JPS6043437B2 - Method for producing azetidinone derivatives - Google Patents

Description

[Detailed description of the invention] The present invention relates to a novel method for producing azetidinone derivatives.

The azetidinone derivative obtained in the present invention is a new compound that has not been described in any literature, and is represented by the following general formula [1].
- [In the formula, R1 represents an aryl lower alkyl group or an aryloxy lower alkyl group.

R2 represents an aryl lower alkyl group that may have a nitro group on the phenyl ring, an aryloxy lower alkyl group that may have a nitro group on the phenyl ring, or a lower alkyl group that may have a halogen atom as a substituent. . R3 represents a lower alkyl group. ], In the present invention, examples of the aryl lower alkyl group represented by R1 include benzyl group, 2-phenylethyl group, p-hydroxybenzyl group, p-nitrobenzyl group, p-chlorobenzyl group, etc. Examples of the aryloxy lower alkyl group include phenoxymethyl group, 2-phenoxyethyl group, p-hydroxyphenoxymethyl group, and p-nitrophenoxymethyl group.

Examples of the aryl lower alkyl group that may have a nitro group on the phenyl ring represented by R2 include benzyl group, p-nitrobenzyl group, diphenylmethyl group, 2-phenylethyl group, 2-(p-nitrophenyl)ethyl Examples of the aryloxy lower alkyl group which may have a nitro group on the phenyl ring include phenoxymethyl group, p- Nitrophenoxymethyl group, 2-phenoxyethyl group, 2-(p-
Examples include nitrophenoxy)ethyl group, 3-phenoxypropyl group, 3-(p-nitrophenoxy)propyl group, and examples of lower alkyl groups that may have a halogen atom as a substituent include methyl group, ethyl group, etc. group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, 2-chloroethyl group, 2,2
, 2-trichloroethyl group, and the like. Examples of the lower alkyl group represented by R3 include methyl group, ethyl group, n)-propyl group, isopropyl group, n)
-butyl group, tert-butyl group and the like. The azetidinone derivative represented by the above general formula [1] is a compound useful as an intermediate for synthesizing penicillin and cephalosporin 7 antibiotics. For example, a cephalosporin compound [■a] or [■b] useful as an antibacterial agent can be derived from the compound of the present invention according to the following reaction formula. [In the formula, Rl, R and R3 are the same as above.

] According to the method of the present invention, the azetidinone derivative represented by the above general formula [1] can be obtained from the azetidinone derivative represented by the general formula [where R4 represents a 2-benzothiazolyl group].

R1 and R2 are the same as above. It is produced by electrolytically treating an azetidinone derivative represented by ] in the presence of a lower alcohol. The compound of general formula [■] used as a starting material in the present invention is a known compound, and is produced, for example, according to the method described in Tetrahedron Letter 3001 (1973).

The electrolytic treatment of the azetidinone derivative represented by the general formula [■] is carried out by applying a necessary amount of electricity in the presence of a lower alcohol.

Examples of lower alcohols include methanol, ethanol, propanol, isopropanol, butanol, Te
Examples include rt-butyl alcohol. Such lower alcohols are usually used as solvents, but in the present invention, mixed solvents of lower alcohols and other solvents can also be used. Examples of solvents used in combination with lower alcohols include ethers such as tetrahydrofuran, diethyl ether, and dioxane; nitriles such as acetonitrile and probionitrile; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethane; Mixed solvents of these can be mentioned. In the method of the present invention, it is preferred that a supporting electrolyte be present in the reaction system.

Examples of the supporting electrolyte include mineral acids such as sulfuric acid, perchloric acid, and phosphoric acid, sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid, and organic acids such as formic acid, acetic acid, and propionic acid. The θ electrolytic reaction can be performed by either constant potential electrolysis or constant current electrolysis.

