JPH0254339B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention is based on the following general formula () (wherein R ¹ and R ² are hydrogen, linear or cyclic alkyl, aralkyl, alkylthio, alkoxy, acylamino, alkoxycarbonyl, or phenyl, and R ³ is hydrogen, linear or cyclic alkyl, phenyl, or protecting a nitrogen atom) This invention relates to a method for producing β-lactam, which is of interest as the basic skeleton of antibiotics and is also useful as an intermediate raw material for industrial and agricultural chemicals and pharmaceuticals. Conventionally, when producing β-lactams, reactions at high concentrations tend to involve intermolecular reactions and result in cyclic dimers and polymers, so reactions have been carried out under diluted conditions. However, the reaction under these diluted conditions required complicated operations such as gradual addition of reaction materials and post-reaction treatment, and was not satisfactory in terms of synthetic chemistry. (For example, Archiv.Pharm. (Weinheim),
301, 230 (1968)) In view of the above facts, the present inventors conducted intensive research to find a method for producing β-lactam without such drawbacks, and as a result, they discovered a production method that is high-yield and industrially useful. Heading The invention has been completed. Therefore, an object of the present invention is to provide a new method for producing β-lactams in high yields using simple operations. The method of the present invention is based on the general formula () (In the formula, R ¹ , R ² and R ³ are the same as above) A β-amino acid represented by the general formula ( ) is a method for producing β-lactam. To explain in more detail, the β-amino acid of the general formula () is in the form of a salt formed by the action of an alkaline substance, and the β-amino acid present in the aqueous layer is transferred from the aqueous layer to the organic layer using a phase transfer catalyst. This is a method in which β-lactam is produced in the layer by the action of a condensing agent. The method of the present invention eliminates the complication of having to carry out the reaction under dry conditions, which was previously necessary, by carrying out the reaction in a two-phase system of an organic layer and an aqueous layer using a phase transfer catalyst. , β in high yield
-This is an industrially useful production method that makes it possible to produce lactams. Furthermore, the method of the present invention is an excellent method that can be applied to optically active amino acids without isomerizing them. The method of the invention is carried out as follows. Water and an organic solvent containing a condensing agent are added to the β-amino acid, alkaline substance, and phase transfer catalyst and stirred. After the reaction is completed, if necessary, an appropriate organic solvent is added, the resulting organic layer is washed with brine or water, and the desired β-lactam can be obtained from the organic layer by conventional operations. The reaction is usually carried out at room temperature, but if necessary, it can also be carried out at the boiling point of the organic solvent. Further, the reaction time varies depending on the reaction scale, reaction temperature, etc., but is usually 10 hours to 30 hours. Examples of organic solvents used in the present invention include halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; aromatic compounds such as benzene, toluene, and xylene; and ethyl ether,
The solvent is not particularly limited as long as it is a solvent that does not participate in the reaction and is not easily soluble in water, such as ethers such as propyl ether. As the condensing agent, methanesulfonyl chloride, methanesulfonyltriazole, o-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, bis(o-nitrophenyl)phenylphosphonate,
Although o-nitrobenzenesulfonyltriazole and the like are used, it is advantageous to use methanesulfonyl chloride, p-nitrobenzenesulfonyl chloride, etc., which are inexpensive and easily available. The amount to be used may be 1 to 5 times the molar amount, preferably 1.5 to 2.5 times the molar amount of the β-amino acid as the raw material. Further, as the phase transfer catalyst, commonly used quaternary ammonium salts and quaternary phosphonium salts are used. Specifically, tetrabutylammonium hydrogen sulfate, triethylbenzylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, trioctylmethylammonium chloride, trioctylmethylammonium bromide, trioctylmethylphosphonium bromide, etc. . The amount used varies depending on the type of β-amino acid, organic solvent, condensing agent, and phase transfer catalyst.
It may be used in an amount of 0.01 to 3 times the molar amount, preferably 0.05 to 1.5 times the molar amount of the amino acid. The alkaline substances may be hydroxides or weak acid salts of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium bicarbonate, sodium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, etc. It is not limited. The amount used is usually 1.0 to 6.0 equivalents relative to the β-amino acid. The present invention provides a widely applicable method for producing β-lactams, and includes β-lactams of the general formula ().
In amino acids, substituents for (chain or cyclic) alkyl, alkylthio, alkoxy, acylamino, alkoxycarbonyl, phenyl, aralkyl represented by R ¹ , R ² and R ³ include halogen, nitro, cyano, alkyl, allyloxy,
The present invention can be carried out without particular limitation as long as it is an organic residue that does not participate in the reaction among alkoxy, acyloxy, alkylthio, allylthio, carbamoyl, carbamoyloxy, acylamino, aminosulfonyl, acyl, silyl, etc.
Examples of the protecting group for the nitrogen atom represented by R ³ include aralkyl such as benzyl, and alkoxy such as methoxy and ethoxy. Furthermore, as R ³ ,
Organic residues that hinder β-lactam formation, such as a hydrogen atom or a group that substantially forms an amide group by bonding with the amino group, are not preferred in the practice of the present invention. Hereinafter, the present invention will be specifically explained with reference to Examples. Example 1 1-Cyclohexyl-4-methyl-2-azetidinone: 3-(cyclohexylamino)butanoic acid (185
mg, 1m mol), potassium bicarbonate (400 mg,
4m mol) and tetrabutylammonium hydrogen sulfate (50mg, 0.15mmol) were weighed out, water (15ml) was added to the mixture, and the mixture was stirred for a while. A solution of methanesulfonyl chloride (228 mg, 2 mmol) in chloroform (5 ml) was added to this aqueous solution, and the mixture was stirred for 24 hours.
After adding ether and water, the organic layer was washed once with water and once with saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 135 mg of 1-cyclohexyl-4-methyl-2-azetidinone was obtained by silica gel column chromatography (ether:hexane=3:1). (Yield: 81%) When vacuum distillation is performed using the Kugelrohr method, the boiling point is bp100-105℃ (bath temperature)/1.5mmHg. IRν ^neat _nax cm ^-1 : 1740 (CO) Example 2 The β-lactams shown in Table 1 were obtained in the same manner as in Example 1. [Table] [Table] In the β-lactams in the table, C ₆ H ₅ represents a phenyl group, and C ₆ H ₁₁ represents a cyclohexyl group.

Claims (1)

[Claims] 1. General formula (wherein R ¹ and R ² are hydrogen, linear or cyclic alkyl, aralkyl, alkylthio, alkoxy, acylamino, alkoxycarbonyl, or phenyl, and R ³ is hydrogen, linear or cyclic alkyl, phenyl, or protecting a nitrogen atom) A β-amino acid represented by a group) is reacted with a condensing agent, a phase transfer catalyst, and an alkaline substance in a two-phase system of an organic solvent and water to form the general formula (wherein R ¹ , R ² and R ³ are the same as above) A method for producing a β-lactam.