JPS6236036B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel thiazoline azetidinone compounds, more specifically, the general formula (R is hydrogen, alkyl, alkyl substituted with halogen, methyl substituted with substituted or unsubstituted phenyl group, methyl substituted with halogen, or trialkylsilyl, Z is O or Cl ₂ ) Thiazoline azetidinone Regarding compounds. The compounds of the present invention are useful as synthetic intermediates for β-lactam antibiotics. The compounds of the present invention have the general formula (wherein R and Z are the same as above) can be obtained by electrolytically reacting the compound represented by the formula (in which R and Z are the same as above) in a homogeneous or heterogeneous water-organic solvent mixed solvent in the presence of a halogen acid and one or more halogen acids. It will be done. Various attempts at halogenation have been made, including RDGCooper JACS 92 2575 (1970), Japanese Patent Application Laid-open No. 100490/1983, and Tetrahedron Letter 781.
(1980), the yield is very low, and there are other problems as well, and no satisfactory reports have been found. The compound of the present invention was synthesized by a manufacturing method different from the conventional method described above, and is a new compound that has not been described in any literature. Compound (2), which is the starting material of the present invention, can be prepared from a penicillin derivative by a previously reported method, such as the above-mentioned JACS 92 ,
2575 (1970). In R of general formula (1), alkyl is substituted with methyl, ethyl, butyl, hexyl, etc., halogen is substituted with chlorine, bromine, iodine, etc., and substituted phenyl group is substituted with alkyl, alkoxy, halogen, nitro group, etc. Examples of the trialkylsilyl include trimethylsilyl, triethylsilyl, dimethylmonobutylsilyl, and monomethyldibutylsilyl. In addition, in the present invention, R is a methyl group substituted with a substituted or unsubstituted phenyl group, and when the compound (2) having such a group is subjected to the electrolytic reaction of the present invention, a methyl group is formed. Hydrogen may also be halogenated. To give a specific example, as shown in Example 5 below, R is -CH(C ₆ H ₅ ) ₂
, this group is converted into − by the electrolytic reaction of the present invention.
Convert _to CCl( _C6H5 ) ₂ . The present invention also includes compounds obtained in such cases. Examples of organic solvents used in the electrolytic reaction of the present invention include carboxylic acid esters such as methyl acetate, ethyl acetate, butyl acetate, methyl formate, ethyl formate, and ethyl propionate, diethyl ether, dibutyl ether, tetrahydrofuran,
Ethers such as dioxane, ethylene, glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dibromoethane, nitriles such as acetonitrile, butyronitrile, methanol, ethanol, isopropanol, butanol, tertiary butanol, etc. One or more are selected from alcohols, hydrocarbons such as pentane, hexane, and cyclohexane, and aromatic compounds such as benzene, toluene, xylene, and chlorobenzene. Examples of the halogen salt added as a supporting electrolyte include alkali metal salts such as sodium chloride, potassium chloride, and lithium chloride, alkaline earth metal salts such as magnesium chloride, barium chloride, and calcium chloride, ammonium chloride, tetramethylammonium chloride, Examples include ammonium halides and quaternary ammonium salts such as tetraethylammonium chloride and tetrabutylammonium chloride. Hydrochloric acid is used as the halogen acid. 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. Examples of organic acids include formic acid, acetic acid, propionic acid, butyric acid, acetic acid, oxalic acid, citric acid, phthalic acid, malic acid, and paratoluenesulfonic 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 ³ , preferably about 10 to 500 mA/cm 3 .
It is in the range of 50mA/ ^cm3 . 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 the electrolysis in the same reaction vessel, or the reaction can be carried out in separate electrolytic vessels and halogenation reaction vessels. Example 1 The above 2-(3-benzoyl-
Methyl 7-oxo-4-thio-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)3-methyl-3-butenoate 50 mg, concentrated sulfuric acid 0.07 ml, methylene chloride 5 ml, sodium chloride A solution of 1 g dissolved in 3 ml of water is placed in a reaction vessel, a 3 cm ² platinum electrode is inserted, and electrolysis is performed at 30 mA, 1.6 to 1.8 V, and 25°C for 2 hours. After the electrolysis is completed, extract with 30 ml of methylene chloride, and wash the extract with sodium sulfite solution, sodium bicarbonate solution, and saline solution. Dry over anhydrous sodium sulfate and remove the solvent to obtain 74 mg of a pale yellow liquid. This was developed with ethylene acetate-benzene using a silica gel column to obtain 51 mg (yield 93%) of the target compound. IR 1780, 1745, 1660, 1600, 858 cm ^-1 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 -CH) 6.37 (1H d J = 4Hz -CH) 7.4 - 8.4 (5H m phenyl) Example 2 When the above reaction was carried out in the same manner as in Example 1 using 50 mg of raw material, 50.5 mg of the target product (yield 93.5
%)Obtained. NMR (CDCl ₃ ) 4.89 (2H s - CH ₂ CCl ₃ ) 4.16 (2H s - CH ₂ Cl) 5.23 (2H d C=CH ₂ ) 5.55 (1H s CH-COOCH ₂ CCl ₃ ) Example 3 Dissolve 1 g of sodium chloride in 3 ml of water, add 50 mg of the above raw material compound, 0.07 ml of concentrated sulfuric acid, and 5 ml of methylene chloride.
ml was placed in a reaction vessel, and the same procedure as in Example 1 was performed to obtain 51.8 mg (yield: 95%) of the target product. NMR (CDCl ₃ ) 1.38 (9H s COO-t-Bu) 3.81 (2H s CH ₂ Cl) 5.14 (2H s C=CH ₂ ) 5.41 (1H s CHCOO-t-Bu) 7.3-7.9 (5H m phenyl) Example 4 Using 50 mg of the above raw material compound and performing the same operation as in Example 1, the target product was 49.8 mg (yield 90.2%).
get. IR 1715cm ^-1 NMR (CDCl ₃ ) 4.18 (2H s CH ₂ Cl) 5.22 (2H d C=CH ₂ ) 5.95 (1H d CH) 6.39 (1H d CH) 7.4-8.3 (5H m phenyl) Example 5 When the same operation as in Example 1 is performed using 50 mg of the above raw material compound, 51.8 mg (yield 91%) of the target compound is obtained. The target product was confirmed by IR and NMR. Example 6 Using 50 mg of the above raw material compound, the same operation as in Example 1 is performed to obtain 49.8 mg (yield 92.8%) of the target compound. NMR ( _CDCl3 ) 5.05 (2H s

