JPS6221072B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing thiazoline azetidinone derivatives, more specifically, the general formula (R ¹ is alkyl, alkenyl, alkoxy, aryl with or without substituents, acyl or aryloxymethyl, or -CX ¹ X ² R ³ , X ¹ , X ²
is hydrogen, halogen, alkoxy or acyloxy,
A thiazoline azetidinone derivative (R ³ is the same as R ¹ , R ² is carboxyl or protected carboxyl) is electrolyzed in a water-organic solvent mixture system in the presence of one or more halogen salts and halogen acids. General formula characterized by carrying out a reaction (R ¹ and R ² are the same as above, X represents halogen)
The present invention relates to a method for producing a halogenated thiazoline azetidinone derivative represented by: The halogenated thiazoline azetidinone derivative 2 of the present invention is an important intermediate for cephalosporin antibiotics. Conventional methods for producing the above compounds include methods using various halogenating agents, for example, methods using N-bromosuccinimide (Japanese Patent Application Laid-Open No. 52-1996-1)
100490), method of applying chlorine gas (Tetrahedron Letter, 781 (1980)), hypochlorous acid-t
- There is a method using butyl (Tetrahedron Letter, 781 (1980)), etc. However, the method using N-bromosuccinimide requires a radical initiator, and side reactions such as olefin isomerization occur, resulting in a mixture of various compounds, resulting in a yield of only 10 to 14% of the target compound. . In addition, the method of using chlorine gas has many drawbacks, such as requiring a large amount of chlorine gas of four times the mole or more, and the reaction rate is extremely slow, requiring three days or more to complete the reaction. The method using t-butyl hypochlorite is superior to the above method (2) in that the desired chlorinated product (2) can be obtained in a short time at room temperature with a yield of 60%. However, it has the drawbacks that the solvent is limited and that t-butyl hypochlorite must be synthesized. The present invention was developed as a result of preparing an active halogenating agent that is generated in the reaction system by electrolyzing a halogen salt or halogen acid without using the above-mentioned halogenating agent, and examining various electrolytic conditions to carry out the reaction. They have discovered that the desired halogenation can proceed efficiently in a water-organic solvent mixed system, and have completed the present invention. That is, the present invention is based on the general formula (R ¹ is alkyl, alkenyl, alkoxy, aryl with or without substituents, acyl or aryloxymethyl, or -CX ¹ X ² R ³ , X ¹ , X ²
is hydrogen, halogen, alkoxy or acyloxy,
A thiazoline azetidinone derivative (R ³ is the same as R ¹ , R ² is carboxyl or protected carboxyl) is electrolyzed in a water-organic solvent mixture system in the presence of one or more halogen salts and halogen acids. General formula characterized by carrying out a reaction (R ¹ and R ² are the same as above, X represents halogen)
The present invention relates to a method for producing a halogenated thiazoline azetidinone derivative represented by: Compound (1), which is the starting material of the present invention, can be prepared from a penicillin derivative by a previously reported method such as RDGCooper.
It can be easily synthesized according to JACS 92 , 2575 (1970). In R ¹ of the general formula (1), examples of alkyl include methyl, ethyl, butyl, hexyl, etc., examples of alkenyl include vinyl, allyl, butenyl, hexenyl, etc., examples of alkoxy include methoxy, propoxy, hexyloxy, etc., and substituents. Aryl, acyl or aryloxymethyl with or without phenyl, tolyl, xylyl,
Examples include naphthyl, methylnaphthyl, acetyl, propionyl, valeryl, benzoyl, phenoxymethyl, tolyloxymethyl, xylyloxymethyl, and naphthyloxymethyl. Examples of the halogen in X ¹ and X ² include fluorine, chlorine, bromine, and iodine, and examples of the acyl of alkoxy and acyloxy include those mentioned above. Examples of the protected carboxyl of R ² include an ester group (CO ₂ R'), an acid halide group (COX), and an acid amide group (CONHR').
Furthermore, as X in general formula (2), halogens similar to those mentioned above, such as X ¹ , can be exemplified. The object compound (2) of the present invention is obtained by electrolytically reacting the compound of general formula (1) above in a homogeneous or heterogeneous water-organic solvent mixture in the presence of one or more halogen salts and halogen acids. It can be obtained by In the present invention, R ¹ is −CX ¹ X ² R ³ and X ¹ , X ²
When a compound in which either or both of these are hydrogen is used as a raw material in the electrolytic reaction of the present invention, the hydrogen may also be replaced by a halogen. To give a specific example, as shown in Examples 1 to 3 below, R ¹
When is _-CH2C6H5 , this group is converted to _-CCl2C6H5 by _the electrolytic _{reaction of the} present invention. The present invention also includes the compounds obtained in such cases and the manufacturing methods. Examples of organic solvents include methyl acetate, ethyl acetate, butyl acetate, methyl formate,
Carboxylic acid esters such as ethyl formate and ethyl propionate, ethers such as diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, and ethylene glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and dibromoethane, acetonitrile, Nitriles such as butyronitrile, alcohols such as methanol, ethanol, isopropanol, butanol, and tertiary butanol, hydrocarbons such as pentane, hexane, and cyclohexane, and aromatic compounds such as benzene, toluene, xylene, and chlorobenzene. Choose one or more from. In addition, the halogen salt added as a supporting electrolyte is
Chlorine salts, bromine salts, iodine salts, etc. are used depending on the type of halogen in the desired halide represented by general formula (2). Examples of halogen salts include alkali metal salts such as sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide, lithium bromide, sodium iodide, potassium iodide, lithium iodide, magnesium chloride, barium chloride, Alkaline earth metal salts such as calcium chloride, magnesium bromide, barium bromide, magnesium iodide, barium iodide, ammonium chloride, tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium chloride, ammonium bromide, tetrabromide Examples include ammonium halides and quaternary ammonium salts such as methylammonium, tetraethylammonium bromide, ammonium iodide, and tetraethylammonium iodide. As the halogen acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc. are used. Furthermore, when using the above-mentioned halogen salt or halogen acid, a mineral acid or organic acid other than the halogen acid may be added at the same time. Examples of the mineral acids to be added include sulfuric acid, nitric acid, carbonic acid, potassium hydrogen sulfate, sodium hydrogen sulfate, and phosphoric acid. In addition, organic acids include formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, citric acid,
Examples include phthalic acid, malic acid, and para-toluenesulfonic acid. The electrolytic reaction of the present invention can be carried out at a current density in the range of about 5 to 500 mA/cm ² , preferably about 10 to 500 mA/cm 2 .
The range is 50mA/ ^cm2 . Further, the electrodes can be made of platinum, carbon, stainless steel, lead oxide, nickel, etc., which are commonly used in electrolytic reactions. Electrolysis is about −20~
It can be carried out at temperatures in the range of 100°C, but preferably about -
It is best to do this at a temperature of 10 to 50°C. When carrying out an electrolytic reaction, a diaphragm may be used or no diaphragm may be used. The amount of current required for this electrolytic reaction depends on the shape of the electrolytic cell,
Although it varies depending on the type of electrode, substrate concentration, substrate reactivity, etc., the target product can be obtained as an almost pure product with a high yield of 85 to 95% by applying electricity with an amount of electricity of about 2 to 50 F/mol. In the present invention, the halogenation reaction can be carried out simultaneously with electrolysis in the same reaction vessel, or can be carried out in separate electrolytic vessels and halogenation reaction vessels. By using an electrolytic method with a very simple device, the present invention achieves high yields under mild conditions at room temperature and pressure with simple operations and without the use of special halogenating agents. Compared to conventional methods, this method is superior in that it can obtain the desired product. Next, the present invention will be explained with reference to Examples. Example 1 2-(3-dichlorophenylmethyl-7-oxo-4-thio-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-3-
Synthesis of methyl chloromethyl-3-butenoate Dissolve 1 g of sodium chloride in 3 c.c. of water, add 0.07 cc of concentrated sulfuric acid, 5 c.c. of methylene chloride, 2-(3-benzyl-7-oxo-4- Add 50 mg of methyl thio-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-3-methyl-3-butenoate 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. This product was developed using a silica gel column with a mixed solvent of benzene:ethyl acetate (5:1) to obtain 62.5 mg (yield: 96%) of the target compound. (IR) 1780 1745cm ^-1 NMR (CDCl ₃ ) 3.75 (3H s COOCH 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) Example 2 Dissolve 1 g of NaCl in 5 c.c. of water, add 0.07 cc of concentrated sulfuric acid and 5 c.c. of ethyl acetate, and then add 50 mg of the same starting material as in Example 1. Prepare the electrolyte. Electrolysis was carried out at 30mA constant current, 1.8-1.9V, 25-27℃ for 2 hours, and the same treatment as in Example 1 was carried out to obtain 61mg (93.5mg) of the target compound.
%) was obtained. The compound was confirmed by IR and NMR, and the same results as in Example 1 were obtained, and the compound was identified. Example 3 An experiment was conducted in the same manner as in Example 1 using 50 mg of the above starting material, and 61 mg (yield 95%) of the above target compound was obtained. NMR (CDCl ₃ ) 1.38 (9H s COO-t-Bu) 3.85 (2H s -CH ₂ Cl) 5.12 (2H s C=CH ₂ ) 5.41 (1H s -CHOO-t-Bu) 6.03 (2H s CH) 7.3-8.0 (5H m phenyl) Example 4 50 mg of methyl 2-(3-benzoyl-7-oxo-4-thio-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-3-methyl-3-butenoate as a starting material. Example 1 using
Prepare the electrolyte solution in the same manner as above. 30mA constant current,
Electrolysis was performed at 1.8-2.0V and 25-26°C for 40 minutes. The same treatment as in Example 1 was carried out to obtain the desired 2-(3-benzoyl-7-oxo-4-thio-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-3-. Methyl chloromethyl-3-butenoate
51 mg (yield 93%) was obtained. (IR) 1780, 1745, 1660, 1600, 858 NMR (CDCl ₃ ) 3.79 (3H s COOCH ₃ ) 4.16 (2H s −CH ₂ Cl) 5.23 (2H d J=4Hz C=CH ₂ ) 5.55 (1H s CH −COOCH ₃ ) 5.96 (1H d J = 4Hz

【formula】) 6.37 (1H d J = 4Hz

[Formula]) 7.4-8.5 (5H m phenyl) Example 5 The above reaction was carried out in the same manner as in Example 4 using 50 mg of the raw material, and 56.5 mg (yield: 93.5%) of the target product was obtained. NMR (CDCl ₃ ) 4.89 (2H s - CH ₂ CCl ₃ ) 4.10 (2H s - CH ₂ Cl) 5.20 (2H d C=CH ₂ ) 5.55 (1H s CH-COOCH ₂ CCl ₃ ) 6.00 (1H d CH) 7.4-8.2 (5H m phenyl) Example 6 2-(3-phenyloxymethyl-7-oxo-4-thio-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-3-
Synthesis of chloromethyl-3-butenoic acid methyl ester Weigh out 1 g of sodium chloride in a test tube with a branch, add 3 ml of water, and dissolve. This stuff has acetic acid
0.05ml, methylene chloride 5ml, 2-(3-phenyloxymethyl-7-oxo-4-thio-2,6-
Diazabicyclo [3.2.0] Hept-2-en-6
-3-methyl-3-butenoic acid methyl ester (50 mg) was added to make a homogeneous solution. This includes a stirrer,
Attach two platinum plates (size 1.5 x 2 cm ² ),
30mA constant current, 1.6~2.0V, 4F/approximately 25℃ condition
Electrolytic reactions are carried out through mol of current. After electrolysis, add 5% diluted hydrochloric acid to the water bath to adjust the pH to 7, and extract with methylene chloride (20ml). The extract is washed with water and then dried and concentrated to obtain 57 mg of crude product. When this product is developed using a silica gel column with a mixed solvent of benzene-ethyl acetate (5:1), 50 mg (yield 91%) of the target compound is obtained. IR (CHCl ₃ ) 1770, 1743 cm ^-1 NMR (CDCl ₃ ) 3.74 (3H s) 3.9 (2H s) 4.88 (2H s) 5.15 (2H m) 5.44 (1H s) 5.91 (2H m) 6.72-7.38 (5H m) Example 7 In a reaction vessel, dissolve 50 mg of the above raw material compound and 1 g of sodium bromide in 3 ml of water, and add 0.07 ml of concentrated sulfuric acid and 5 ml of methylene chloride. Insert platinum plate electrode and stir
