JPH02358B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula [In the formula, R ₂ is a lower alkyl group, R ₃ is the formula -
CH ₂ R ₅ (in the formula, R ₅ represents a lower alkoxy group),
R ₄ is a −CHR ⁶ OCOR ⁷ group (in the formula, R ⁶ represents a hydrogen atom or a methyl group, and R ⁷ represents a lower alkyl group or a lower alkoxy group when R ⁶ is a hydrogen atom,
When R ⁶ is a methyl group, it represents a lower alkoxy group. )
This invention relates to a method for producing a cephalosporin derivative represented by The present inventors have discovered that the novel object compound of the present invention is useful as an oral agent with strong antibacterial activity (Japanese Patent Application No. 136449/1982). 7-[2- represented by the above formula (1) of the present invention
(2-Aminothiazol-4-yl)-2-(syn)-alkoxyiminoacetamide] Cephalosporin derivative has the formula [In the formula, R ₁ represents a phenyl group or a lower alkyl group which may have a substituent, and R ₂ has the same meaning as described above. ] Alkoxyiminobutyric acid or its reactive derivative at the carboxyl group and the formula [In the formula, R ₃ represents the formula -CH ₂ R ₅ (in the formula, R ₅ represents a lower alkoxy group), and R ₄ represents the formula -CHR ⁶ OCOR ⁷
group (wherein R ⁶ represents a hydrogen atom or a methyl group,
R ⁷ represents a lower alkyl group or a lower alkoxy group when R ⁶ is a hydrogen atom, and represents a lower alkoxy group when R ⁶ is a methyl group. ) by reacting the 7-aminocephalosporin derivative represented by the formula [In the formula, R ₁ , R ₂ , R ₃ and R ₄ have the same meanings as described above. ] to produce a compound represented by
This compound can be obtained by reacting with thiourea. The inventors have discovered a new method for synthesizing a cephalosporin derivative () that has excellent antibacterial activity and is orally absorbable, and have completed the present invention. In the above formula, R ₁ is methyl, ethyl, propyl,
1 to 6 carbon atoms such as isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl group
represents a lower alkyl group or a phenyl group, and the phenyl group may have a substituent. That is, it may be substituted with a lower alkyl group such as methyl or ethyl group, a lower alkoxy group such as methoxy or ethoxy group, or a halogen atom such as chlorine or bromine. In this case, they do not have to be of the same type. Generally preferred as R ₁ are phenyl, paramethylphenyl, methyl, ethyl groups and the like. R ₂ is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, n
- 1 or more carbon atoms such as pentyl, n-hexyl group
6 is a lower alkyl group, and a methyl or ethyl group is particularly preferred. R ₃ represents the formula −CH ₂ R ₅ ;
The substituent R ₅ includes lower alkoxy groups such as methoxy, ethoxy, n-propoxy, and isopropoxy groups, and R ₄ includes alkanoyloxymethyl (e.g. acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, benzoyloxy methyl group, etc.) or lower alkoxycarbonyloxymethyl or ethyl (e.g. 1-ethoxycarboxynyloxyethyl, 1-n
-propoxycarbonyloxyethyl, tertiary butyloxycarbonyloxymethyl group, etc.) which are eliminated under physiological conditions. Next, the reaction of the present invention will be explained. Compound () is a new substance; for example, compound ( _a ) in which R ₁ is a 4-methylphenyl group and R ₂ is a methyl group was synthesized by the following route. In a reaction in which compounds () and () are reacted to obtain (), () is used in its free form or as a reactive derivative thereof. When used in its free form, an appropriate condensing agent is used. As the condensing agent, di-substituted carbodiimides such as N,N'-dicyclohexylcarbodiimide, N,
Bylsma is prepared from azolide compounds such as N'-carbonyldiimidazole, dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylene, dimethylformamide and phosphorus oxychloride. Examples include ear reagent. As the reactive derivative of the compound having the formula (), acid halides, acid anhydrides, mixed acid anhydrides, active esters, active amides, acid azides, etc. are used. Mixed acid anhydrides include mixed acid anhydrides with carbonic acid monoesters such as carbonic acid monomethyl ester and carbonic acid monoisobutyl ester, and mixed acid anhydrides with lower alkanoic acids which may be substituted with halogen such as pivalic acid and trichloroacetic acid. Examples of active esters include p-nitrophenyl ester, pentachlorophenyl ester, N-hydroxyphthalimide ester, and N-hydroxybenztriazole ester. The reaction is generally carried out in a suitable solvent. There are no limitations on the solvent as long as it does not affect the reaction.
For example, acetone, tetrahydrofuran, dioxane, ethyl acetate, chloroform, dichloromethane, dimethylformamide, acetonitrile, water, etc. or mixtures thereof are used. Depending on the type of reactive derivative used in this reaction, a base may be present as necessary. Examples of bases include alkali metal compounds such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, aliphatic, aromatic, or nitrogen-containing heterocyclic bases such as triethylamine,
Dimethylaniline, N-methylpiperidine, N-
Examples include methylpyrrolidine, pyridine, collidine, and lutidine. There is no particular limitation on the reaction temperature, but the reaction is usually carried out at room temperature or under cooling. The time required for the reaction varies mainly depending on the type of acylation method, reaction temperature, etc., but is usually from ten hours to several tens of hours. After the reaction is complete, the compound having formula () is recovered from the reaction mixture in a conventional manner. If necessary, it can be purified by recrystallization, chromatography, etc., but it can also be used as a raw material for the next step without separation. The reaction of producing compound () by reacting compound () with thiourea is usually carried out by bringing the two into contact in a suitable solvent. The solvent used is not limited as long as it does not adversely affect this reaction, but for example, water, methanol, ethanol, dimethylformamide, dimethylacetamide, acetone, acetonitrile, tetrahydrofuran, or a mixture thereof can be used. It will be done. In some cases, it may be better to add a base such as sodium acetate or sodium bicarbonate to accelerate and complete the reaction. There is no particular limitation on the reaction temperature, but it can usually be carried out at room temperature. The reaction time is usually several tens of minutes to several hours, although it depends on the reaction conditions. After the reaction is complete, the produced () is collected from the reaction mixture by a conventional method. For example, it can be isolated by vacuum concentration, extraction, reprecipitation, chromatography, etc. Examples of the compound () produced by the method of the present invention include (1) 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3
-Methoxymethyl-3-cephem-4-carboxylic acid acetyloxymethyl ester (2) 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3
-Methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (3) 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3
-Methoxymethyl-3-cephem-4-carboxylic acid methoxycarbonyloxymethyl ester (4) 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3
-Methoxymethyl-3-cephem-4-carboxylic acid isobutyryloxymethyl ester (5) 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3
-Methoxymethyl-3-cephem-4-carboxylic acid 1-ethoxycarbonyloxyethyl ester (6) 7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamide]-3
-Methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (7) 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3
-Ethoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (8) 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3
-Methoxymethyl-3-cephem-4-carboxylic acid 1-isopropyloxycarbonyloxyethyl ester, etc. (all of which are syn-type).Next, reference examples and examples will be given to specifically describe the method for producing the compounds of the present invention. However, the present invention is not limited thereto. Reference Example 1 7.1 g of 4-bromo-3-oxobutyric acid tert-butyl ester and silver para-toluenesulfonate
Add 9.45 g to 50 ml of dry acetonitrile and stir at room temperature for 3 days protected from light. The reaction solution is filtered and the solution is concentrated under reduced pressure. The obtained crystals containing an oily substance are dissolved in ethyl acetate and insoluble materials are removed by filtration. Concentrate the liquid under reduced pressure to obtain a brown oil. The oily substance was separated and purified by silica gel column chromatography using cyclohexane-ethyl acetate as the developing solvent, and the resulting colorless oily substance was recrystallized from ether-n-hexane to yield 4-paratoluenesulfonyloxy-3.
-4.5 g of oxobutyric acid tertiary butyl ester was obtained as colorless columnar crystals. Melting point 67-69℃ NMR (CDCl ₃ ) δ _ppn : 1.43 (9H, s, tert-Butyl) 2.43 (3H, s,

[Formula]) 3.43 (2H, s, -CH ₂ = CO ₂ tBu) 4.60 (2H, s, -SO ₂ OCH ₂ = = CO-) 7.20 - 7.90 (4H, benzene ring) Elemental analysis value C ₁₅ H ₂₀ O ₆ S Calculated value: C, 54.92; H, 6.15; S, 9.78 Actual value: C, 55.03; H, 6.07; S, 9.86 Reference example 2 4-paratoluenesulfonyloxy-3-oxobutyric acid tertiary butyl ester 4.5 40ml of g
of sodium nitrite dissolved in acetic acid and added over 10 minutes at room temperature. After stirring for an additional 50 minutes at room temperature, 200 ml of ethyl acetate was added to the reaction mixture, and the ethyl acetate solution was washed with brine. The ethyl acetate solution is dried over magnesium sulfate and concentrated to give a brown oil. When this was separated and purified using silica gel column chromatography using cyclohexane-ethyl acetate as the developing solvent, 4-paratoluenesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tert-butyl ester was obtained as colorless crystals at 1.66
g was obtained. Melting point 106-108℃ (decomposition), (recrystallization solvent, ether-petroleum ether) NMR (CDCl ₃ ) δ _ppn : 1.52 (9H, s, tert-Butyl) 2.43 (3H, s,

[Formula]) 5.04 (2H, s, -SO ₂ OCH ₂ ==CO-) 7.20-7.92 (4H, benzene ring) 10.23 (1H, s,

[Formula]) Analysis value C ₁₅ H ₁₉ NO ₇ S Calculated value: C, 50.48; H, 5.36; N, 3.92; S8.98 Actual value: C, 50.62; H, 5.08; N, 3.83; S8.97 Reference Example 3 1.66 g of 4-paratoluenesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tertiary butyl ester was dissolved in 20 ml of dry acetone, and 960 mg of anhydrous potassium carbonate and 0.466 ml of dimethyl sulfate were added under ice cooling. Stir at room temperature for 3 hours. Pour the reaction solution into 200 ml of ice water and extract with methylene chloride. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give a brown oil. When this was separated and purified using silica gel column chromatography using cyclohexane-ethyl acetate as the developing solvent, 4-paratoluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid tert-butyl ester was obtained as a pale yellow oil.
650 mg was obtained. NMR (CDCl ₃ ) δ _ppn : 1.50 (9H, s, tert-Butyl) 2.43 (3H, s,

【formula】) 4.07(3H,s,

[Formula]) 5.05 (2H, s, -SO ₂ OCH ₂ ==CO-) 7.20-7.90 (4H, benzene ring) Reference example 4 4-paratoluenesulfonyloxy-3-oxo-2-(syn)-methoxy Dissolve 478 mg of iminobutyric acid tertiary butyl ester in 1 ml of methylene chloride and add 2 ml of trifluoroacetic acid.
Stir at room temperature for 4 hours. Methylene chloride and excess trifluoroacetic acid are distilled off under reduced pressure, and the resulting brown oil is dissolved in isopropyl ether and left to stand. 4-paratoluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid is obtained as colorless. 178 mg of crystals were obtained. Melting point 131-132℃ (decomposition) Elemental analysis value C ₁₂ H ₁₃ NO ₇ S Calculated value: C, 45.72; H, 3.84; N, 4.45; S,
10.18 Actual value: C, 45.50; H, 3.92; N, 4.32; S,
9.98 NMR (d-6 acetone) δ _ppn : 2.47 (3H, s,