The current density is usually in the range of 1 to 500 rr1A/C4, preferably 5 to 200 mA/Clt. The amount of electricity required for the reaction varies depending on the substrate concentration, the type of solvent, the shape of the electrolytic cell, etc., but is usually 2 to 50 F'/MOl. As electrodes, platinum, carbon, stainless steel, titanium,
Commonly used electrodes such as nickel can be used. The reaction temperature is not particularly limited as long as it is below a temperature at which the raw materials and products do not decompose or denature;
The temperature is preferably -20 to 30°C. As the electrolytic cell, both an electrolytic cell without a diaphragm and an electrolytic cell with a diaphragm can be used. According to the present invention, the desired azetidinone derivative represented by the general formula [1] can be produced in good yield by simple operations, as is clear from the Examples below. Examples will be described below.

Example 1 Compound [■] (R1=benzyl, R2=methyl, R4=
Benzothiazolyl) 250.3 mg in methanol 50 m
1 and add 0.4 ml of concentrated sulfuric acid.

Platinum electrodes were charged (4 x 3cri), and the temperature was heated to 0-2°C with stirring.
Electrolytic reaction is carried out for 2 hours at A/d. After the reaction is completed, the mixture is extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was separated and purified on a silica gel column using a solvent of benzene-ethyl acetate (3:1), yielding 167.9 m9 of the target product [1] (R1 = benzyl, R2 = methyl, R3 = methyl). 5.16 (4S, .4H), 6.71 (
DllH), 7.27(S,.5l-[) Example 2 Compound [■] (R1=benzyl, R2=methyl, R4=
50.2 m9 of benzothiazolyl) was dissolved in 4 mt of methanol and 4.5 Tnt of toterahydrofuran, and dissolved in concentrated sulfuric acid 0.
．． Add 07mt.

Insert a platinum electrode, -14 to -12°C, 5n1A/Cl
The electrolytic reaction was carried out at t for 1 hour and 35 minutes. Example 1 after completion of reaction
By performing the same treatment as above, 30.2 mg of the target product [1] (R1 = benzyl, R2 = methyl, R3 = methyl) is obtained (
yield 79%). Identification was confirmed by translation and NMR.

Example 3 Compound [■] (R1=benzyl, R2=methyl, R4=
Benzothiazolyl) 50.67? ! 9 with methanol 8m
0.07 mt of concentrated sulfuric acid was added, and a carbon electrode was charged.

A four-powder electrolytic reaction is performed at 0-2°C and 10rnA/Ai.

After the reaction is completed, the same treatment as in Example 1 yields the desired product [1]
(R1=benzyl, R2=methyl, R3=methyl) 30
．． Obtain 2 mg (yield 77%). The substance was confirmed and identified by separation and NMR. Example 4 Compound [■] (R1=benzyl, R2=methyl, R4=
Dissolve 49.5 mg of benzothiazolyl in 8 ml of methanol, and add 0.07 ml of concentrated sulfuric acid and 42 ml of copper sulfate.

A platinum electrode was inserted, and a one-powder electrolytic reaction was carried out at 0 to 2° C. and 10 rnA/C7ll for 1 hour. Current direction during electrolysis (9)
Converted every second. After the reaction was completed, the same treatment as in Example 1 was carried out to obtain the target product [1] (R1=benzyl, R2=methyl, R
3=methyl) 32.07 m9 are obtained. (Yield?%) ■Identification was confirmed by NMR.

The compounds shown in Table 1 below are obtained in the same manner as in Examples 1 to 4 using appropriate starting materials.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents an aryl lower alkyl group or an aryloxy lower alkyl group. R^2 is an aryl lower alkyl group that may have a nitro group on the phenyl ring, an aryloxy lower alkyl group that may have a nitro group on the phenyl ring, or a lower alkyl group that may have a halogen atom as a substituent. shows. R^4 represents a 2-benzothiazolyl group. ] The azetidinone derivative represented by the formula is electrolytically treated in the presence of a lower alcohol to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_3 represents a lower alkyl group. R^1 and R^2 are the same as above. ] A method for producing an azetidinone derivative, the method comprising obtaining an azetidinone derivative represented by the following. 2. The method according to claim 1, wherein the electrolytic treatment is performed using a supporting electrolyte. 3. The method according to claim 2, wherein the supporting electrolyte is at least one selected from sulfuric acid, perchloric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, and propionic acid. 4. The method according to any one of claims 1 to 3, wherein the electrolytic treatment is carried out at -70 to 80°C.