl sulfonic acid anhydrides such as methanesulfonic acid anhydride, ethanesulfonic acid anhydride, and trifluoromethanesulfonic acid anhydride, benzenesulfonic acid anhydride, and arylsulfone such as toluenesulfonic acid anhydride. An acid anhydride can be exemplified, but preferably, methanesulfonic acid anhydride,
It is preferable to use trifluoromethanesulfonic anhydride, benzenesulfonic anhydride, or toluenesulfonic anhydride. The amount of the sulfonyl halide or sulfonic anhydride used in the above reaction may be usually 1 to 10 equivalents relative to the β-lactam compound represented by the general formula (6), but if necessary, the general formula (6) It is preferable to add a base until the β-lactam compound represented by

In the present invention, 3- represented by the general formula (4) is used.
A 3-alkenylcephem compound represented by the general formula (2) can be produced by reacting a sulfonylcephem compound with an organotin compound represented by the general formula (5) in the presence of metallic copper or a copper compound.

As the copper compound, copper (I) halide, such as copper (I) chloride, copper (I) bromide, copper (I) iodide, etc., and copper (I) inorganic salts, such as copper (I) oxide, etc. , Copper (I) organic salts such as copper cyanide, copper (II) chloride, copper (II) bromide, copper (II) halides such as copper (II) iodide, copper (II) nitrate, copper sulfate Examples thereof include inorganic copper (II) compounds, and organic acid copper (II) salts such as copper acetate, copper oxalate, and copper stearate. These copper compounds may be used alone or in combination of two or more, and metallic copper, copper (I) halide salts, and copper (II) halide compounds are preferably used.
The amount of the metal copper or copper compound used is usually 1 to 10 equivalents with respect to the compound of the general formula (4) to complete the reaction, but if necessary, it may be added until the compound of the general formula (4) is exhausted. Good. In this reaction, the reaction yield may be improved by the presence of the additive. Examples of the type of additive include pyridine compounds such as pyridine, dipyridyl, and terpyridyl.

The reaction of the present invention is carried out in a suitable solvent. As the solvent used in this reaction, all of the above-mentioned solvents that can be used in the production of the general formula (4) can be used, but preferably tetrahydrofuran, dioxane, dioxolane, dimethylformamide, dimethylacetamide, N
Preference is given to using methylpyrrolidinone and dimethylsulfoxide. These may be used alone or in admixture of two or more. Further, these solvents can also be used as a water-containing solvent. These solvents are compounds of the general formula (4) 1 kg
Per 10 to 200 liters, preferably 2
It is preferable to use about 0 to 100 liters. The reaction temperature of the above reaction is usually -10 to 80 ° C, preferably 0 to 5
It is performed in the range of 0 ° C. The reaction of the present invention proceeds well even at a reaction temperature near room temperature. If necessary, it can be carried out in a sealed container or in an inert gas such as nitrogen gas. The resulting 3-alkenylcephem derivative represented by the general formula (2) can be isolated by an ordinary purification operation.

The 3-alkenylcephem compound represented by the general formula (2) thus obtained is used as a diene, and the Dienofile represented by the general formula (3) is reacted with the Diels-Alder reaction to form the general formula ( The tricyclic cephem compound represented by 1) can be produced. This reaction is carried out in a suitable solvent. As the solvent used in this reaction, all of the above-mentioned solvents that can be used in the production of the general formula (4) can be used, but it is preferable to use methylene chloride, chloroform, dichloroethane, or methane dibromide.
These may be used alone or in admixture of two or more. Further, these solvents can also be used as a water-containing solvent. These solvents are generally used in an amount of about 10 to 200 liters, preferably about 20 to 100 liters, per 1 kg of the compound of the general formula (2).

