JPS6146477B2 - - Google Patents

Description

[Detailed description of the invention]

This invention is a novel 7-substituted compound with antibacterial activity.
It relates to 3-cephem-4-carboxylic acid derivatives and methods for producing the same, and more specifically, the general formula _[ In _the formula _, The present invention relates to 7-substituted-3-cephem-4-carboxylic acids represented by the following formulas, derivatives of the carboxy group thereof, salts thereof, and methods for producing the same. The object compound of this invention () and the starting materials compounds () and () described below are all geometric isomers, such as syn isomer, anti isomer, or a mixture thereof. formula

Those with [formula] are syn isomers, partial structural formula

Those having the following formula are defined as anti isomers. In the general formula () representing the object compound of this invention, the lower alkenyl group of R ₂ is allyl,
Examples include 2-butenyl and 3-butenyl. As the lower alkyl group for R ₂ , R ₃ and R ₄ ,
Examples include straight chain or branched hydrocarbon residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Furthermore, examples of the halogen atom for R ₄ include chloro, bromine, and iodo. Examples of derivatives at the carboxy group of these 7-substituted-3-cephem-4-carboxylic acids () include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, and pentyl ester. , hexyl ester, 1
- Alkyl esters such as cyclopropylethyl ester, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, 2-
Alkanoyloxyalkyl esters such as acetoxyethyl ester, 2-propionyloxyethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, alkanesulfonyl alkyl esters such as mesylmethyl ester, ethanesulfonyl ethyl ester, 2-
Alkyl esters with one or more suitable substituents such as mono(di or tri)haloalkyl esters such as iodoethyl esters and 2,2,2-trichloroethyl esters, alkenyl esters such as vinyl esters, allyl esters, ethynyl esters , alkynyl esters such as propynyl esters, benzyl esters, 4-methoxybenzyl esters, 4-nitrobenzyl esters, phenethyl esters, trityl esters, diphenyl methyl esters, diphenyl ethyl esters, bis(methoxyphenyl) methyl esters, 3・4-
dimethoxybenzyl ester, 4-hydroxy-
1 such as 3,4-ditertiary butylbenzyl ester
Aralkyl esters, phenyl esters, triethyl esters, tertiary butyl phenyl esters, 4r chlorophenyl esters, xylyl esters, mesityl esters, cumenyl esters, etc., which may have one or more suitable substituents. Examples include esters such as aryl esters which may have one or more suitable substituents. These 7-
The salts of substituted-3-cephem-4-carboxylic acids () and their derivatives at the carboxy group are preferably alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts. metal salts, such as
Salts with organic bases such as ammonium salts, trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N/N-dibenzylethylenediamine salts, arginine salts,
Examples include salts with amino acids such as lysine salts. The object compound () of this invention is, for example, a compound of the general formula (In the formula, R ₃ and R ₄ have the same meanings as above) 7-amino-3-cephem-4-carboxylic acids, derivatives at the amino group and/or carboxy group, or salts thereof, are represented by the general formula (In the formula, X and R ₂ have the same meanings as above.) It can be produced by reacting with a substituted iminoacetic acid represented by the following formula, or a reactive derivative or salt thereof at the carboxy group. Derivatives at the amino group of compound () used as raw materials in this method include reaction products of compound () and silyl compounds such as trimethylsilylacetamide, bis(trimethylsilyl)acetamide, and trimethylsilyl chloride;
Examples include compounds produced by reaction with condensing agents such as phosphorus oxychloride, phosphorus trichloride, and thionyl chloride, which will be described later. Furthermore, as the derivatives and salts thereof at the carboxy group of the compound (), the derivatives and salts thereof at the carboxy group exemplified in the explanation of the target compound () above are exemplified here as well. The other raw material compound () is all new and can be produced, for example, by the method shown in the following formula. Method (where X and R ₂ have the same meanings as before, Hal
(respectively means a halogen atom and R ₅ means a lower alkyl group) Examples of reactive derivatives at the carboxy group of substituted iminoacetic acids () include acid halides, acid azides, acid anhydrides, activated amides, and activated esters. However, in more detail, substituted phosphoric acid mixtures such as acid chloride, dialkyl phosphoric acid mixed acid anhydride, phenyl phosphoric acid mixed acid anhydride, diphenyl phosphoric acid mixed acid anhydride, dibenzyl phosphoric acid mixed acid anhydride, halogenated phosphoric acid mixed acid anhydride, etc. Acid anhydrides, dialkyl phosphorous mixed acid anhydrides, sulfite mixed acid anhydrides, thiosulfuric acid mixed acid anhydrides, sulfuric acid mixed acid anhydrides, alkyl carbonic acid mixed acid anhydrides, aliphatic carboxylic acids (e.g. pivalic acid, pentanoic acid, Acid anhydrides such as isopentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid) mixed acid anhydrides, aromatic carboxylic acid (e.g. benzoic acid) mixed acid anhydrides, symmetrical acid anhydrides, imidazole, 4-
Acid amides, dianomethyl esters, dimethylaminomethyl esters, vinyl esters, propargyl esters with substituted imidazoles, dimethylpyrazoles, triazoles, tetrazoles, etc.
-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,
Pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, 4-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl Thioester or N-hydroxy such as N·N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-4-chloro-1H-benzotriazole, etc. Examples include esters such as esters with compounds, and these are appropriately selected depending on the type of compound () used. Examples of the salts of the compound () include salts with inorganic bases such as alkali metal salts and alkaline earth metal salts as described above, and salts with organic bases such as trimethylamine, triethylamine, and pyridine. This reaction typically involves water, acetone, dioxane,
Benzene, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran,
The reaction is carried out in a solvent such as ethyl acetate, dimethylformamide, pyridine, etc., as well as a general organic solvent that does not adversely affect the reaction. These solvents can also be used in any combination. Although the reaction temperature is not particularly limited, it is often carried out under cooling to heating. When using the compound () in the form of a free acid or its salt in this reaction, for example, N.
N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N.
N'-diethylcarbodiimide, N・N'-diisopropylcarbodiimide, N-ethyl-N'-(3
-dimethylaminopropyl)carbodiimide,
N・N'-carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, ethoxyacetylene, β-chlorovinylethyl ether, 1-(4-chlorobenzenesulfonyloxy)- 4-chloro-1H-benzotriazole, phosphorous acid trialkyl ester, polyphosphoric acid ethyl ester, polyphosphoric acid isopropyl ester, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, N-ethyl benzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3'-sulfonate, or the so-called Vilsmeier reagent prepared from dimethylformamide and thionyl chloride or phosphorus oxychloride, etc. It is advantageous to carry out the reaction in the presence of a condensing agent. In this method, the target compound (), its carboxyl group derivatives, or their salts may be isomerized from the syn isomer to the anti isomer, or from the anti isomer to the syn isomer, respectively, during the reaction or post-treatment. The above-mentioned isomerization can be suppressed by carrying out this reaction under mild conditions such as in the presence of the above-mentioned Vilsmeier reagent and under cooling. In addition, the target compound () has the general formula (In the formula, R ₂ , R ₃ and R ₄ have the same meanings as before,
(Y means a halogen atom), derivatives at the carboxy group, or salts thereof, represented by the general formula HX-CH ₂ -CH ₂ -SH () (wherein, X has the same meaning as above) It can also be produced by reacting with a thiol compound. Compounds used as raw materials in this method ()
Examples of the halogen represented by Y include chlorine, bromine, and iodo. Further, as the derivatives at the carboxyl group of the compound () and their salts, those exemplified as the derivatives at the carboxyl group of the target compound () and their salts are exemplified here as they are. In addition, the raw material compound () is made into a 3-oxo-4-halobutylamide compound by, for example, reacting the above-mentioned compound () with diketene and halogen,
Next, this was treated with sodium nitrite to give 2-
Hydroxyimino-3-oxo-4-halobutylamide is obtained, and if necessary, this is alkylated to obtain 2-alkoxyimino-3-oxo-4.
- It can be produced by forming it into a halobutylamide. This reaction is usually carried out in a solvent, and the solvents used include tetrahydrofuran, dioxane, water, methanol, ethanol, dimethylformamide, dimethyl sulfoxide, acetonitrile, and other general organic solvents that do not have an adverse effect on the reaction. These solvents can be used in any combination. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating. In this method, by using the syn isomer of the starting compound () and carrying out the reaction under mild conditions, the syn isomer of the target compound () can be selectively obtained. Further, this reaction may be carried out in the presence of a dehydrating agent. In addition, when the target compound is obtained as a mixture of syn isomer and anti isomer by these methods, it is then subjected to silica gel column chromatography, high performance liquid chromatography, fractional recrystallization, selective hydrolysis, etc. It may be separated into each isomer without being subjected to a separation method known per se. The target compound (), its carboxyl group derivatives, and their salts obtained by these methods are isolated and purified by conventional methods, and the free target compound () is converted into pharmacologically acceptable salts, if desired. It's okay. In addition, when the above reaction is performed using the starting compound () or a derivative at the carboxy group of () as a raw material, depending on the salt of the derivative at the carboxy group or the reaction conditions, during the reaction or post-treatment. In some cases, the derivative at the carboxyl group is eliminated to obtain the target compound (2) having a free carboxyl group, and these cases are also included in the method of the present invention. Furthermore, when the reaction product is a derivative of the carboxy group of the compound (2), it may be cleaved into a free carboxylic acid by a conventional method such as hydrolysis or reduction. The object compounds of this invention () and their salts are all new compounds, have a wide range of antibacterial vectors, and are useful as antibacterial agents. In addition, in the target compound () of this invention, the syn isomer has much higher antibacterial activity than the corresponding anti-isomer, and the syn isomer is far more valuable as an antibacterial agent. Are better. Among the target compounds () of this invention, for example, 7
-[2-(2,3-dihydro-1,4-dithiin-
5-yl)-2-methoxyiminoacetamide]-
The antibacterial activity of 3-cephem-4-carboxylic acid (syn isomer) was measured by the agar plate dilution method, and the results (minimum inhibitory concentration) are shown below.

[Table] The object compound of this invention () and its pharmaceutically acceptable salts are administered in the form of a composition containing an effective and non-toxic amount thereof and suitable for oral or parenteral administration. In this case, oral preparations include solid preparations such as tablets, capsules, granules, troches, and powders, and liquid preparations such as syrups, and parenteral preparations include injections and suppositories. These compositions are formulated in a conventional manner with inorganic or organic solid or liquid pharmaceutical carriers commonly used in pharmaceutical formulations. The dosage of this target compound () varies depending on the age and symptoms of the person, but it is usually 0.5 to 0.5 per day.
5.0g, preferably 0.25-2.0g. Next, the method for producing the object compound () of the present invention will be explained using examples, and the method for producing the raw material compound () will be explained using reference examples. Reference Example 1 (i) Add 65 g of ethyl 2-chloroacetyl-2-methoxyiminoacetate to a mixture of 25 g of 2-mercaptoethanol, 35 g of triethylamine, and 70 ml of dry chloroform.
ml of the solution was added dropwise with stirring at 20°C for 30 minutes, and then stirred at the same temperature for 25 hours.
Add 10% hydrochloric acid to this under ice cooling to adjust the pH to 1.0, separate the chloroform layer, wash it twice with water, and then dry it with magnesium sulfate. This is 40℃
Concentration under reduced pressure gives a yellow oil. This was dissolved in 600 ml of toluene, 5.5 g of p-toluenesulfonic acid was added, and the mixture was heated under reflux for 2 hours while removing the produced water. The reaction solution was cooled to room temperature, insoluble materials were removed, and the solution was diluted with 100 ml of water.
2 times with 100 ml of saturated aqueous sodium bicarbonate solution
After washing twice with 100 ml of water and drying with magnesium sulfate. This was concentrated under reduced pressure at 40°C, and the residue was subjected to column chromatography using 1 kg of silica gel 60 (manufactured by Merck & Co., Ltd.) and eluted with benzene. The eluate was concentrated under reduced pressure at 40°C.
The concentrate was washed with diisopropyl ether and dried to give pale yellow crystals of 2-(2.
21 g of ethyl 3-dihydro-1.4-oxathin-6-yl)-2-methoxyiminoacetate (syn isomer) are obtained. Infrared absorption spectrum _νnudjolnax : 1715, 1650, 1620 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ : ppm): 1.25 (3H, t,
J = 7Hz), 3.13 (2H, t, J = 4Hz),
3.83 (3H, s), 4.15~4.40 (4H, m),
5.88 (1H, s) (ii) 2-(2,3-dihydro-1,4 obtained above)
24 ml of 1N aqueous sodium hydroxide solution is added to a solution consisting of 4.6 g of ethyl -oxathiin-4-yl)-2-methoxyiminoacetate (syn isomer) and 50 ml of methanol, and the mixture is stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure at 40°C, and the residue was dissolved in water. After washing this once with ethyl acetate,
Adjust the pH to 1.0 with 10% hydrochloric acid. This is extracted with ethyl acetate, washed with ice water, and then dried over magnesium sulfate. This was concentrated under reduced pressure at 40℃, the residue was washed with diisopropyl ether, and when dried, mp129-131℃ (decomposition), white crystals of 2-
(2,3-dihydro-1,4-oxathiine-
3.8 g of 6-yl)-2-methoxyiminoacetic acid (syn isomer) are obtained. Infrared absorption spectrum _νnujiolnax : 2550-2600, 1725, 1650,
1620cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ : ppm): 3.06 (2H, t,
J=4Hz), 3.80 (3H, s), 4.18 (2H,
t, J = 4Hz), 5.80 (1H, s) Reference example 2 (i) 2-mercaptoethanol 7.8g, 2-(2-
A solution of 11 g of triethylamine and 30 ml of dry chloroform was added dropwise to a mixed solution of 20.8 g of ethyl (chloroacetyl)-2-methoxyiminoacetate and 200 ml of dry chloroform while stirring at 20°C, followed by stirring at the same temperature for 3 hours.
The reaction solution was washed twice successively with 10% hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and water, and then dried over magnesium sulfate. After concentrating this under reduced pressure at 40°C, the residue is dissolved in 200 ml of dry toluene. Add 3g of p-toluenesulfonic acid to this solution.
was added and stirred while distilling off the water produced.
Heat to reflux for 30 minutes. The reaction solution was left at room temperature, treated with activated carbon, and then 150 ml of ethyl acetate was added.
This is washed twice with saturated aqueous sodium bicarbonate solution and twice with water, and dried over magnesium sulfate. This was concentrated to dryness under reduced pressure at 40°C, resulting in a yellow oily 2-(2,3-dihydro-1.
18.5 g of ethyl 4-oxathin-6-yl)-2-methoxyiminoacetate (mixture of syn and anti isomers) are obtained. Infrared absorption spectrum ν ^film _nax : 2800 to 2900, 1715, 1620 cm ^-1 (ii) 2-(2.3-dihydro-1.4 obtained above)
-oxathiin-6-yl)-2-methoxyiminoacetate ethyl 16 g, methanol 160 ml and
Mix 85 ml of 1N aqueous sodium hydroxide solution and stir at room temperature for 25 minutes. Add 10% hydrochloric acid to the reaction solution to adjust the pH to 4.5, and then concentrate under reduced pressure at 40°C.
Add a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate to the residue, and shake thoroughly at pH 7.5.
Separate the aqueous layer, extract the organic layer with a saturated aqueous solution of sodium bicarbonate, combine the extract with the previously separated aqueous layer, and adjust the pH to 1.0 with 10% hydrochloric acid.
This is extracted with ethyl acetate, the extract is washed with water, and then dried over magnesium sulfate. This is 40
After concentration under reduced pressure at °C, washing the residue with diisopropyl ether yields mp108-110 °C (decomposition),
Yellow crystals of 2-(2,3-dihydro-1,4-
3.5 g of oxathiin-6-yl)-2-methoxyiminoacetic acid (anti-isomer) are obtained. Infrared absorption spectrum _νnujiolnax : 2550-2650, 1695, 1620,
1600cm ^-1 nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ : ppm): 3.06 (2H, t,
J=5Hz), 4.20 (2H, t, J=5Hz),
4.89 (3H, s), 6.43 (1H, s) Reference Example 3 (i) Add 2-chloroacetyl-2-methoxyiminoacetic acid to a mixture of 20.6 g of ethane-1,2-dithiol, 21 g of triethylamine, and 60 ml of dry chloroform. A solution of 41.4 g of ethyl dissolved in 100 ml of dry chloroform was added dropwise over 1 hour while stirring at 20°C. After stirring this at 18-21°C for 25 hours, the pH was adjusted to 1.0 with 10% hydrochloric acid. The chloroform layer is separated, washed three times with 100 ml of water, and then dried over magnesium sulfate. This was concentrated to dryness at 40°C under reduced pressure, and the residue was dissolved in toluene at 300°C.
Dissolve in ml. Add 3 g of P-toluenesulfonic acid to this solution, and heat under reflux for 3 hours while removing water. After cooling the reaction solution to room temperature and removing insoluble materials, the solution was concentrated under reduced pressure at 40°C. The residue is dissolved in 300 ml of ethyl acetate, washed three times with saturated aqueous sodium bicarbonate solution and then twice with water, and then dried over magnesium sulfate. This is 40℃
Concentrate to dryness under reduced pressure to obtain a yellow oil. This was subjected to column chromatography (eluent: benzene) using 1 kg of silica gel 60 (manufactured by Merck & Co., Ltd.), and the benzene eluate was concentrated under reduced pressure at 40°C. When this was washed with diisopropyl ether and dried, the mp65-67℃, white crystal 2-
(2,3-dihydro-1,4-dithiin-5-
11 g of ethyl)-2-methoxyiminoacetate (syn isomer) are obtained. Infrared absorption spectrum _νnudjolnax : 1725, 1670cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ : ppm): 1.25 (3H, t,
J=7Hz), 3.25 (4H, s), 3.80 (3H,
s), 4.30 (2H, q, J=7Hz), 6.78
(1H, s) (ii) 2-(2,3-dihydro-1,4 obtained above)
-dithin-5-yl)-2-methoxyiminoacetate (syn isomer) 2.47 g, methanol
A mixture of 30 ml and 20 ml of 1N aqueous sodium hydroxide solution is stirred at room temperature for 24 hours. After concentrating the reaction solution under reduced pressure, the residue is dissolved in water. This is washed with ethyl acetate, and 10% hydrochloric acid is added dropwise under ice cooling to adjust the pH to 1.0, followed by extraction with ethyl acetate. The extract was washed with ice water and dried over magnesium sulfate. It was concentrated under reduced pressure at 40°C, and the residue was washed with diisopropyl ether and dried.
-(2,3-dihydro-1,4-dithiin-5
2.0 g of -yl)-2-methoxyiminoacetic acid (syn isomer) are obtained. Infrared absorption spectrum _νnujiolnax : 2500-2600, 1720, 1670,
1620cm ^-1 nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ : ppm): 320 (4H, s),
3.80 (3H, s), 6.61 (1H, s) Reference Example 4 (i) Add 18.7 g of triethylamine to a solution consisting of 10.0 g of 2-mercaptoethylamine salt residual salt and 100 ml of chloroform, then add 2-methoxyimino-2-chloroacetyl. Add 26.2 g of ethyl acetate (70% purity) with stirring under ice cooling, and stir at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted four times with diethyl ether. The extract is washed once with a saturated aqueous solution of sodium chloride and then extracted four times with 10% hydrochloric acid. The hydrochloric acid extract is washed twice with diethyl ether, adjusted to pH 6.5 with a saturated aqueous solution of sodium bicarbonate, and extracted four times with diethyl ether. After drying this with magnesium sulfate and distilling off the solvent under reduced pressure, an oily 2-(2,3-dihydro-4H)
5.2 g of ethyl-1,4-thiazin-5-yl)-2-methoxyiminoacetate (syn isomer) are obtained. Infrared absorption spectrum _νnujiolnax : 3400 (shoulder), 1740, 1635 Nuclear magnetic resonance absorption spectrum δ (CCl ₄ :ppm): 1.36 (3H, t, J=7
Hz), 2.9-3.2 (2H, m), 3.5-3.8 (2H,
m), 3.89 (3H, s), 4.30 (2H, q, J
=7Hz), 5.00 (1H, s) (ii) 2-(2,3-dihydro-4H-
5.8 g of ethyl 1,4-thiazin-5-yl)-2-methoxyiminoacetate (syn isomer) was added to a solution consisting of 7.7 g of acetic anhydride and 3.48 g of odoric acid, which had been heated in advance at 50°C for 42 hours. After adding while cooling with ice, stir overnight at room temperature. Cold water to reaction solution
After adding 100 ml, extract three times with ethyl acetate. The extract was diluted with a saturated aqueous solution of sodium chloride.
After washing with an aqueous sodium hydrogen carbonate solution four times and then once with a saturated aqueous sodium chloride solution, it is dried over magnesium sulfate. After concentrating this under reduced pressure, the residue was diisopropyl ether15
Crystallize in ml. The crystals were collected and washed with diisopropyl ether, resulting in a 2-
(4-formyl-2,3-dihydro-4H-1.
5.0 g of ethyl 4-thiazin-5-yl)-2-methoxyiminoacetate (syn isomer) are obtained. Infrared absorption spectrum _νnujiolnax : 1735, 1725, 1675 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (CDCl ₃ : ppm): 3.16 (3H, t, J=7
Hz), 3.95 (3H, s), 2.96~3.28 (2H,
m), 3.78-4.20 (2H, m), 4.38 (2H,
q, J=7Hz), 6.15 (1H, s), 8.62
(1H, s) (iii) 2-(4-formyl-2,3-dihydro-4H-1,4-thiazin-5-yl)- obtained above
Ethyl 2-methoxyiminoacetate (syn isomer)
Add 22.3 ml of 1N aqueous potassium hydroxide solution to a suspension of 4.8 g and 48 ml of ethanol, and stir at room temperature for 1 hour and 15 minutes. Ethanol is distilled off from the reaction solution, water is added to the remaining solution to adjust the total volume to 100 ml, and the mixture is washed once with diethyl ether. While cooling, adjust the pH to 1 with 10% hydrochloric acid and salt out. This is extracted with ethyl acetate, and the extract is washed with a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. This was concentrated under reduced pressure, and 15 ml of diethyl ether was added to the residue for crystallization. The precipitate was collected and washed with diethyl ether, resulting in 2-(4-formyl-2,3-dihydro-4H 3.51 g of -1,4-thiazin-5-yl)-2-methoxyiminoacetic acid (syn isomer) are obtained. Infrared absorption spectrum _νnudjolnax : 1710, 1610 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ : ppm): 3.08 (2H, m),
3.80 (2H, m), 3.83 (3H, s), 6.40
(1H, s), 8.47 (1H, s) Reference example 5 (i) 31 g of sodium O-ethylxanthate,
31.2 g of ethyl 2-chloroacetyl-2-methoxyiminoacetate was added dropwise to a solution consisting of 150 ml of methanol and 150 ml of water, and the mixture was stirred at 15°C for 1 hour. After removing methanol from the reaction solution under reduced pressure,
The residue is extracted with benzene to obtain ethyl 2-ethoxythiocarbonylthioacetyl-2-methoxyiminoacetate. Infrared absorption spectrum ν ^film _nax : 1735, 1700, 1593 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (CCl ₄ , ppm): 1.30 (3H, t, J=7
Hz), 1.40 (3H, t, J=7Hz), 4.12
(3H, s), 4.25 (2H, q, J=7Hz),
4.32 (2H, s) 4.58 (2H, q, J=7
Hz) Ethyl 2-ethoxythiocarbonylthioacetyl-2-methoxyiminoacetate obtained above41
g, 8 ml of concentrated sulfuric acid and 300 ml of benzene are heated under reflux for 2 hours while distilling off the water produced during the reaction. The reaction solution is washed successively with water, an aqueous sodium bicarbonate solution, and water, and then dried over magnesium sulfate. When this was treated with activated carbon and the solvent was distilled off under reduced pressure, an oily 2-(2-oxo-1,3-
34.3 g of ethyl dithiol-4-yl)-2-methoxyiminoacetate are obtained. Add this to silica gel
Separation and purification by column chromatography (eluent: benzene) yields 13.5 g of the syn isomer and 8.5 g of the anti isomer of the above compound. Synth isomer Infrared absorption spectrum ν ^film _nax : 1735, 1710, 1650 cm- ¹ Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ : ppm): 1.35 (3H,
t, J=7Hz), 3.95 (3H, s), 4.34
(2H, q, J = 7Hz), 7.63 (1H, s) Anti-isomer Infrared absorption spectrum ν ^film _nax : 1740, 1720, 1640cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ : ppm): 1.30 ( 3H,
t, J=7Hz), 4.08 (3H, s), 4.33
(2H, q, J = 7Hz), 8.00 (1H, s) (ii) Ethyl 2-(2-oxo-1,3-dithiol-4-yl)-2-methoxyiminoacetate (anti-isomer body) 1.7g to ethanol 20
ml and add sodium carbonate decahydrate to this.
A solution of 2.2 g dissolved in 10 ml of water is added, and the mixture is stirred at room temperature for 3 hours. Ethanol is distilled off from the reaction solution, the remaining solution is acidified with hydrochloric acid, and then extracted with diethyl ether. The diethyl ether extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain an oily substance. When this is left in the refrigerator to solidify, 2-(2-oxo-1,3
0.75 g of -dithiol-4-yl)-2-methoxyiminoacetic acid (anti-isomer) are obtained. Infrared absorption spectrum _νnudyolnax : 3270, 1730, 1625 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ : ppm): 4.02 (3H, s),
8.0 (1H, s) (iii) On the other hand, the 2-(2-oxo-1.3 obtained above)
-dithiol-4-yl)-2-methoxyiminoethyl acetate (syn isomer) 1 g, tetrahydrofuran 10 ml and ethanol 20 ml, add 1.3 g of sodium carbonate decahydrate to 20 ml of water.
After adding the solution dissolved in ml, stir at room temperature for 3 hours. The solvent is distilled off from the reaction solution under reduced pressure, and the remaining solution is washed with diethyl ether, and then the pH is adjusted to 2. Extract this with diethyl ether,
The extract is washed with a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. When these solvents are distilled off under reduced pressure, 2-(2-oxo-1.3
0.2 g of -dithiol-4-yl)-2-methoxyiminoacetic acid (syn isomer) is obtained. Infrared absorption spectrum ν ^film _nax : 1725, 1625 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ : ppm): 3.93 (3H, s),
7.57 (1H, s) Reference Example 6 (i) In a solution consisting of 3.5 g of 2-mercaptophenol, 3.0 g of triethylamine and 35 ml of dry chloroform, 6.2 g of ethyl 2-chloroacetyl-2-methoxyiminoacetate was dissolved in 60 ml of dry chloroform. The solution was added dropwise over 30 minutes while stirring at 20°C, and then stirred at 18-22°C for 25 hours. The reaction solution is washed successively with 10 hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and water, and dried over magnesium sulfate. This is concentrated under reduced pressure at 40°C, and the residue is dissolved in 100 ml of toluene. In this solution, P-
Add 1 g of toluenesulfonic acid and heat under reflux for 3 hours while distilling off the water produced from the reaction system.
The reaction solution is allowed to cool at room temperature, 50 ml of ethyl acetate is added thereto, and then treated with activated carbon. This is washed with a 1N aqueous sodium hydroxide solution and then with water, dried over magnesium sulfate, and concentrated under reduced pressure at 40°C. 140g of silica gel 60 (manufactured by Merck)
Separate and purify by column chromatography (eluent: benzene). When the purified product was washed with diisopropyl ether and dried, 2-(1.4
1.2 g of ethyl -benzoxathiin-2-yl)-2-methoxyiminoacetate (syn isomer) are obtained. Infrared absorption spectrum _νnudjolnax : 3050, 1725, 1600 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ : ppm): 1.25 (3H, t,
J=7Hz), 3.92 (3H, s), 4.33 (2H,
q, J=7Hz), 6.25 (1H, s), 7.24
(4H, m) (ii) 1.2 g of ethyl 2-(1,4-benzoxathiin-2-yl)-2-methoxyiminoacetate (syn isomer) obtained above, 17 ml of methanol, and 1N aqueous sodium hydroxide solution. The mixture consisting of 8 ml is stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure at 40°C, the residue was dissolved in water, and then washed with ethyl acetate. After adjusting the pH to 1.0 with 10% hydrochloric acid, extract with ethyl acetate. The extract is washed with water and dried over magnesium sulfate. This is 40
When concentrated under reduced pressure at °C, mp143-145 °C (decomposition)
2-(1,4-benzoxathiin-2-yl)-2-methoxyiminoacetic acid (syn isomer)
Obtain 0.9g. Infrared absorption spectrum _νnujiolnax : 2600-2500, 1735, 1600 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ : ppm): 3.90 (3H, s),
6.15 (1H, s), 6.8-7.2 (4H, m) Reference Example 7 (i) Ethyl 2-chloroacetyl-2-methoxyiminoacetate was added to a solution consisting of 7.1 g of O-benzenedithiol, 5.5 g of triethylamine, and 70 ml of chloroform. After adding a solution of 11.4 g dissolved in 50 ml of chloroform at 20°C with stirring, 18
Stir at ~20°C for 5 hours. After washing the reaction solution with 10% hydrochloric acid, it is extracted with 1N aqueous sodium hydroxide solution. Add 10% hydrochloric acid to the extract under ice cooling.
