JPS6236038B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel thiazolinoazetidinone derivative and a method for producing the same. The thiazolinoazetidinone derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula []. [In the formula, R ¹ represents an aryl group or an aryloxy 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. show. X ¹ and X ² represent a hydrogen atom or a halogen atom. ] The thiazolinoazetidinone derivative represented by the above general formula [ ] is a compound useful as an intermediate for synthesizing penicillin and cephalosporin 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, R ¹ , R ² , X ¹ and X ² are the same as above. ] The thiazolinoazetidinone derivative represented by the above general formula [] can be produced by various methods. [In the formula, R ¹ , R ² , X ¹ and X ² are the same as above. ] is produced by reacting a basic compound with a chlorinated thiazolinoazetidinone derivative. In the present invention, examples of the aryl group represented by R ¹ include phenyl group, tolyl group, xylyl group, naphthyl group, p-chlorophenyl group, p-methoxyphenyl group, p-nitrophenyl group, p-
Examples of aryloxy groups include phenoxy, tolyloxy, xylyloxy, naphthyloxy, p-chlorophenyloxy, and p-chlorophenyloxy groups.
Examples include methoxyphenyloxy group, p-nitrophenyloxy group, and p-hydroxyphenyloxy 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 group, Examples of aryloxy lower alkyl groups that may have a nitro group on the phenyl ring include 3-phenylpropyl group and 3-(p-nitrophenyl)propyl group, such as phenoxymethyl group and p-nitrophenyl group. dimethyl group, 2
-Phenoxyethyl group, 2-(p-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, n-propyl group, isopropyl group, and n-butyl group. , tert-butyl group, 2-chloroethyl group, 2,2,2-trichloroethyl group, and the like. Examples of the halogen atom represented by X ¹ and X ² include a chlorine atom, a bromine atom, and a fluorine atom. The chlorinated thiazolinoazetidinone derivative represented by the general formula [] used as a starting material in the present invention is a new compound, and is produced, for example, by the method shown in the reaction formula below. [In the formula, R ¹ , R ² , X ¹ and X ² are the same as above. ] Electrolytic halogenation of the compound represented by the general formula [ ] can be carried out using, for example, water and methyl acetate, ethyl acetate, methyl formate, ethyl propionate, chloroform,
The compound represented by the general formula [] may be electrolytically treated in the presence of a known halogen acid and/or halide in a mixed solvent with an organic solvent such as carbon tetrachloride. The conditions for electrolytic treatment are usually about 5~
Approximately 2-50F/mol at current density in the range of 500mA/ ^cm2
It is sufficient to conduct electrolysis at a temperature in the range of about 20 to 100°C by applying an amount of electricity. The reaction between the compound represented by the general formula [] and chlorine is carried out in a suitable organic solvent under irradiation with light. As the organic solvent used, any solvent inert to chlorine can be used, such as dichloromethane, dibromoethane, dichloroethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, methyl acetate, ethyl acetate, methyl formate, Esters such as butyl acetate and ethyl propionate; ethers such as diethyl ether, dibutyl ether, tetrahydrofuran, and dioxane; nitriles such as acetonitrile and butyronitrile; hydrocarbons such as pentane, hexane, and cyclohexane;
Examples include aromatic hydrocarbons such as benbin, toluene, xylene, and chlorobenzene, carbon disulfide, and mixed solvents thereof. Molecular chlorine is usually used as chlorine. The ratio of the compound represented by the general formula [] and chlorine to be used is not particularly limited and can be appropriately selected within a wide range, but the latter is usually 0.5 to 10 times the molar amount of the former, preferably It is preferable to use 1 to 5 times the molar amount.
The reaction is usually carried out at about -20 to 100°C. When a basic compound is allowed to act on the compound represented by the general formula [], a dehydrochlorination reaction occurs to produce the compound of the present invention represented by the general formula [].
Although a wide range of conventionally known basic compounds can be used, it is preferable to use organic amines.
Specifically, dimethylamine, diethylamine, triethylamine, ethyldiisopropylamine,
piperidine, lutidine, pyridine, 1,5-diazabicyclo[5,4,0]undecene-5,1,
Examples include 5-diazabicucro[4,3,0]nonene-5. The amount of the basic compound to be used is not particularly limited and can be appropriately selected within a wide range, but it is usually 0.5 to 10 times the molar amount, preferably 1 to 5 times the molar amount of the compound represented by the general formula []. amount used. This dehydrochlorination reaction may be carried out in an organic solvent, or the basic compound used may be used as a solvent. As the organic solvent, a wide range of solvents can be used that are inert to the starting compound, target compound, and basic compound, such as halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, and dibromoethane, diethyl ether, and Ethers such as butyl ether, tetrahydrofuran, dioxane,
Examples include hydrocarbons such as pentane, hexane, heptane, and octane, and aromatic hydrocarbons such as benzene, chlorobenzene, toluene, and xylene. The reaction may be carried out at room temperature, under heating or under cooling, but is preferably carried out usually within the range of -20 to 80°C. The compound of the present invention thus obtained can be easily isolated and purified from the reaction mixture by conventional separation means such as solvent extraction and column chromatography. Compounds structurally similar to the compounds of the present invention include the formula The compound shown in JACS, 97, 5008 (1975)
and Pure Appl.Chem., 43 , 423 (1975), and the compound is synthesized according to the following reaction formula. The reaction for obtaining the compound of formula [] from the compound of formula [] is carried out using N-bromosuccinimide and a radical initiator under heating and ultraviolet irradiation.
This bromination was possible because the compound of the formula [] has a methoxy group at the 3-position; in the case of a compound in which a hydrogen atom is substituted for the methoxy group, bromination can proceed. do not. In contrast, according to the method of the present invention, the target compound can be obtained simply and in high yield under mild conditions without using any special reagents. Moreover, separation and purification of the target product are easy, there is no problem of waste such as by-products, and this method is extremely advantageous from an industrial perspective. Reference examples and examples are listed below. Reference Example 1 1 g of sodium chloride is dissolved in 3 ml of water, and 0.07 ml of concentrated sulfuric acid, 5 ml of methylene chloride, and 50 mg of the compound [] (R ¹ = phenyl, R ² = methyl) are added to prepare an electrolytic solution. Insert a 3 cm ² platinum plate electrode.
Electrolyze at 30 mA constant current, 1.6 to 1.8 V, and 25°C for about 2 hours. After the electrolysis is complete, extract with methylene chloride (30ml). Extract liquid is sodium sulfite water, hydrogenated sodium water,
After washing with brine and drying over anhydrous sodium sulfate, the solvent was removed to obtain 74 mg of a pale yellow liquid. When this product was developed using a silica gel column with a mixed solvent of benzene:ethyl acetate (5:1), the target compound [] (R ¹ = phenyl, R ² = methyl, X ¹ = X ² =
Cl) was obtained in an amount of 62.5 mg (yield 96%). (IR) 1780, 1745cm ^-1 NMR (CDCl ₃ ) 3.75 (3H, s, COOH ₃ ) 3.81 (2H, s, -CH ₂ Cl) 5.14 (2H, s, C=CH ₂ ) 5.41 (1H, s,