The reaction temperature for the above reaction is usually from -10 to 15
It is carried out at 0 ° C., preferably 10 to 90 ° C. The reaction of the present invention proceeds well even at a reaction temperature near room temperature.
If necessary, it can be carried out in a sealed container or in an inert gas such as nitrogen gas. General formula (1) obtained
The cephem derivative represented by can be isolated by a conventional purification operation. In the present invention, the 3-sulfonyl cephem compound represented by the general formula (4) is easily reacted with the organotin compound represented by the general formula (5) in the presence of metallic copper or a copper compound to obtain the general formula ( 3 represented by 2)
-A tricyclic cephem compound represented by the general formula (1) having antibacterial activity by using an alkenyl cephem compound as a diene starting material and performing a Diels-Alder reaction with a dienophile represented by the general formula (3) Can be easily produced with high yield and high purity.

In order to show the usefulness of the compound of the present invention, an antibacterial test was carried out by an agar plate dilution method, and the minimum inhibitory concentration (MIC) for bacterial growth is shown below. MIC value (μg / ml) Inoculum size 10 ⁶ cells / ml Bacterial species Test compound E. coli NIHJ JC-2 1D 1F 3.13 1.56

[0032]

EXAMPLES The present invention will be specifically described below with reference to Reference Examples and Examples. Incidentally, Ph is C ₆ H ₅ - shows a.

Example 1 Compound (4a) (R ¹ = PhCH ₂ CONH, R ² = H, R
³ = CH ₂ C ₆ H ₄ OCH ₃ -p, R ⁴ = CF ₃ ) 100 mg, tributylvinyltin 80 ml, copper (I) chloride 25 mg 10 ml
Weigh in an eggplant-shaped flask, and add 1 ml of N-methylpyrrolidone (NMP), and stir at room temperature for 6 hours. Pour the reaction mixture into 2N hydrochloric acid and extract with ethyl acetate.
It was washed twice with water and once with saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off from the obtained extract under reduced pressure, and the residue was purified and separated by silica gel column chromatography to obtain compound (2a) (R ¹ = PhC
H ₂ CONH, R ² = H, R ³ = CH ₂ C ₆ H ₄ OCH ₃ -p,
Ra = H, Rb = H, Rc = H) (70 mg, 88%) was obtained. ¹ H NMR (CDCl ₃ ) δ 3.62 (s, 2H), 3.
81 (s, 3H), 4.94 (d, J = 11.2Hz, 1
H), 5.14 (d, J = 11.2Hz, 1H), 5.0
8 (s, 1H), 5.14 (d, J = 11.2Hz, 1
H), 5.16 (d, J = 17.9 Hz, 1 H), 5.22
(D, J = 4.0 Hz, 1 H), 5.55 (dd, J = 4.
0, 8.6Hz, 1H), 6.17 (dd, J = 11.2,
17.9 Hz, 1H), 6.22 (s, 1H), 6.42
(D, J = 8.6 Hz, 1 H), 6.87 (d, J = 10.
4Hz, 1H), 7.25 (d, J = 10.4Hz, 2
H), 7.17 to 7.39 (m, 5H)

Example 2 When the tin compound was changed to tributyl cispropenyl tin and the same reaction as in Example 1 was carried out, compound (2b) (R
¹ = PhCH ₂ CONH, R ² = H, R ³ = CH ₂ C ₆ H ₄ OC
H ₃ -p, Ra = H, Rb = CH ₃ , Rc = H cis) (72 m
g, 89%) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.63 (d, J = 6.0
Hz, 3H), 3.64 (s, 2H), 3.81 (s, 3)
H), 4.81 (d, J = 1.7Hz, 1H), 5.03
(D, J = 13.8 Hz, 1 H), 5.11 (d, J = 1
3.8 Hz, 1 Hz), 5.26 (d, J = 4.9 Hz, 1
H), 5.62 (d, J = 9.0Hz, 1H), 5.62
(Dd, J = 4.9, 8.4 Hz, 1 H), 5.63 (d
t, J = 6.0, 9.0 Hz, 1 H), 6.02 (d, J =
1.7 Hz, 1 H), 6.16 (d, J = 8.4 Hz, 1
H), 6.87 (d, J = 9.0Hz, 2H), 7.23
(D, J = 9.0 Hz, 2 H), 7.18 to 7.40 (m,
5H)

Example 3 The tin compound was changed to tributyl 2-methyl-1-propenyl tin and the same reaction as in Example 1 was carried out. As a result, the compound (2c) (R ¹ = PhCH ₂ CONH, R ² = H, R ³ = C
H ₂ C ₆ H ₄ OCH ₃ -p, Ra = H, Rb = CH ₃ , Rc = C
_{H 3) (75mg, 91%} ) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.59 (S, 3H),
1.67 (d, J = 1.3 Hz, 3 H), 3.64 (S, 2
H), 3.81 (s, 3H), 4.74 (s, 1H),
4.98 (d, J = 11.8 Hz, 1 H), 5.12 (d,
J = 11.8Hz, 1H), 5.25 (d, J = 4.1H
z, 1H), 5.40 (d, J = 1.3Hz, 1H), 5.
64 (dd, J = 4.1, 9.0 Hz, 1H), 5.87
(S, 1H), 6.14 (d, J = 9.0Hz, 1H),
6.87 (d, J = 9.0Hz, 2H), 7.22 (d, J
= 9.0 Hz, 2H), 7.18 to 7.40 (m, 5H)

Example 4 When the tin compound was changed to tributyl trans-1-octenyl tin and the same reaction as in Example 1 was carried out, the compound (2d) (R ¹ = PhCH ₂ CONH, R ² = H, R ³ = C
H ₂ C ₆ H ₄ OCH ₃ -p, Ra = H, Rb = H, Rc = [(C
H _{2) 5} -CH ₃ trans] (74mg, 79%) was obtained. ¹ H NMR (CDCl ₃ ) δ 0.88 (t, J = 5.9
Hz, 3H), 1.18 to 1.36 (m, 8H), 1.93
(Dt, J = 5.9, 6.7 Hz, 2 H), 3.61 (s,
2H), 3.80 (s, 3H), 5.02 (d, J = 1
1.8Hz, 1H), 5.12 (s, 1H), 5.15
(D, J = 11.8 Hz, 1 H), 5.21 (d, J = 4.
0Hz, 1H), 5.55 (dd, J = 4.0, 8.8H
z, 1H), 5.59 (dt, J = 6.7, 15.8Hz,
1H), 5.84 (d, J = 15.8Hz, 1H), 6.0
3 (s, 1H), 6.48 (d, J = 8.8Hz, 1
H), 6.87 (d, J = 7.1Hz, 2H), 7.24
(D, J = 7.1 Hz, 2 H), 7.18 to 7.39 (m,
5H)

Example 5 Compound (2a) (R ¹ = PhCH ₂ CONH, R ² = H, R
³ = CH ₂ C ₆ H ₄ OCH ₃ -p, Ra = H, Rb = H, Rc =
H) 76 mg and acrolein 48 ml were weighed in a 10 ml eggplant-shaped flask, 2 ml of dichloroethane was added and the mixture was allowed to stand at room temperature 2
Stir for 1 hour. The reaction mixture was poured into 1N hydrochloric acid, extracted with ethyl acetate, washed twice with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The obtained extract is distilled off the solvent under reduced pressure,
When the residue was purified and separated by silica gel column chromatography, the compound (1A) (R ¹ = PhCH ₂ CONH, R ² = H, R
³ = CH ₂ C ₆ H ₄ OCH ₃ -p, X = CH ₂ , Y = CHCH
O, X and Y were single bonds) (80 mg, 93%). ¹ H NMR (CDCl ₃ ) δ 1.38 to 2.44, 2.6
7-2.79 (m, 5H), 3.58 (s, 2H), 3.
80 (s, 3H), 4.11 (d, J = 5.1Hz, 1
H), 5.02 (s, 1H), 5.08 (d, J = 12.
1Hz, 1H), 5.15 (d, J = 12.1Hz, 1
H), 5.50 (d, J = 4.3 Hz, 1 H), 5.65
(Dd, J = 4.3, 9.3 Hz, 1 H), 5.94 (d,
J = 3.3Hz, 1H), 6.14 (d, J = 9.3Hz,
1H), 6.83 to 6.95, 7.14 to 7.40 (m, 9
H), 9.66 (s, 1H)

Example 6 Example 1 was repeated except that methyl acrolein was used instead of acrolein.
When a reaction similar to that of Compound (1B) (R ¹ =
PhCH ₂ CONH, R ² = H, R ³ = CH ₂ C ₆ H ₄ OCH ₃
-p, X = CH ₂ , Y = C (CH ₃ ) CHO, X and Y are 1
(Heavy bond) (71 mg, 86%) was obtained. ¹ H NMR (CDCl ₃ ) δ 0.88 (s, 3H),
1.48 (m, 1H), 1.68 (m, 1H), 2.13
(M, 2H), 3.45 (d, J = 16.6Hz, 1
H), 3.58 (d, J = 16.6Hz, 1H), 3.54
(S, 1H), 3.78 (s, 3H), 5.04 (s, 1
H), 5.04 (d, J = 11.7Hz, 1H), 5.17
(D, J = 11.7 Hz, 1 H), 5.44 (d, J = 4.
3Hz, 1H), 5.62 (dd, J = 4.3, 9.2H)
z, 1H), 5.89 (bs, 1H), 6.55 (d, J
= 9.2 Hz, 1 H), 6.83 to 6.92, 7.15 to 7.
36 (m, 9H), 9.45 (s, 1H)

Example 7 When acrolein was changed to 3-vinyl-3-cephem and the same reaction as in Example 1 was carried out, compound (1C) was obtained.
[R ¹ = PhCH ₂ CONH, R ² = H, R ³ = CH ₂ C ₆ H ₄
OCH ₃ -p, X = CH ₂ , Y = CH- (Δ3-cephem), and X and Y are single bonds] (79 mg, 79%) were obtained. ¹ H NMR (CDCl ₃ ) δ 1.49 (m, 1H),
1.67 (m, 1H), 2.05 (m, 1H), 2.23
(M, 1H), 3.15 (d, J = 18.5Hz, 1
H), 3.36 (d, J = 18.5Hz, 1H), 3.38
(M, 1H), 3.60 (d, J = 15.5Hz, 1
H), 3.63 (d, J = 11.5Hz, 1H), 3.66
(D, J = 11.5 Hz, 1 H), 3.68 (d, J = 1
5.5Hz, 1H), 3.78 (s, 3H), 3.79
(M, 3H), 4.44 (d, J = 5.0Hz, 1H),
4.90 (d, J = 4.7 Hz, 1 H), 4.97 (s, 1
H), 5.09 (d, J = 11.8Hz, 1H), 5.11
(D, J = 12.8 Hz, 1 H), 5.15 (d, J = 1
2.8Hz, 1H), 5.17 (d, J = 11.8Hz, 1
H), 5.31 (d, J = 4.7Hz, 1H), 5.64
(Dd, J = 4.7, 9.7 Hz, 1 H), 5.82 (d
d, J = 4.7, 8.7 Hz, 1 H), 5.87 (d, J =
4.0 Hz, 1 Hz), 6.10 (d, J = 9.7 Hz, 1
H), 6.29 (d, J = 8.7 Hz, 1 H), 6.84-
6.94, 7.18 to 7.44 (m, 18H)

Example 8 When acrolein was changed to diethyl azodicarboxylate and the same reaction as in Example 1 was carried out, the compound (1
D) (R ¹ = PhCH ₂ CONH, R ² = H, R ³ = CH ₂ C
₆ H ₄ OCH ₃ -p, X = N-COOEt, Y = N-COO
Et, X and Y were single bonds) (103 mg, 98%). ¹ H NMR (CDCl ₃ ) δ 1.25 (m, 6H),
3.57 (s, 2H), 3.72 (d, J = 18.3Hz,
1H), 3.81 (s, 3H), 4.24 (m, 4H),
4.64 (dd, J = 5.0, 18.3 Hz, 1H), 5.
07 (d, J = 11.7 Hz, 1 H), 5.15 (d, J
= 11.7 Hz, 1H), 5.13 (s, 1H), 5.49
(D, J = 4.4 Hz, 1 H), 5.72 (dd, J = 4.
4,9.4 Hz, 1 Hz), 5.99 (d, J = 5.0 Hz,
1H), 6.14 (s, 1H), 6.17 (d, J = 9.
4Hz, 1H), 6.85-6.96, 7.17-7.42
(M, 9H)

Example 9 When acrolein was changed to nitrosobenzene and the same reaction as in Example 1 was carried out, compound (1E) (R ¹ = Ph
CH ₂ CONH, R ² = H, R ³ = CH ₂ C ₆ H ₄ OCH _3-
p, X = O, Y = N-Ph, X and Y are single bonds) (88 m
g, 94%) was obtained. ¹ H NMR (CDCl ₃ ) δ 3.51 (d, J = 15.
8Hz, 1H), 3.55 (d, J = 15.8Hz, 1
H), 3.75 (d, J = 16.5 Hz, 1 H), 3.78
(S, 3H), 3.94 (dd, J = 5.0, 16.5H
z, 1H), 5.08 (d, J = 12.0Hz, 1H),
5.14 (d, J = 12.0Hz, 1H), 5.27 (s,
1H), 5.51 (d, J = 4.0Hz, 1H), 5.74
(Dd, J = 4.0, 9.3 Hz, 1 H), 6.00 (s,
1H), 6.12 (d, J = 5.0Hz, 1H), 6.45
(D, J = 9.3 Hz, 1 H), 6.84 to 6.90, 7.
02 ~ 7.40 (m, 14H)

Example 10 When acrolein was changed to acetylenedicarboxylic acid dimethyl ester and the same reaction as in Example 1 was carried out, compound (1F) (R ¹ = PhCH ₂ CONH, R ² = H, R ³
_{= CH 2 C 6 H 4 OCH} 3 -p, X = C-COOMe, Y = C
-COOMe, X and Y are double bonds) (95 mg, 94%)
was gotten. ¹ H NMR (CDCl ₃ ) δ 2.98 (ddd, 3.
5, 6.0, 24.4 Hz, 1 H), 3.25 (ddd,
3.5, 6.0, 24.4 Hz, 1 H), 3.58 (s, 2
H), 3.80 (s, 3H), 3.81 (s, 3H),
3.82 (s, 3H), 4.80 (t, J = 6.0Hz, 2
H), 5.04 (d, J = 11.8Hz, 1H), 5.06
(S, 1H), 5.16 (d, J = 11.8Hz, 1
H), 5.51 (d, J = 4.4Hz, 1H), 5.68
(Dd, J = 4.4, 9.3 Hz, 1 H), 5.92 (t,
J = 3.5Hz, 1H), 6.02 (d, J = 9.3Hz,
1H), 6.85 to 6.93, 7.12 to 7.43 (m, 9
H)

Example 11 When 3-vinyl-2-cephem was used as the dienophile and the same reaction as in Example 1 was carried out, the compound (1
G) [R ¹ = PhCH ₂ CONH, R ² = H, R ³ = CH ₂ C
₆ H ₄ OCH ₃ -p, X = CH ₂ , Y = CH- (Δ2-cephem), and X and Y are single bonds] (90 mg, 90%) were obtained. ¹ H NMR (CDCl ₃ ) δ 1.39 (m, 2H),
1.82 (m, 1H), 2.11 (m, 1H), 2.53
(M, 1H), 3.55 (d, J = 15.8Hz, 1
H), 3.60 (d, J = 15.8Hz, 1H), 3.60
(D, J = 16.8 Hz, 1 H), 3.65 (d, J = 1
6.8Hz, 1H), 3.78 (s, 6H), 3.95
(D, J = 4.8Hz, 1H), 4.75 (s, 1H),
4.95 (s, 1H), 4.97 (d, J = 11.8Hz,
1H), 5.02 (d, J = 11.8Hz, 1H), 5.1
5 (d, J = 11.8 Hz, 1 H), 5.19 (d, J =
11.8Hz, 1H), 5.20 (d, J = 4.1Hz, 1
H), 5.35 (d, J = 4.4Hz, 1H), 5.54
(Dd, J = 4.4, 9.2 Hz, 1 H), 5.59 (d
d, J = 4.1, 8.3 Hz, 1 H), 5.82 (s, 1
H), 5.85 (d, J = 5.3Hz, 1H), 6.13
(D, J = 9.2 Hz, 1 H), 6.57 (d, J = 8.3
Hz, 1H), 6.81 to 6.91, 7.16 to 7.34
(M, 18H)

[0044]

INDUSTRIAL APPLICABILITY In the present invention, 3- represented by the general formula (4)
3-the sulfonylcephem compound represented by the general formula (2), which is easily obtained by reacting an organotin compound represented by the general formula (5) in the presence of metallic copper or a copper compound.
By using the alkenylcephem compound as a diene starting material and carrying out a Diels-Alder reaction with a dienofile represented by the general formula (3), a tricyclic cephem compound represented by the general formula (1) having antibacterial activity is obtained. It can be easily produced in high yield and high purity.

Claims (3)

[Claims] 1. A cephem compound represented by the general formula (1). Embedded image [In the formula, R ¹ represents an amino group, a protected amino group or a hydrogen atom. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group or a lower alkyl group having a hydroxyl group or a protected hydroxyl group as a substituent. R ³
Represents a hydrogen atom or a carboxylic acid protecting group. Ra, Rb, R
c represents a hydrogen atom or a lower alkyl group or aryl group which may have a substituent. X and Y each represent an oxygen atom, a carbon atom having a substituent or a nitrogen atom having a substituent, and X and Y are bonded by a single bond or a double bond. ] 2. A cephem compound represented by the general formula (1), characterized in that a dienophile represented by the general formula (3) is allowed to act on a cephem compound represented by the general formula (2). Manufacturing method. Embedded image [In the formula, R ¹ represents an amino group, a protected amino group or a hydrogen atom. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group or a lower alkyl group having a hydroxyl group or a protected hydroxyl group as a substituent. R ³
Represents a hydrogen atom or a carboxylic acid protecting group. Ra, Rb, R
c represents a hydrogen atom or a lower alkyl group or aryl group which may have a substituent. Xa ... Ya (3) [wherein Xa and Ya each represent an oxygen atom, a carbon atom which may have a substituent or a nitrogen atom which may have a substituent, and Xa and Ya are a double bond or a triple bond] Are bound by binding. ] 3. A 3-sulfonyloxycephem compound represented by the general formula (4) is reacted with an organotin compound represented by the general formula (5) in the presence of metallic copper or a copper compound, The manufacturing method of the cephem compound represented by General formula (2). Embedded image [Wherein R ¹ , R ² and R ³ are the same as above. R ⁴ represents a halogen atom or an aliphatic hydrocarbon group which may have a substituent, an alicyclic hydrocarbon group or an aromatic hydrocarbon group. ] [Chemical 4] [In the formula, R ⁵ represents an aliphatic hydrocarbon group which may have a substituent, an alicyclic hydrocarbon group or an aromatic hydrocarbon. R
a, Rb and Rc represent a hydrogen atom or a lower alkyl group or aryl group which may have a substituent. ]