Perform the electrolytic reaction at 40mA and 35℃. After the reaction was completed, the same treatment as in Example 1 was performed to obtain 55.5 mg (yield 90.5%) of the target compound. It was confirmed by IR and NMR that it was the desired product. Example 8 3 ml of 35% hydrochloric acid, 50 mL of the same raw material compound as Example 1
5 ml of methylene chloride are placed in a container, a 3 cm ² platinum electrode is inserted, and the same procedure as in Example 1 is carried out to obtain 57.5 mg of the same target product as in Example 1. Yield 88%, IR,
It was confirmed by NMR that it was the desired product. Example 9 Dissolve 1 g of sodium chloride in 3 ml of water, add 5 ml of chloroform, and add 50 mg of the same raw material compound as in Example 1.
By adding and performing the same operation as in Example 1, the target object is obtained.
Obtain 57.0 mg. The yield was 87.5%, and it was confirmed to be the desired product by IR and NMR. Example 10 Dissolve 1 g of sodium chloride in 3 ml of water, add 0.5 ml of 35% hydrochloric acid and 5 ml of methylene chloride, and perform the same procedure as in Example 1 to obtain 61.8 mg of the desired product. Yield 95
%, IR, and NMR confirmed that it was the desired product. Example 11 The above reaction was carried out using 50 mg of the starting compound, and the above target compound was obtained by the same operations and treatments as in Example 1. IR 1715cm ^-1 NMR (CDCl ₃ ) 4.20 (2H s CH ₂ Cl) 5.28 (2H d C=CH ₂ ) 5.92 (1H d CH) 6.42 (1H d CH) 7.5-8.4 (5H m phenyl) Example 12 The above reaction was carried out using 50 mg of the starting compound, and the same procedure as in Example 1 was carried out to obtain 48.2 mg of the target product (yield: 89.8
%). NMR (CDCl ₃ ) 3.91 (2H s CH ₂ Cl) 4.98 (2H s

[Formula]) 5.20 (2H d C=CH ₂ ) 6.72-7.38 (5H m phenyl)

Claims (1)

[Claims] 1. General formula (R ¹ is alkyl, alkenyl, alkoxy, aryl with or without a substituent, acyl or aryloxymethyl, or -CX ¹ X ² R ³ , X ¹ , X ²
is hydrogen, halogen, alkoxy or acyloxy,
A thiazoline azetidinone derivative (R ³ is the same as R ¹ , R ² is carboxyl or protected carboxyl) is electrolyzed in the presence of one or more halogen salts and halogen acids in a water-organic solvent mixture system. General formula characterized by carrying out a reaction (R ¹ and R ² are the same as above, X represents halogen)
A method for producing a halogenated thiazoline azetidinone derivative represented by 2. The method according to claim 1, wherein the organic solvent is a lower carboxylic acid ester or a halogenated hydrocarbon. 3. The method according to claim 1, wherein the halogen salt is NaCl, KCl, NaBr or KBr. 4. The method according to claim 1, wherein the halogen acid is HCl or HBr. 5. The method according to any one of claims 1 to 4, in which a mineral acid or an organic acid other than halogen acid is allowed to coexist. 6. The method according to claim 1, wherein the electrolytic reaction temperature is about -20 to 100°C. 7. The method according to claim 1, wherein the current density of the electrolytic reaction is about 5 to 500 mA/ ^cm2 .