[Formula]) 4.12 (2H s CH ₂ Cl) 5.25 (2H d C=CH ₂ ) 7.10-8.03 (4H m phenyl) Example 7 Methyl 2-(3-dichlorophenylmethyl-7-oxo-4-thio-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-3-chloromethyl-3-butenoate Synthesis 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-thio-2,6-diazabicyclo[3.2 .0] Add 50 mg of methyl 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 saline, drying with anhydrous sodium sulfate,
Removal of the solvent gave 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 -CHCOOCH ₃ ) 6.05 (2H s -CH ) 7.3-7.9 (5H m phenyl) Example 8 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 7 to prepare an electrolytic solution. Prepare. Electrolysis was carried out at 30mA constant current, 1.8-1.9V, 25-27℃ for 2 hours, and the same treatment as in Example 7 was carried out to obtain 61mg of the target compound (yield:
93.5%). The compound was confirmed by IR and NMR, and the same results as in Example 7 were obtained, and the compound was identified. Example 9 An experiment was conducted in the same manner as in Example 7 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 -CHCOO-t-Bu) 6.03 (2H s CH) 7.3-8.0 (5H m phenyl) Example 10 Using 50 mg of the above compound as a raw material, the same operation as in Example 7 is carried out to obtain 56.3 mg of the target product. Yield 91.5% NMR (CDCl ₃ ) 4.04 (2H s CH ₂ Cl) 4.75 (2H s CH ₂ CCl ₃ ) 5.18 (2H s C=CH ₂ ) 5.54 (1H s CHCOOCH ₂ CCl ₃ ) 7.0-7.65 (5H m phenyl) Example 11 Using 50 mg of the above compound as a raw material, the same operation as in Example 7 is performed to obtain 59.0 mg of the target product. Yield 88.9% 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 When the same operation as in Example 7 is performed using 50 mg of the above raw material compound, 56.2 mg (yield 91.5%) of the target compound is obtained. NMR (CDCl ₃ ) 4.08 (2H s CH ₂ Cl) 5.05 (2H s

[Formula]) 5.23 (2H d C=CH ₂ ) 7.10-8.05 (4H m phenyl)

Claims (1)

[Claims] 1. General formula (R is hydrogen, alkyl, alkyl substituted with halogen, methyl substituted with substituted or unsubstituted phenyl group, methyl substituted with halogen, or trialkylsilyl, Z is O or Cl ₂ ) Thiazoline azetidinone Compound.