【formula】 6.05(2H,s,

[Formula] 7.3-7.9 (5H, m, phenyl) Reference example 2 Compound [] (R ¹ = phenyl, R ² = methyl, X ¹
=X ² =Cl) 50mg was dissolved in methylene chloride 0.5ml,
Add 1.5 ml of chlorine saturated methylene chloride solution. Immediately, reaction is carried out for 1 hour at 20 to 27°C while irradiating with light using a 750W tungsten lamp. After the reaction is completed, the reaction solution is poured into ice water and the methylene chloride layer is separated. After washing with an aqueous sodium thiosulfate solution and saturated saline, drying with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in benzene.
Separation and purification with a silica gel column using ethyl acetate (9:1) as a solvent yielded 50.05 mg of the compound []
R ¹ = phenyl, R ² = methyl, X ¹ = X ² = Cl). Yield 86% IR (cm ^-1 ) 1770, 1760 NMR (CDCl ₃ δ) 3.80 (s, 3H), 3.98 (bs, 2H) 4.12 (s, 2H), 5.12 (s, 1H) 6.10 (d, 1H) ), 6.28 (d, 1H) 7.2-7.5 (m, 3H) 7.5-7.8 (m, 2H) Example 1 Compound [] (R ¹ = phenyl, R ² = methyl, X ¹
=X ² =H) 55mg is dissolved in 0.6ml of methyl chloride, 88μ of triethylamine is added thereto, and the mixture is stirred at room temperature. After 2 hours of reaction, 5 ml of ether was added and then water was added for washing. followed by 10% hydrochloric acid,
Wash with saturated saline. The ether layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. When the residue was purified with a silica gel column, the desired product [] (R ¹ = phenyl, R ² = methyl,
X ¹ =X ² =H) is obtained. Yield 98% IR (cm ^-1 ) 1770, 1720 NMR (CDCl ₃ δ) 3.76 (s, 3H), 3.90 (s, 2H) 4.07 (bs, 2H), 4.63 (bs, 2H) 5.83 (d, 1H ), 6.30 (bd, 1H) 7.25 (s, 5H) Examples 2 to 7 The same operations and processes as in Example 1 are performed. The results are shown in Tables 1 and 2. In addition, Ph in the table means a phenyl group.

【table】

【table】

[Table] Examples 8 to 19 The same operations and treatments as in Example 1 were performed. The results are shown in Table 3. In addition, Ph in the table means a phenyl group.

【table】

【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents an aryl group or an aryloxy 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. show. X ¹ and X ² represent a hydrogen atom or a halogen atom. ] A thiazolinoazetidinone derivative represented by 2 General formula [In the formula, R ¹ represents an aryl group or an aryloxy 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. show. X ¹ and X ² represent a hydrogen atom or a halogen atom. ] By reacting a basic compound with a thiazolinoazetidinone derivative represented by [In the formula, R ¹ , R ² , X ¹ and X ² are the same as above. A method for producing a thiazolinoazetidinone derivative, which comprises obtaining a thiazolinoazetidinone derivative represented by the formula: