JPH08245630A - Production of 3-cephem compound - Google Patents

Abstract

PURPOSE: To obtain the subject high-purity compound useful as an antimicrobial agent having a wide range of antimicrobial spectra in high yield according to simple operations by using a specific halomethylcephem compound as a starting raw material. CONSTITUTION: A 3-halomethylcephem compound of formula I [R<1> is H or a (protected)amino; R<2> is H, a halogen, a lower alkoxy, a lower acyl or a (substituted)lower alkyl; R<3> is H or a carboxylic acid; X is a halogen] is reacted with an alkenyl compound of the formula R<4> -(CH2 )n -Z [R<4> is a (substituted)1- alkenyl; n is 0 or 1; Z is a halogen or a (substituted)lower alkyltin] in the presence of copper metal or a copper compound (e.g. copper chloride) to afford the objective compound of formula II. Furthermore, the reaction is preferably carried out in an inert solvent, e.g. tetrahydrofuran under conditions of 0-50 deg.C.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The 3-cephem compound of the present invention is
It is useful as an antibacterial agent having a broad antibacterial spectrum (for example, JP-A-48-119959, JP-A-1).
-313482, JP-A-63-212187, and JP-A-62-51688).

[0002]

2. Description of the Related Art Conventionally, as a method for producing a 3-cephem compound represented by the general formula (3) of the present invention, a 3-phosphoranylideneethylcephalosporin compound derived from a 3-halogenoethylcephalosporin compound is used. A method for synthesizing a 3-substituted allylcephem compound by coupling a carbonyl compound with a carbonyl compound has been disclosed (Japanese Patent Laid-Open No. 48-19595).
No. 93). This method itself is difficult to synthesize 3-
Halogenoethyl cephem must be used as a starting material and is unsuitable for industrial synthesis. Further, as shown in the figure, a method of reacting 3-trifluoromethanesulfonyloxycephem with a corresponding allyltin compound in the presence of a palladium catalyst and a method of reacting allyl tinplate have been reported (J. Org. Chem., 1990, 5
5,5837 and J. Org. Chem., 1993, 58,
2299).

[0003]

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In this method, it is necessary to use a palladium catalyst which is a noble metal catalyst, and the reaction of cuprate requires not only the reaction with cuprate at an extremely low temperature (-78 ° C) but also Δ2 and C. (3) There is a problem that by-products such as -H form are generated. Compound (1)
A method of reacting (X = Cl) with a corresponding alkenyltin compound in the presence of a palladium catalyst has also been reported (Tetra
(Hedron Lett., 1988, 29, 5739), this reaction also requires the use of a palladium catalyst which is a precious metal catalyst, and a more practical method has been desired.

[0005]

[Chemical 4]

Further, a method has been reported in which an allenyl compound is subjected to a reductive cyclization coupling with an allyl halide in the presence of catalytic amounts of a lead compound and a nickel compound (J. Chem. Soc., Chem. Commun., 1994, 1
461). In this method, an unstable allene compound is used as a starting material for the reaction, and thus it cannot be said to be a practical method.

[0007]

Embedded image

[0008]

The object of the present invention is to develop a novel carbon-carbon bond forming reaction using a 3-halomethylcephem compound represented by the general formula (1) as a starting material. It is an object of the present invention to provide a method capable of producing a 3-cephem compound represented by (3) by a simple operation and in high yield and high purity.

[0009]

In the present invention, a 3-halomethylcephem compound represented by the general formula (1) is reacted with an alkenyl compound represented by the general formula (2) in the presence of metallic copper or a copper compound. Therefore, 3 represented by the general formula (3)
-A method for producing a 3-cephem compound, which comprises obtaining a cephem compound.

[0010]

[Chemical 6] [In the formula, R ¹ represents a hydrogen 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, 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. X represents a halogen atom. ]

R ⁴ — (CH ₂ ) nZ (2) [wherein R ⁴ is a 1-alkenyl group which may have a substituent,
n represents 0 or 1, Z represents a halogen atom or a lower alkyltin group which may have a substituent. ]

[0012]

[Chemical 7] [Wherein R ¹ , R ² , R ³ , R ⁴ and n are the same as defined above. ]

More specifically, each group shown in the present specification is as follows. Examples of the protected amino group represented by R ¹ include Protective Groups in Organic Synthesis.
ganic Synthesis, Theodora W. Greene, 198
One year, hereinafter referred to simply as "literature") Chapter 7 (218-)
287), 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 phenylglycylamide having an amino group protected, p-hydroxyphenylglycylamide and p having one or both of an amino group and a hydroxyl group protected.
Examples thereof include amides such as hydroxyphenylglycylamide and imides such as phthalimide and nitrophthalimide. 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 the protective group for the hydroxyl group of p-hydroxyphenylglycylamide, 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. R
Examples of the protecting group for carboxylic acid represented by 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.
Examples thereof include p-nitrobenzyl group, diphenylmethyl group, trichloromethyl group and tert-butyl group.

1-which may have a substituent represented by R ⁴
Examples of the alkenyl group include a vinyl group, a 1-propenyl group, a 1-butenyl group, a 1-pentenyl group and the like. Examples of the substituent include a halogen atom, a hydroxyl group, a nitro group, a cyano group, a lower alkyl group, an aryl group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a mercapto group, a lower alkylthio group, an arylthio group, and formyl. Examples thereof include an oxy group, an acyloxy group, a folylyl group, an acyl group, an alkoxy group, an aryloxy group, a carboxyl group, an alkoxycarbonyl group, and an aryloxycarbonyl group, and one or more of the same or different kinds selected from the above-mentioned substituents. One or more substituents may be substituted on the same or different carbons.

Examples of the halogen atom represented by Z include fluorine, chlorine, bromine and iodine, but chlorine, bromine and iodine are preferably used. Examples of the lower alkyl group of the lower alkyl tin group which may have a substituent represented by Z include linear or branched C _{1 to} C such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl. The alkyl group of ₆ can be illustrated. Examples of the kind of the substituent which may be substituted on the lower alkyl group include all the substituents which may be substituted on the 1-alkenyl group which may have a substituent represented by R ⁴ above.

As the 1-alkenyl compound represented by the general formula (2), the cephem compound represented by the general formula (1) (n
= 1) can also be used. The 3-halomethylcephem compound represented by the general formula (1), which is the starting material of the present invention, is a known compound, for example, S.I. Torii et. a
l., Tetrahedron Lett., 1982, 2187. In the present invention, the 3-halomethylcephem compound represented by the general formula (1) is reacted with the compound represented by the general formula (2) in the presence of metallic copper or a copper compound, and the compound represented by the general formula (3) is represented by 3 -Cephem compounds can be prepared.

Examples of the copper compound include copper (I) halide, such as copper (I) chloride, copper (I) bromide, and copper (I) iodide, and copper (I) inorganic salts such as copper (I) oxide. , 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 admixture 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 (1) to terminate the reaction, but if necessary, it is added until the compound of the general formula (1) 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. Examples of the solvent used in this reaction include lower alkyl esters of lower carboxylic acids such as methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate and ethyl propionate. Ketones such as acetone, methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone, and diethyl ketone, diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve, dimethoxyethane Etc., ethers such as tetrahydrofuran, cyclic ethers such as tetrahydrofuran, dioxane, dioxolane, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitri Halogen such as nitriles, etc., substituted or unsubstituted aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, anisole, etc., halogens such as dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride, carbon tetrachloride, CFCs, etc. Hydrocarbons, 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, cyclic amides such as N-methylpyrrolidinone, and dimethyl sulfoxide. Preferably tetrahydrofuran, dioxane, dioxolane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone (N
MP), dimethylimidazole (DMI) and dimethylsulfoxide are preferably used. These alone or 2
Used as a mixture of two or more species. Further, these solvents can also be used as a water-containing solvent. These solvents are usually 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 (1). The reaction temperature of the above reaction is usually -10 to 80.
C., preferably in the range of 0 to 50.degree. 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 obtained 3-cephem derivative represented by the general formula (3) can be isolated by a usual purification operation.

[0021]

The present invention will be described in detail below with reference to examples.
It In addition, Ph is C₆H_Five-Indicates. Example 1 Compound (1a) (R¹= PhCH₂CONH, R²= H, R
³= CH₂C₆H_FourOCH ₃-P, X = Cl) 200 mg, tri
Butyl vinyl tin 144 ml, copper (I) chloride 41 mg, bipyri
Weigh 64 mg of Zir in a 10 ml eggplant-shaped flask and N-
Add 10 ml of methylpyrrolidone (NMP) at room temperature for 3 hours
Stir. Pour the reaction mixture into 1N hydrochloric acid and wash with ethyl acetate.
And then washed twice with water and twice with saturated saline solution.
After that, it was dried over anhydrous sodium sulfate. Got
The solvent of the extracted extract was distilled off under reduced pressure, and the residue was removed.
Compound when purified and separated by Rica gel column chromatography
(3a) (R¹= PhCH₂CONH, R²= H, R³= C
H₂C₆H_FourOCH₃-P, n = 0, R^Four= -CH = CH₂)
(159 mg, 81%) is obtained.¹ 1 H NMR (CDCl₃) Δ: 2.88 (dd, J = 7.
3,13.9Hz, 1H), 3.22 (d, J = 18.3H
z, 1H), 3.39 (d, J = 18.3Hz, 1H),
3.37 (dd, J = 5.4, 13.9 Hz, 1H), 3.
58 (d, J = 17.0 Hz, 1 H), 3.68 (d, J
= 17.0 Hz, 1H), 3.79 (s, 3H), 4.90
(D, J = 4.7 Hz, 1 H), 5.05 (dd, J = 1.
2,5.3 Hz, 1 H), 5.12 (d, J = 1.2 Hz,
1H), 5.17 (s, 2H), 5.75 (ddd, J =
5.3, 5.4, 7.3Hz, 1H), 5.76 (dd, J
= 4.7, 9.0 Hz, 1H), 6.16 (d, J = 9.0)
Hz, 1H), 6.85-7.40 (m, 9H)