After adjusting the pH to 1, back-extract with ethyl acetate.
This extract is washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. 12g of residue in toluene
1.5g of P-toluenesulfonic acid dissolved in 120ml
After adding, the mixture is heated under reflux for 3 hours while distilling off the water produced during the reaction. The reaction solution was allowed to cool to room temperature, dissolved in 200 ml of ethyl acetate, and treated with activated carbon. This is washed with saturated aqueous sodium bicarbonate solution, then water, and dried over magnesium sulfate. When this is concentrated under reduced pressure at 40℃, 4g of oil is obtained.
get. This oily substance was subjected to column chromatography (eluent: benzene) using 100 g of silica gel 60 (manufactured by Merck & Co., Ltd.), and the benzene eluate was concentrated under reduced pressure at 40°C.
Yellow crystalline 2-(1,4-benzodithiine-2)
1.0 g of ethyl (-yl)-2-methoxyiminoacetate (syn isomer) is obtained. Infrared absorption spectrum _νnudjolnax : 1725, 1620, 1600 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 1.20 (3H, t,
J=7Hz), 3.90 (3H, s), 4.20 (2H,
q, J=7Hz), 7.03 (1H, s), 7.2-7.5
(4H, m) (ii) 2-(1,4-benzodithiine- obtained above)
1.0 g of ethyl (2-yl)-2-methoxyiminoacetate (syn isomer), 12 ml of ethanol, and
A solution consisting of 6 ml of 1N aqueous sodium hydroxide solution is stirred at room temperature for 8 hours. The reaction solution is concentrated under reduced pressure at 40°C, the residue is dissolved in water, and washed with ethyl acetate. Add 10% hydrochloric acid to this under ice cooling,
Adjust the pH to 1.0 and extract with ethyl acetate. After washing the extract with water and drying with magnesium sulfate
Concentration under reduced pressure at 40°C yields 0.8 g of 2-(1,4-benzodithin-2-yl)-2-methoxyiminoacetic acid (syn isomer). Infrared absorption spectrum ν ^film _nax : 2550-2600, 1735, 1650, 1625
,
1600cm ^-1 nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 3.9 (3H, s),
7.00 (1H, s), 7.2-7.5 (4H, m) Reference example 8 (i) 180.0 g of 4-chloro-3-oxo-2-n-propoxyiminobutyric acid ethyl ester was mixed with 2-
After adding with stirring to a solution consisting of 71.6 g of mercaptoethanol and 1.8 g of chloroform, 93.1 g of triethylamine and 200 g of chloroform
ml solution is added dropwise over a period of 5 minutes. This was stirred for 1 hour and 20 minutes at an internal temperature of 20°C. 10% of reaction solution
% hydrochloric acid, twice with a saturated aqueous solution of sodium bicarbonate, and then with water, and then dried over magnesium sulfate. When this is concentrated under reduced pressure,
Oily 4-(2-hydroxyethylthio)-3-
178.7 g of oxo-2-n-propoxyiminobutyric acid ethyl ester are obtained. Infrared absorption spectrum ν film _nax : 2980, 1740, 1685 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (C Cl ₃ , ppm): 0.99 (3H, t, J=
8.0Hz), 1.39 (3H, t, J=7.0Hz), 1.50
~2.10 (2H, m), 2.80 (2H, t, J = 6.0
Hz), 3.74 (2H, s), 4.31 (2H, t, J
= 8.0Hz), 4.34 (2H, q, J = 7.0Hz) (ii) 4-(2-hydroxyethylthio)-3-oxo-2-n-propoxyiminobutyric acid ethyl ester 178.0g, p-toluenesulfonic acid 25.0g
A solution consisting of 1.6 and 1.6 toluene is stirred at 150°C for 30 minutes while removing the water produced.
The reaction solution was treated with activated carbon, 1 part of ethyl acetate was added, and then 2 parts of the solution was added with a saturated aqueous solution of sodium bicarbonate.
Wash twice with water. As a result of drying this with magnesium sulfate and concentrating it under reduced pressure, oily 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetic acid ethyl ester (syn isomer and anti- 153.4 g of mixture of isomers) are obtained. Infrared absorption spectrum ν film _nax : 2970, 2940, 2880, 1735, 1665
cm ^-1 nuclear magnetic resonance absorption spectrum δ (CDCl ₃ , ppm): 0.92 (3H, t, J=
7.0Hz), 1.35 (3H, t, J = 7.8Hz), 1.27
~1.9 (2H, m), 3.06 (2H, m), 4.0 ~
4.6 (6H, m), 5.67, 6.49 (1H, s, s) (iii) 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetic acid ethyl ester ( 1 g of mixture of syn and anti isomers) in 10 ml of methanol and
Add to a solution consisting of 6 ml of 1N aqueous sodium hydroxide solution and stir at room temperature for 18 hours. Methanol is distilled off from the reaction solution under reduced pressure. Add 15 ml of a saturated aqueous solution of sodium hydrogen carbonate and 15 ml of ethyl acetate to the residue, shake thoroughly, and then separate the aqueous layer.
After adjusting the pH to 1.0 with 10% hydrochloric acid, extract with 20 ml of ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and then dried under reduced pressure. A mixture of n-hexane and diethyl ether (1:1) is added to this to powder it and the precipitate is removed. When this is washed with the same mixture, 2-(2・3
0.30 g of -dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetic acid (syn isomer) is obtained. Infrared absorption spectrum _νnudjolnax : 1740 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 0.86 (3H, t,
J=7.5Hz), 1.59 (2H, m), 3.07 (2H,
t, J = 4.0Hz), 3.98 (2H, t, J = 7.0
Hz), 4.28 (2H, t, J = 4.0Hz), 5.80
(1H, s) Reference Example 9 (i) 4-chloro-3-oxo-2-n-hexyloxyiminobutyric acid ethyl ester 255.0g, 2
- 86.1 g of mercaptoethanol, 111.3 g of triethylamine and 2.8 g of chloroform are treated in the same manner as in Reference Example 8(i) and stirred at room temperature for 3.5 hours. When the reaction solution was treated in the same manner as in Reference Example 8(i),
290.5 g of 4-(2-hydroxyethylthio)-3-oxo-2-n-hexyloxyiminobutyric acid ethyl ester are obtained. Infrared absorption spectrum ν film _nax : 2930, 1740, 1680 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (CDCl ₃ , ppm): 0.70-2.07 (14H,
m), 2.53-3.07 (4H, m), 3.07 (2H,
m), 4.22 (2H, t, J=8Hz), 4.38
(2H, q, J = 7Hz) (ii) 4-(2-hydroxyethylthio)-3-oxo-2-n-hexyloxyiminobutyric acid ethyl ester 300g, p-toluenesulfonic acid 42.0g
g and 2.5 g of toluene were treated in the same manner as in Reference Example 8(ii), and heated under reflux for 1.5 hours. When the reaction solution was treated in the same manner as in Reference Example 8(ii), 2-(2,3-dihydro-1,4-oxathiin-6-yl)-
2-n-hexyloxyiminobutyric acid ethyl ester (mixture of syn and anti isomers)
Obtain 186.8g. Infrared absorption spectrum ν film _nax : 2930, 1735, 1665 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (CDCl ₃ , ppm): 0.67-2.00 (1H,
m), 3.10 (2H, m), 3.93-4.63 (6H,
m), 5.63, 6.47 (H, ss) (ii) 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminobutyric acid ethyl ester (syn isomer and anti mixture of isomers), 472 ml of 1N aqueous sodium hydroxide solution and 1.8 methanol at room temperature.
After stirring for 35 minutes, remove the insoluble matter. After the solution was stirred at room temperature for 43 hours, it was treated in the same manner as in Reference Example 8(iii) to obtain 2-(2,3-dihydro-1,4-
43 g of oxathiin-6-yl)-2-n-hexyloxyiminoacetic acid (syn isomer) are obtained. Infrared absorption spectrum _νnudyolnax : 1735 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 0.67-2.13
(11H, m), 3.10 (2H, m), 4.00~4.60
(4H, m), 5.80 (1H, s) Reference Example 10 (i) A solution consisting of 50 g of 4-bromo-2-hydroxyimino-3-oxobutyric acid ethyl ester and 100 ml of chloroform was mixed with 20.5 g of 2-mercaptoethanol and triethylamine. It was added dropwise to a solution consisting of 26.6 g and 100 ml of chloroform at room temperature with stirring over 1.5 hours, and then stirred at the same temperature for 2 hours. Chloroform was distilled off from the reaction solution under reduced pressure, 600 ml of water and 600 ml of ethyl acetate were added to the residue, and the mixture was adjusted to 1H1.0 with concentrated hydrochloric acid. The ethyl acetate layer was separated, washed with 200 ml of water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily 4-(2-hydroxyethylthio)-2-hydroxyimino-3-oxo. 38.8 g of butyric acid ethyl ester are obtained. Infrared absorption spectrum ν film _nax : 3450, 2980, 2930, 1730 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (CDCl ₃ , ppm): 1.37 (3H, t), 2.83
(2H, m), 3.67-4.0 (4H, m), 4.42
(2H, q) (ii) Potassium iodide 3.98g Allyl bromide 2.90g
and 45 ml of acetone, and after stirring at room temperature for 1 hour, insoluble materials were removed. 4-(2-hydroxyethylthio)-2-hydroxyimino-3-oxobutyric acid ethyl ester
4.07g, potassium carbonate 4.15g and acetone 40
ml of suspension and stirred at room temperature for 2 hours. Remove insoluble matter. Concentrate the liquid under reduced pressure.