Examples 2 to 6 Examples in which this reaction was carried out in the same manner as in Example 1 except that the solvent was changed while leaving other conditions unchanged will be shown. Example Solvent Yield (%) 2 DMF 80 3 DMSO 61 4 DMI 72 5 CH ₂ Cl ₂ / DMF 69 6 THF / DMF 75

Example 7 Compound (1a) (R ¹ = PhCH ₂ CONH, R ² = H, R
³ = CH ₂ C ₆ H ₄ OCH ₃ -p, X = Cl) 200 mg, allyl bromide 500 ml, metallic copper 26 mg, bipyridyl 64 mg
Weigh in a 0 ml eggplant-shaped flask, add 10 ml of NMP, and stir at room temperature for 7 hours. 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 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 (3b) (R ¹ = PhCH ₂ CONH, R ² =
_{^{H, R 3 = CH 2 C}} 6 H 4 OCH 3 -p, n = 1, R 4 = -C
H = CH ₂₎ is (172mg, 85%) is obtained. ¹ H NMR (CDCl ₃ ) δ: 2.01 to 2.68 (m,
4H), 3.19 (d, J = 18.1Hz, 1H), 3.4
1 (d, J = 18.1 Hz, 1H), 3.62 (s, 2
H), 3.79 (s, 3H), 4.89 (d, J = 4.7)
Hz, 1H), 4.96 (d, J = 10.3Hz, 1
H), 4.99 (d, J = 17.7 Hz, 1H), 5.1
7 (s, 2H), 5.73 (dd, J = 4.7, 8.9H
z, 1H), 5.72 (dd, J = 10.3, 17.7H)
z, 1H), 6.25 (d, J = 8.9Hz, 1H), 6.
82-7.41 (m, 9H)

Examples 8 and 9 Examples in which this reaction was carried out in the same manner as in Example 7 except that the kind of allyl halide was changed under other conditions as they are.

Example 8 Allyl chloride yield
62% Example 9 Allyl iodide Yield 60%

Example 10 [When (1a) is used as the allyl compound, that is,
General formula as the 1-alkenyl compound represented by the formula (2)
Use the cephem compound (n = 1) represented by (1)
Example of Case] Compound (1a) (R¹= PhCH₂CONH, R²= H, R
³= CH₂C₆H_FourOCH ₃-P, X = Cl) 200 mg, metal
26 mg copper and 64 mg bipyridine 10 ml eggplant type flask
Weigh it, add 10 ml of NMP and stir at room temperature for 4 hours.
It Pour the reaction solution into 1N hydrochloric acid and extract with ethyl acetate.
It was washed out and washed twice with water and once with saturated saline solution.
Then, it was dried over anhydrous sodium sulfate. Got
For the extract, the solvent was distilled off under reduced pressure, and the residue was converted to silica.
When purified and separated by gel column chromatography, the compound (3
c) (R¹= PhCH₂CONH, R²= H, R³= CH₂C
₆H_FourOCH₃-P) (176 mg, 95%) is obtained.¹ 1 H NMR (CDCl₃) Δ: 2.44 (t, J = 8.3)
Hz, 2H), 2.91 (t, J = 8.3Hz, 2H),
3.19 (d, J = 18.3 Hz, 2H), 3.31 (d,
J = 18.3Hz, 2H), 3.63 (s, 4H), 3.7
9 (s, 6H), 4.88 (d, J = 4.7Hz, 2
H), 5.16 (s, 4H), 5.75 (dd, J = 4.
7,9.2 Hz, 2 Hz), 6.46 (d, J = 9.2 Hz,
2H), 6.70 to 7.41 (m, 18H)

[0027]

The 3-halomethylcephem compound of the general formula (1) of the present invention is reacted with the compound of the general formula (2) in the presence of metallic copper or a copper compound to give the 3- of the general formula (3). The cephem derivative can be produced by a safe and simple operation with high yield and high purity.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location // A61K 31/545 ADZ A61K 31/545 ADZ C07B 61/00 300 C07B 61/00 300

Claims (1)

[Claims] 1. A 3-halomethylcephem compound represented by the general formula (1) is reacted with an alkenyl compound represented by the general formula (2) in the presence of metallic copper or a copper compound to give the general formula (3). ) The 3-cephem compound represented by these is obtained, The manufacturing method of the 3-cephem compound characterized by the above-mentioned. Embedded image [In the formula, R ¹ represents a hydrogen 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, 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. X represents a halogen atom. R ⁴ — (CH ₂ ) nZ (2) [wherein R ⁴ is a 1-alkenyl group which may have a substituent,
n represents 0 or 1, Z represents a halogen atom or a lower alkyltin group which may have a substituent. ] [Chemical 2] [Wherein R ¹ , R ² , R ³ , R ⁴ and n are the same as defined above. ]