After adding 35 ml of diethyl ether and 50 ml of water to the residue and shaking thoroughly, the organic layer is separated.
This was washed with 20 ml of water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 4.30 g of oily 2-allyloxyimino-4-(2-hydroxyethylthio)-3-oxobutyric acid ethyl ester. Infrared absorption spectrum ν film _nax : 3460, 2980, 2930, 2860,
1730, 1680cm ^-1 Nuclear magnetic resonance absorption spectrum δ (CDCl ₃ , ppm): 1.36 (3H, t), 2.76
(2H, m), 3.68 (2H, m), 4.10-4.67
(4H, m), 4.75 (2H, m), 5.32 (2H,
m), 5.96 (1H, m) (iii) A solution consisting of 0.40 g of p-toluenesulfonic acid, 4.30 g of 2-allyloxyimino-4-(2-hydroxyethylthio)-3-oxobutyric acid ethyl ester and 43 ml of toluene. and heat under reflux for 20 minutes while removing the water produced. After cooling, add 10 ml of ethyl acetate to the reaction solution, then add 40 ml of water.
Wash twice with ml. After drying this with magnesium sulfate and distilling off the solvent under reduced pressure, an oily substance was formed.
Obtain 3.3g. This was subjected to silica gel column chromatography, eluted with chloroform, and the eluate was concentrated under reduced pressure.
dihydro-1,4-oxathiin-6-yl)
-2-allyloxyiminobutyric acid ethyl ester
Obtain 2.92g. Infrared absorption spectrum ν film _nax : 3060, 2980, 2940, 2880, 1730
cm ^-1 nuclear magnetic resonance absorption spectrum δ (CDCl ₃ , ppm): 1.33 (3H, t), 3.07
(2H, m), 4.17-4.50 (4H, m), 4.67
(2H, m), 5.30 (2H, m), 5.67 (1H,
s), 6.60 (1H, m) (iv) 1.22 ml of 1N sodium hydroxide aqueous solution, 2-
(2,3-dihydro-1,4-oxathiine-
The mixture was added to a solution consisting of 0.90 g of ethyl 6-yl)-2-allyloxyiminoacetate and 9 ml of methanol, and stirred at room temperature for 22 hours. Methanol is distilled off from the reaction solution, and the residue is dissolved in 20 ml of water. Adjust the pH to 7.0 with concentrated hydrochloric acid, wash with 20 ml of ethyl acetate, adjust the pH to 1.5 with concentrated hydrochloric acid, and extract with 50 ml of ethyl acetate. Extract with water
Wash with 50 ml, dry with magnesium sulfate, and concentrate under reduced pressure. The residue was recrystallized from a mixture of diisopropyl ether, diethyl ether and n-hexane (1:1:1) to give colorless crystals of 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2- 0.50 g of allyloxyiminoacetic acid syn isomer) is obtained. mp119~121
℃. Infrared absorption spectrum _νnujiolnax : 3060, 1730 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (CDCl ₃ , ppm): 3.05 (2H, m), 4.40
(2H, m), 4.68 (2H, m), 5.30 (2H,
m), 5.80 (1H, s), 6.02 (1H, m) Example 1 A Vilsmeier reagent is prepared using 0.44 g of dry dimethylformamide, 2 ml of ethyl acetate and 0.92 g of phosphorus oxychloride. To this is added 10 ml of ethyl acetate and 1.2 g of 2-(2,3-dihydro-1,4-dithin-5-yl)-2-methoxyiminoacetic acid (syn isomer) to prepare a solution of acid chloride. On the other hand, a mixture consisting of 1.07 g of 7-amino-2-methyl-3-cephem-4-carboxylic acid, 4.5 g of trimethylsilylacetamide and 20 ml of ethyl acetate is stirred at room temperature for 1 hour. The acid chloride solution obtained above was added all at once while stirring at -15°C, and then stirred at -10°C for 1 hour. After washing the reaction solution with 60 ml of water, add 150 ml of water.
Adjust the pH to 6.5 with sodium bicarbonate. After the aqueous layer is separated and washed with diethyl ether, nitrogen gas is introduced to remove the organic solvent. This was adjusted to pH 2.2 with 10% hydrochloric acid while stirring on ice, and the precipitate was collected, washed with water, and dried to give a pale yellowish white powder of 7.
-[2-2,3-dihydro-1,4-dithiin-
5-yl)-2-methoxyiminoacetamide]-
1.45 g of 2-methyl-3-cephem-4-carboxylic acid (syn isomer) are obtained. Infrared absorption spectrum _νnujiolnax : 3300, 2600-2500, 1790,
1735, 1670, 1635 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 1.43 (3H, d, J
=7Hz), 3.18 (4H, s), 3.70~3.80 (4H,
m), 5.10 (1H, d, J = 5Hz), 5.79
(1H, d, d, J=5Hz, 8Hz), 6.50
(1H, d, J=6Hz), 6.55 (1H, s), 9.65
(1H, d, J=8 Hz) Example 2 (1) A Vilsmeier reagent is prepared using 440 mg of dry dimethylformamide, 2.0 ml of dry ethyl acetate, and 920 mg of phosphorus oxychloride. To this was added 10 ml of dry ethyl acetate and 2-(2,3-dihydro-
A solution of acid chloride is prepared by adding 1.2 g of 1,4-dithin-5-yl)-2-methoxyiminoacetic acid (syn isomer). On the other hand, a mixture consisting of 1.68 g of 4-nitrobenzyl ester of 7-amino-3-cephem-4-carboxylic acid, 4.6 g of trimethylsilylacetamide and 20 ml of dry ethyl acetate is stirred at 40-50 DEG C. for 1.5 hours.
After cooling this to −15° C., the solution of acid chloride obtained above is added all at once while stirring. After stirring this at -10℃ for 1 hour, 60ml of water was added.
Stir at below 10°C for 1.5 hours. When the precipitate is removed, washed with water, and dried, a yellow powder of 7 is obtained.
-[2-(2,3-dihydro-1,4-dithin-5-yl)-2-methoxyiminoacetamide]-4-nitrobenzyl ester of -3-cephem-4-carboxylic acid (syn isomer) 2.1 g get. Infrared absorption spectrum _νnujiolnax : 3350, 1785, 1700, 1690,
1635, 1610, 1530, 1350 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 3.20 (4H, s),
3.53 (2H, d, J = 4Hz), 3.90 (3H,
s), 5.16 (1H, d, J=5Hz), 5.35
(2H, s), 5.68 (1H, d, d, J=5
Hz, 8Hz), 6.48 (1H, s), 6.58 (1H,
d, J=5Hz), 7.58 (2H, d, J=9
Hz), 8.23 (2H, d, J=9Hz), 9.60
(1H, d, J=8Hz) (2) 7-[2-(2,3-dihydro-1,4-dithin-5-yl)-2-methoxyiminoacetamide]-3-cephem-4-carboxylic acid 4
-Nitrobenzyl ester (syn isomer) 2.0
g, methanol 20ml, tetrahydrofuran 40
ml, acetic acid 0.3ml, water 3ml and palladium on carbon
Mix 0.8g and catalytically reduce the mixture at room temperature and pressure for 4 hours. After the reaction solution was filtered under reduced pressure to remove the catalyst, the solution was concentrated to dryness at 40° C. under reduced pressure. Add 20 ml of ethyl acetate to the residue, adjust the pH to 6.5 to 7.0 with a saturated aqueous solution of sodium bicarbonate, stir for 30 minutes, and then filtrate under reduced pressure. Wash the insoluble matter with 10 ml of water, combine the washing liquid and the liquid, and separate the aqueous layer. Wash this with ethyl acetate and adjust the pH to 5.0 with 10% hydrochloric acid. Add 0.1 g of charcoal powder to this, stir for 5 minutes, and then filter under reduced pressure. After washing the liquid with diethyl ether, nitrogen gas is introduced to remove the organic solvent. This was adjusted to pH 2 with 10% hydrochloric acid and extracted twice with 50 ml of ethyl acetate. The extract is washed with ice water, dried over magnesium sulfate, and filtered. The liquid is concentrated under reduced pressure at 40°C, and 30 ml of diethyl ether is added to the residue for crystallization. The precipitate was collected, washed with diethyl ether, and dried to give a pale yellow powder of 7-[2-(2,3-dihydro-1,4-dithin-5-yl)-2-
0.9 g of methoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer) is obtained. Infrared absorption spectrum _νnujiolnax : 3300, 2500-2600, 1790,
1735, 1660, 1640 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 3.16 (4H, s),
3.58 (2H, d, J = 4Hz), 3.77 (3H,
s), 5.09 (1H, d, J=5Hz), 5.78
(1H, d, d, J = 5Hz, 8Hz), 6.43
(1H, d, J=5Hz), 6.54 (1H, s),
9.60 (1H, d, J = 8Hz) Example 3 Production of raw material compounds: (1) 5 g of 4-nitrobenzyl ester of 7-amino-3-cephem-4-carboxylic acid, 13.8 g of trimethylsilylacetamide, bis(trimethylsilyl) A mixture consisting of 10 ml of acetamide and 50 ml of dry ethyl acetate is stirred at 45° C. for 1.5 hours. On the other hand, add 1.5 g of diketene to 7 g of methylene chloride.
ml of the solution was cooled to -40°C, a solution consisting of 2.88 g of bromine and 7 ml of methylene chloride was added dropwise over 20 minutes, and the mixture was stirred at -30°C for 1 hour. Add this to the ethyl acetate solution obtained above at −15°C.
After stirring at the same temperature for 30 minutes, add water 51
Add ml. Separate the ethyl acetate layer, and extract the aqueous layer with ethyl acetate. The extract is combined with the separated ethyl acetate layer, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. When the residue is dried under reduced pressure, powdered 7-(3-oxo-4-
6.15 of the 4-nitrobenzyl ester of (bromobutyramide)-3-cephem-4-carboxylic acid is obtained. Infrared absorption spectrum _νnujiolnax : 1780, 1740, 1630 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 3.62 (4H, broad
s), 4.37 (2H, s), 5.08 (1H, d, J
=5Hz), 5.40 (2H, s), 5.77~6.05
(1H, m), 6.67 (1H, t, J=5Hz),
7.68 (2H, d, J=9Hz), 8.04 (2H,
d, J = 9Hz), 9.07 (1H, d, J = 8
Hz) (2) 8.40 g of 4-nitrobenzyl ester of 7-(3-oxo-4-bromobutyramide)-3-cephem-4-carboxylic acid was suspended in a mixture of 150 ml of tetrahydrofuran and 30 ml of water, and then acetic acid was added. Add 50ml of ethyl. Add 15 ml of an aqueous solution of 1.20 g of sodium sulfite to this at 20℃, and at the same temperature.
Stir for 1.5 hours. Pour the reaction solution into 300 ml of ice water and stir for 20 minutes. Remove the precipitate, wash with water,
When dried, 7-(2-hydroxyimino-3-
6.4 g of crude crystals of 4-nitrobenzyl ester (syn isomer) of oxo-4-bromobutyramido-3-cephem-4-carboxylic acid are obtained.
When this product is recrystallized from ethyl acetate, mp153~
Obtain purified product at 162℃. Infrared absorption spectrum _νnujiolnax : 3250, 1780, 1720, 1705,
1650, 1610, 1600 (sh), 1500-1520 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 3.67 (2H, d,
J=4Hz), 4.63 (1.5H, s), 4.88
(0.5H, s), 5.18 (1H, d, J=5Hz),
5.45 (2H, s), 5.93 (1H, d, d, J=
5Hz, 8Hz), 6.72 (1H, t, J=4
Hz), 7.73 (2H, d, J=9Hz), 8.28
(2H, d, J = 9Hz), 9.38 (1H, d, J
= 8 Hz), 11.27 (1 H, s) Production of target compound: (1) Suspend 0.25 g of 2-aminoethanethiol hydrochloride in a mixture of 1 ml of water and 2 ml of tetrahydrofuran.
Then adjust the pH to 7.5 with a saturated aqueous solution of sodium hydrogen carbonate. This solution was mixed with 7-(2-hydroxyimino-3-oxo-4-bromobutyramide)-3
The mixture was added to a suspension consisting of 1.05 g of 4-nitrobenzyl ester (syn isomer) of cefem-4-carboxylic acid and 30 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off from the reaction solution under reduced pressure, and water and ethyl acetate were added to the residue.
The ethyl acetate layer is separated, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate, and then ethyl acetate is distilled off under reduced pressure. Washing the residue with diethyl ether gives 7-[2-(2.
3-dihydro-1,4-thiazin-5-yl)
-2-Hydroxyiminoacetamide]-3-
0.5 g of 4-nitrobenzyl ester (syn isomer) of cefem-4-carboxylic acid is obtained. Infrared absorption spectrum _νnujiolnax : 3350-3200, 1780, 1730,
1670, 1630, 1605, 1520 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 2.93 (2H, m),
3.30-3.83 (4H, m), 5.03 (1H, s),
5.18 (1H, d, J = 5Hz), 5.47 (2H,
broad s), 5.88 (1H, d, J=5Hz),
6.70 (1H, t, J=5Hz), 7.75 (1H,
d, J=9Hz), 8.30 (1H, d, J=9
Hz) (2) 4-nitrobenzyl ester of 7-[2-(2,3-dihydro-1,4-thiazin-5-yl)-2-hydroxyiminoacetamide]-3-cephem-4-carboxylic acid ( syn isomer)
0.5g with 15ml of tetrahydrofuran and methanol
Dissolve in 15ml of mixture. Add 0.3 g of 10% palladium on carbon and catalytically reduce the mixture at room temperature and pressure. After the reaction, the catalyst is removed and the liquid is concentrated under reduced pressure. After adding water and ethyl acetate to the residue, add an aqueous sodium hydrogen carbonate solution to adjust the pH to 8.0.
shall be. After removing the insoluble matter, separate the aqueous layer and add 10%
Adjust the pH to 5.5 with hydrochloric acid and wash sequentially with ethyl acetate and methylene chloride. After introducing nitrogen gas and removing the remaining organic solvent, the pH was adjusted to 3.3 with 10% hydrochloric acid, and a nonionic adsorption resin, HP-20, was added.
(Trademark, manufactured by Mitsubishi Chemical Industries, Ltd.) Adsorb into 30ml. After washing with water, it is eluted with 40% aqueous acetone. Acetone was distilled off from the eluate under reduced pressure, and the residue was freeze-dried to obtain powdered 7-
[2-(2,3-dihydro-1,4-thiazine-
90 mg of 5-yl)-2-hydroxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer) are obtained. Infrared absorption spectrum _νnujiolnax : 3400-3200, 1750, 1650,
1590cm ^-1 nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 2.90 (2H, m),
3.80~3.30 (4H, m), 5.00 (2H, m),
5.63 (1H, m), 6.3 (1H, m) The following compounds are obtained in the same manner. (a) 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-allyloxyiminoacetamide]-3-cephem-4-
Carboxylic acid (syn isomer) (b) 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-propoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer) Isomers) Example 4 0.41 g of dimethylformamide, 1.5 g of ethyl acetate
ml and 0.85 g of phosphorous oxychloride. To this was added 1.15 g of 2-(2,3-dihydro-1,4-dithin-5-yl)-2-methoxyiminoacetic acid (syn isomer) and 10 ml of ethyl acetate to prepare a solution of acid chloride. On the other hand, 1.07 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid and 3 g of trimethylsilylacetamide were added to 25 ml of ethyl acetate.
Stir at ℃ for 7 hours. After cooling this to -15°C, the acid chloride solution obtained above is added with stirring, and the mixture is stirred at -5 to -10°C for 1 hour. Add 50 ml of water to this reaction solution and separate the organic layer. Water 50 for this
ml, adjust the pH to 7.0 with sodium bicarbonate, and separate the aqueous layer. After washing this with ether, nitrogen gas is introduced to remove the remaining organic solvent. This was adjusted to pH 2.5 with 10% hydrochloric acid while stirring on ice, and the precipitate was removed, washed with water, and dried to give a pale yellow powdery 7-[2-(2,3-dihydro-1.
4-dithin-5-yl)-2-methoxyiminoacetamide]-3-methyl-3-cephem-4
- 0.8 g of carboxylic acid (syn isomer) is obtained. Infrared absorption spectrum _νnujiolnax : 3300, 2500-2600, 1785,
1720, 1660, 1640, 1620cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 2.00 (3H, s),
3.17 (4H, s), 3.43 (2H, AB−q, J=
12Hz), 3.75 (3H, s), 5.10 (1H, d, J
= 5Hz), 5.65 (1H, d, d, J = 5Hz, 8
Hz), 6.62 (1H, s), 9.70 (1H, d, J=
8 Hz) Example 5 (1) Prepare Vilsmeier reagent using 1.25 g of dry dimethylformamide, 2.61 g of phosphorous oxychloride and 6 ml of dry ethyl acetate. After adding 20 ml of ethyl acetate to this and cooling it to -10℃,
(2,3-dihydro-1,4-oxathiine-
Add 3.0 g of 6-yl)-2-methoxyiminoacetic acid (syn isomer) at once and stir at the same temperature for 30 minutes to prepare a solution of acid chloride. On the other hand,
4.51 g of 4-nitrobenzyl ester of 7-amino-3-cephem-4-carboxylic acid, 14.2 g of trimethylsilylacetamide and ethyl acetate.
After stirring 180 ml of the mixture at 45°C for 1 hour, -
Cool to 15°C. The acid chloride solution obtained above was added all at once to this, and the mixture was stirred at -15°C for 1 hour. The reaction solution was mixed with 100 ml of water, 60 ml of a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride.
After sequentially washing with 100 ml of water, drying with magnesium sulfate, and distilling off the solvent under reduced pressure. Washing the residue with ether gave 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2
-Methoxyiminoacetamide] 4.8 g of 4-nitrobenzyl ester (syn isomer) of -3-cephem-4-carboxylic acid is obtained. Infrared absorption spectrum _νnudjolnax : 3280, 1770, 1730, 1650 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 3.08 (2H, broad
s), 3.64 (2H, AB-q, J=18Hz),
3.80 (3H, s), 4.27 (2H, broad s),
5.12 (1H, d, J=8Hz), 5.40 (2H,
s), 5.76 (1H, s), 5.80 (1H, d,
d, J = 5Hz, 8Hz), 6.65 (1H, t, J
= 4Hz), 7.70 (2H, d, J = 9Hz), 8.22
(2H, d, J = 9Hz), 9.40 (1H, d, J
=8Hz) (2) 4-nitrobenzyl ester of 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetamide]-3-cephem-4-carboxylic acid (Syn isomer)
Suspend 3.30 g in a mixture of 150 ml of tetrahydrofuran, 70 ml of methanol, 10 ml of water, and 1 ml of acetic acid. Add 2.3g of 10% palladium carbon to this,
Stir at room temperature for 45 minutes while introducing hydrogen gas. After the reaction, the catalyst is removed from the reaction solution, and the solution is concentrated to dryness under reduced pressure. Add water and a saturated aqueous solution of sodium hydrogen carbonate to the residue to adjust the pH to 7.0 (liquid volume: approximately 50 ml). After removing insoluble materials, the liquid was washed twice with 30 ml of ethyl acetate and once with 20 ml of methylene chloride, and then nitrogen gas was introduced to remove the organic solvent. PH this with 10% hydrochloric acid under ice cooling.
2.0, the precipitate was collected, washed with water, and dried to give 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetamide]-3-cephem-4-. 1.55 g of carboxylic acid (syn isomer) are obtained. Infrared absorption spectrum _νnujiolnax : 3225, 1770, 1660 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 3.07 (2H, broad
s), 3.57 (2H, AB-q, J=18Hz),
3.78 (3H, s), 4.27 (2H, broad s),
5.06 (1H, d, J = 5Hz), 5.71 (1H,
s), 5.72 (1H, d, d, J=5Hz, 8
Hz), 6.45 (1H, t, J=4Hz), 9.58
(1H, d, J=8 Hz) Example 6 (1) Prepare Vilsmeier reagent using 0.4 g of dimethylformamide and 0.86 g of phosphorus oxychloride. Suspend this in 20 ml of dry ethyl acetate, -
After cooling to 5°C, 1.0 g of 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (syn isomer) was added, and the mixture was stirred at the same temperature for 30 minutes. On the other hand, the hydrochloride of 4-nitrobenzyl ester of 7-amino-3-chloro-3-cephem-4-carboxylic acid 2.0
g and trimethylsilylacetamide 5.2 g
Dissolve in 40 ml of ethyl acetate and cool to -30°C. Add the solution obtained above to this and -20 to -10
After stirring for 2 hours at °C, water is added. This is extracted with 100 ml of ethyl acetate, and the aqueous layer is further extracted with 60 ml of ethyl acetate. Both extracts are combined, washed successively with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure.
The residue was washed with diisopropyl ether and dried to give 7-[2-(2,3-dihydro-1,4
2.6 g of 4-nitrobenzyl ester (syn isomer) of -oxathiin-6-yl)-2-methoxyiminoacetamide]-3-chloro-3-cephem-4-carboxylic acid are obtained. Infrared absorption spectrum _νnujiolnax : 3250, 1775, 1730, 1655,
1610, 1590, 1525 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO−d ₆ , ppm): 3.10 (2H, broad
s), 3.83 (3H, s), 3.93 (2H, broad
s), 4.28 (2H, broad s), 5.32 (1H,
d, J=5Hz), 5.48 (2H, s), 5.75
(1H, s), 5.85 (1H, d, d, J=5
Hz, 8Hz), 7.73 (1H, d, J = 9Hz),
8.27 (1H, d, J = 9Hz), 9.73 (1H,
d, J=8Hz) (2) 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetamide]-3-chloro-3-cephem-4
- 2.5 g of 4-nitrobenzyl ester of carboxylic acid (syn isomer) in 40 ml of tetrahydrofuran.
and 40 ml of methanol. Add 1.2 g of 10% palladium on carbon and catalytically reduce the mixture at room temperature and pressure for 4 hours. The catalyst is removed from the reaction solution, and the solution is concentrated under reduced pressure. Water and ethyl acetate are added to the residue, the pH is adjusted to 7.5 with a saturated aqueous solution of sodium hydrogen carbonate, and insoluble materials are removed. Separate the aqueous layer from the liquid, layer it with ethyl acetate, and adjust the pH to 1.5 with 10% hydrochloric acid. The ethyl acetate layer was separated and washed with a saturated aqueous solution of sodium chloride.
After drying with magnesium sulfate, the solvent is distilled off under reduced pressure. Diisopropyl ether was added to the residue to powder it, and the precipitate was collected and dried to give 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetamide]-3. -chloro-3-cephem-
1.3 g of 4-carboxylic acid (syn isomer) are obtained. Infrared absorption spectrum _νnujiolnax : 3260, 1760, 1720, 1655,
1620, 1580, 1530 cm ^-1 nuclear magnetic resonance absorption spectrum δ (DMSO−d ₆ , ppm): 3.10 (2H, broad
s), 3.85 (3H, s), 3.87 (broad s),
4.33 (2H, broad s), 5.27 (1H, d, J
=5Hz), 5.77 (1H, s), 5.87 (1H,
d, d, J = 5Hz, 8Hz), 9.7 (1H,
d, J = 8 Hz) Example 7 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (syn isomer) 1.4 g, dry N-N-dimethylformamide 0.59 ml, 1.17 g of phosphorus oxychloride and 12.3 ml of dry ethyl acetate and 7-amino-2-
1.35 g of methyl-3-cephem-4-carboxylic acid,
When a solution consisting of 5.75 g of trimethylsilylacetamide and 40 ml of ethyl acetate was treated in the same manner as in Example 1, 7-[2-(2,3-dihydro-1,4-
oxathiin-6-yl)-2-methoxyiminoacetamide]-2-methyl-3-cephem-4
- 1.45 g of carboxylic acid (syn isomer) are obtained. Infrared absorption spectrum _νnudjolnax : 3160, 1765, 1660, 1635 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 1.42 (3H, d, J
=7.0Hz), 3.07 (2H, m), 3.79 (3H, s),
4.27 (2H, m), 5.03 (1H, d, J = 5.0
Hz), 5.72 (2H, m), 6.40 (1H, d, J=
7.0Hz), 9.63 (1H, d, J = 8.0Hz) Example 8 (1) 1.26ml of dry N-N-dimethylformamide,
1.48 ml of phosphorus oxychloride, 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n
-Propoxyiminoacetic acid (syn isomer) 3.48g
and 5 ml of dry ethyl acetate are treated in a conventional manner to obtain a solution of the activated acid. Separately, 7-
4- of amino-3-cephem-4-carboxylic acid
Nitrobenzyl ester 5.0g, trimethylsilylacetamide 12.6g, bis(trimethylsilyl)acetamide 8.3g and ethyl acetate 700g
ml solution is stirred at 40° C. for 1 hour. The activated acid solution obtained above was added at once at -30°C, and the mixture was stirred at -10 to -30°C for 2 hours. After adding 50 ml of water to the reaction solution and returning it to room temperature,
Separate the ethyl acetate layer. This is washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. This is concentrated under reduced pressure, and the residue is triturated with diisopropyl ether. Remove the precipitate,
Washing with diisopropyl ether gives 7-
[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetamide]-4-nitrobenzyl ester of -3-cephem-4-carboxylic acid (syn isomer)
Obtain 6.80g. Infrared absorption spectrum _νnujiolnax : 3250, 1780, 1730, 16607cm
^-1 nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 0.79 (3H, t,
J=7.0Hz), 1.52 (2H, m), 3.00 (2H,
m), 3.55 (2H, m), 3.89 (2H, t, J
=6Hz), 4.20 (2H, m), 5.60 (1H,
d, J=4Hz), 5.33 (2H, s), 5.62
(1H, s), 5.75 (1H, dd, J=4.0Hz,
8.0Hz), 6.58 (1H, m), 7.62 (2H, d,
J = 8.0Hz), 8.15 (2H, d, J = 8.0Hz),
9.54 (1H, d, J = 8.0Hz) (2) 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetamide]-3-cephem- When 6.7 g of 4-nitrobenzyl ester of 4-carboxylic acid (syn isomer), 200 ml of tetrahydrofuran, 67 ml of methanol, 2 ml of acetic acid, 6 ml of water and 3.3 g of 10% palladium on carbon were treated in the same manner as in Example 5-(2), 7-[2-(2,3-dihydro-1,4
-oxathiin-6-yl)-2-n-propoxyiminoacetamide]-3-cephem-4
-2.59 g of carboxylic acid (syn isomer) are obtained. Infrared absorption spectrum _νnudjolnax : 3300, 1790, 1776, 1660 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 0.87 (3H, t,
J=7.6Hz), 1.30-1.96 (2H, m), 3.10
(2H, m), 3.60 (2H, d, J=4.0Hz),
4.00 (2H, t, J=6.4Hz), 4.31 (2H,
m), 5.10 (1H, d, J = 5.0Hz), 5.72
(1H, s), 5.79 (1H, d, d, J=5
Hz, 8Hz), 6.48 (1H, m), 9.58 (1H,
d, J = 8.0 Hz) Example 9 A Vilsmeier reagent is prepared from 0.579 g of N.N-dimethylformamide, 1.214 g of phosphorus oxychloride, and 3 ml of ethyl acetate according to a conventional method, and 7 ml of ethyl acetate is added thereto. Add to this 2- at -10℃
(2,3-dihydro-1,4-oxathiin-6
2.00 g of -yl)-2-n-hexyloxyiminoacetic acid (syn isomer) are added under stirring to obtain a solution of the activated acid. Separately, 1.46 g of 7-amino-3-cephem-4-carboxylic acid, 3.84 g of trimethylsilylacetamide, and bis(trimethylsilyl)
Prepare a solution consisting of 4.40 ml of acetamide and 24 ml of ethyl acetate. To this was added the activated acid solution obtained above all at once at -10°C, and then at the same temperature.
Stir for 1.5 hours. Add 30 ml of water and 15 ml of ethyl acetate to the reaction solution, shake thoroughly, and then separate the organic layer. Add to this a saturated aqueous solution of sodium hydrogen carbonate.
After adding 30 ml and shaking thoroughly, separate the aqueous layer. Adjust this to PH2.0 with concentrated hydrochloric acid, and use ethyl acetate.
Extract with 60ml. This extract is washed twice with 20 ml of water, dried over magnesium sulfate, and then ethyl acetate is distilled off under reduced pressure. 50 ml of diisopropyl ether was added to the residue, and the precipitate was removed. ]-3-cephem-4-carboxylic acid (syn isomer) 2.40 g is obtained. Infrared absorption spectrum _νnujiolnax : 3280, 1785, 1730, 1660 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 0.67-1.83 (11H,
m), 3.07 (2H, m), 3.60 (2H, q, J=
14Hz), 3.99 (2H, t, J=6Hz), 4.37
(2H, m), 5.06 (1H, d, J=5Hz), 5.68
(1H, s), 5.74 (1H, d, d, J=5Hz,
8Hz), 6.46 (1H, t, J=5Hz), 9.55
(1H, d, J=8 Hz) Example 10 A Vilsmeier reagent is prepared from 0.175 g of N.N-dimethylformamide, 0.367 g of phosphorus oxychloride and 0.5 ml of ethyl acetate according to a conventional method, and 5 ml of ethyl acetate is added thereto. To this, 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-
Allyloxyiminoacetic acid (syn isomer) 0.500g
is added at −15° C. and stirred at the same temperature for 20 minutes to obtain a solution of activated acid. This is 7-amino-3
-Cefem-4-carboxylic acid 0.524g, trimethylsilylacetamide 1.4g, bis(trimethylsilyl)acetamide 1.5ml and ethyl acetate 7.5g
ml of solution at -15°C and stirred at the same temperature for 2 hours. Add 10ml of water to the reaction solution,
After adjusting the pH to 7.0 with an aqueous sodium hydrogen carbonate solution, separate the aqueous layer. This water layer was diluted with 10% hydrochloric acid to pH 3.
7-
0.73 g of [2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-allyloxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer) is obtained. Infrared absorption spectrum _νnujiolnax : 3225, 1770, 1708, 1660 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 3.07 (2H, m),
3.55 (2H, d, J = 4Hz), 4.27 (2H,
m), 4.53 (2H, m), 5.07~5.40 (3H,
m), 5.67-6.27 (3H, m), 6.45 (1H, t,
J=4Hz), 9.60 (1H, d, J=8Hz) Example 12 (1) 7-amino-3-chloro-3-cephem-4
- 4-nitrobenzyl ester hydrochloride of carboxylic acid 5.0 g, trimethylsilylacetamide
A solution consisting of 11.3 g and 100 ml of dry ethyl acetate and 3.13 g of 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetic acid (syn isomer), dry N. N-
1.13ml dimethylformamide, phosphorus oxychloride
When a solution consisting of 1.33 ml and 54.4 ml of ethyl acetate was treated in the same manner as in Example 6(1), 7-[2-
(2,3-dihydro-1,4-oxathiine-
7.10 g of 4-nitrobenzyl ester (syn isomer) of 6-yl)-2-n-propoxyiminoacetamide]-3-chloro-3-cephem-4-carboxylic acid are obtained. Infrared absorption spectrum _νnudjolnax : 1780, 1730, 1675, 1607 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 0.87 (3H, t,
J=7.0Hz), 1.30-1.90 (2H, m), 3.10
(2H, m), 3.98 (2H, t, J=6.4Hz),
4.28 (2H, m), 5.32 (1H, d, J = 5.0
Hz), 5.48 (2H, s), 5.73 (1H, s),
6.87 (1H, d, d, J = 5.0Hz, 8.2Hz),
7.74 (2H, d, J = 9.0Hz), 8.29 (2H,
d, J=9.0Hz) (2) 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetamide]-3-chloro-3-cephem- 7.0 g of 4-nitrobenzyl ester of 4-carboxylic acid (syn isomer), 2 ml of acetic acid, 10 g of water
Example 6
- After treatment in the same manner as in (2), the resulting crystals were recrystallized from 20 ml of methylene chloride, resulting in 7-[2-
(2,3-dihydro-1,4-oxathiine-
2.31 g of 6-yl)-2-n-propoxyiminoacetamide]-3-chloro-3-cephem-4-carboxylic acid (syn isomer) are obtained. Infrared absorption spectrum _νnujiolnax : 3300, 1784, 1740, 1665 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 0.87 (3H, t,
J=8.0Hz), 1.61 (2H, m), 3.08 (2H,
m), 3.83 (2H, q, J = 16.8Hz), 3.97
(2H, t, J=8.0Hz), 4.28 (2H, m),
5.23 (1H, d, J = 5.0Hz), 5.68 (1H,
s), 5.74 (1H, d, d, J = 5.0Hz, 9.0
Hz), 9.64 (1H, d, J = 9.0Hz) Example 13 (1) 7-amino-3-chloro-3-cephem-4
- 4-nitrobenzyl ester hydrochloride of carboxylic acid 4.06 g, trimethylsilylacetamide
A solution consisting of 9.19 g and 40 ml of ethyl acetate,
2-(2,3-dihydro-1,4-dithiin-
5-yl)-2-methoxyiminoacetic acid (syn isomer) 2.2 g, N・N-dimethylformamide
0.8g, phosphorus oxychloride 1.67g and ethyl acetate
When a solution consisting of 24 ml was treated in the same manner as in Example 6(1), 7-[2-(2,3-dihydro-1,4
-dithin-5-yl)-2-methoxyiminoacetamide]-3-chloro-3-cephem-
5.1 g of 4-nitrobenzyl ester of 4-carboxylic acid (syn isomer) are obtained. Infrared absorption spectrum _νnujiolnax : 3280, 1790, 1740, 1680 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 3.20 (4H, s),
3.80 (3H, s), 3.93 (2H, ABq, J=18
Hz), 5.30 (1H, d, J = 5Hz), 5.48
(2H, s), 5.87 (1H, d, d, J=8
Hz, 5Hz), 6.6 (1H, s), 7.73 (2H,
d, J=9Hz), 8.30 (2H, d, J=9
Hz), 9.63 (1H, d, J = 8Hz) (2) 7-[2-(2,3-dihydro-1,4-dithin-5-yl)-2-methoxyiminoacetamide]-3-chloro- 5.0 g of 4-nitrobenzyl ester of 3-cephem-4-carboxylic acid (syn isomer), 50 ml of tetrahydrofuran (30 ml of methanol, 2 g of 10% palladium on carbon, 7 g of water)
ml and 0.7 ml of acetic acid were treated in the same manner as in Example 6(2) to obtain 7-[2-(2,3-dihydro-1,4
-dithin-5-yl)-2-methoxyiminoacetamide]-3-chloro-3-cephem-
1.6 g of 4-carboxylic acid (syn isomer) are obtained. Infrared absorption spectrum _νnujiolnax : 3300, 1780, 1730, 1660 cm ^-1 Nuclear magnetic resonance absorption spectrum δ (DMSO-d ₆ , ppm): 3.20, (4H,
s), 3.81 (2H, AB-q, J=18Hz),
3.80 (3H, s), 5.72 (1H, dd, J=8
Hz, 5Hz), 6.55 (1H, s), 9.77 (1H,
d, J=8Hz)

Claims (1)

[Claims] 1. General formula _[ In _the formula _, 7-substituted-3-cephem-4-carboxylic acids represented by the following formulas, derivatives at the carboxy group thereof, and salts thereof. 2. The compound according to claim 1, wherein X is a sulfur atom. 3. The compound according to any one of claims 1 to 2, wherein _R2 is a lower alkyl group. 4 Claims 1 to 4 in which R ₂ is a methyl group
A compound according to any of Item 2. 5. The compound according to any one of claims 1 to 4, wherein _R3 is a lower alkyl group and _R4 is a hydrogen atom. 6. The compound according to claim 5, wherein R ₃ is a methyl group. 7. The compound according to any one of claims 1 to 4, wherein R ₃ and R ₄ are hydrogen atoms. 8. The compound according to any one of claims 1 to 4, wherein _R3 is a hydrogen atom and _R4 is a lower alkyl group. 9. The compound according to claim 8, wherein R ₄ is a methyl group. 10. The compound according to claim 1, wherein X is an imino group. 11 Claim 1 in which R ₂ is a hydrogen atom
A compound according to item 1 or item 10. 12. The compound according to claim 11, wherein R ₃ and R ₄ are hydrogen atoms. 13. The compound according to claim 1, wherein X is an oxygen atom. 14. The compound according to claim 13, wherein R ₂ is a lower alkyl group. 15 Claim 1 in which R ₂ is a methyl group
Compound according to item 3. 16. The compound according to any one of claims 13 to 15, wherein both R ₃ and R ₄ are hydrogen atoms. 17. The compound according to any one of claims 1 and 13 to 15, wherein R ₃ is a hydrogen atom and R ₄ is a halogen atom. 18. The compound according to claim 17, wherein the halogen atom of R ₄ is a chlorine atom. 19. The compound according to claim 13, wherein R ₂ is a propyl group. 20. The compound according to claim 19, wherein R ₃ and R ₄ are both hydrogen atoms. 21. The compound according to claim 1 or 13, wherein R ₂ is an alkenyl group. 22 Claim 1 in which R ₂ is an allyl group
or a compound according to item 13. 23. The compound according to claim 21 or 22, wherein R ₃ and R ₄ are both hydrogen atoms. 24. The compound according to any one of claims 1 to 23, wherein the derivative at the carboxy group is an ester. 25. The compound according to claim 24, wherein the ester is P-nitrobenzyl ester. 26 Claims 1 to 2 which are syn isomers
A compound according to any one of Item 5. 27 General formula (In the formula, R ₃ is a hydrogen atom or a lower alkyl group, R ₄
means a hydrogen atom, a halogen atom, or a lower alkyl group, respectively. [In the formula, X means a sulfur atom, an oxygen atom or an imino group, and _R2 means a hydrogen atom, a lower alkenyl group or a lower alkyl group] By acting, the general formula (In the formula, X, R ₂ , R ₃ and R ₄ have the same meanings as above.) A method for producing 7-substituted-3-cephem-4-carboxylic acids, derivatives at the carboxy group thereof, or salts thereof. 28 General formula (In the formula, Y is a halogen atom, _R2 is a hydrogen atom, a lower alkenyl group or a lower alkyl group, _R3 is a hydrogen atom or a lower alkyl group, and _R4 is a hydrogen atom, a halogen atom, or a lower alkyl group, respectively. ) is reacted with a thiol compound represented by the general formula HX-CH ₂ -CH ₂ -SH (wherein, X means a sulfur atom, an oxygen atom or an imino group) to form a compound represented by the general formula (In the formula, X, R ₂ , R ₃ and R ₄ have the same meanings as above.) A method for producing 7-substituted-3-cephem-4-carboxylic acids, derivatives at the carboxy group thereof, or salts thereof.