[Formula]) 4.10 (3H, s, N-OCH ₃ ==) 5.20 (2H, s, -SO ₂ OCH ₂ == CO) 7.25-7.95 (4H, benzene ring) 9.80 (1H, bs, -CO ₂ H=) Reference Example 5 8.25 g of 4-bromo-3-oxobutyric acid tertiary butyl ester and 11.3 g of silver ethanesulfonate
Add to 50 ml of dry acetonitrile and stir and reflux for 30 minutes. The reaction solution is filtered and the solution is concentrated under reduced pressure. The obtained oil is dissolved in benzene, washed with water, washed with sodium chloride, washed with brine, dried over anhydrous magnesium sulfate, and the solvent is concentrated under reduced pressure to obtain a brown oil. When the oily substance is separated and purified using silica gel column chromatography using cyclohexane-ethyl acetate as the developing solvent,
4-ethanesulfonyloxy-3-oxobutyric acid tert-butyl ester as a yellow oil
7.7g was obtained. NMR (CDCl ₃ ) δ _ppn 1.32-1.62 (9H+3H, s+t, tert-Butyl
+CH ₃ = CH ₂ SO ₃ -) 3.30 (2H, q, J = 7.0, CH ₃ CH ₂ = SO ₃ -) 3.47 (2H, s, -CH ₂ = CO ₂ t _Bu 4.87 (2H, s, -SO ₂ OCH ₂ = CO-) Reference Example 6 Dissolve 7.7 g of 4-ethanesulfonyloxy-3-oxobutyric acid tertiary butyl ester in 50 ml of acetic acid, and add 2.2 g of sodium nitrite and 0.1 g of sodium nitrite under ice cooling.
Add ml of concentrated sulfuric acid. After stirring the reaction solution at room temperature for 40 minutes, 500 ml of ethyl acetate was added, and the ethyl acetate solution was washed with brine. When the ethyl acetate solution is dried over anhydrous magnesium sulfate and concentrated, yellowish brown crystals are obtained. The crystals were recrystallized from ether-petroleum ether to obtain 5.9 g of 4-ethanesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tert-butyl ester as colorless crystals.
Melting point 85-87℃ (decomposition) NMR ( _CDCl3 ) δ _ppn 1.47 (3H, t, J=7.0, _CH3 = CH2SO2O-) 1.57 (9H, s, t _- Butyl) 3.33 ( _2H , q , J = 7.0, CH ₃ = CH ₂ SO ₂ O-) 5.23 (2H, s, -SO ₂ OCH ₂ = CO-) 10.50 (1H, s,

[Formula]) Elemental analysis value C ₁₀ H ₁₇ NO ₇ S Calculated value: C, 40.71; H, 5.81; N, 4.75; S, 10.87 Actual value: C, 40.29; H, 5.73; N, 4.61; S, 11.17 Reference example 7 4-ethanesulfonyloxy-3-oxo-2
-Dissolve 5.9 g of hydroxyiminobutyric acid tertiary butyl ester in 50 ml of dry acetone, add 4.14 g of anhydrous potassium carbonate and 1.86 ml of dimethyl sulfate under ice cooling, and stir at room temperature for 1 hour. reaction solution
Pour into 500ml of ice water and extract with ethyl acetate.
The extract is washed with brine, dried over magnesium sulfate, and concentrated to give a brown oil. When this was separated and purified using silica gel column chromatography using benzene-ethyl acetate as the developing solvent, a pale yellow oil was obtained.
3.13 g of 2-(syn)-methoxyiminobutyric acid tert-butyl ester was obtained. NMR (CDCl ₃ ) δ _ppn 1.43 (3H, t, J = 7.0, CH ₃ = CH ₂ SO ₂ O-) 1.50 (9H, s, t-Butyl) 3.27 (2H, q, J = 7.0, CH ₃ CH ₂ = SO ₂ O−) 4.07 (3H, s,

[Formula] 5.18 (2H, s, -SO ₂ OCH ₂ = CO-) Reference Example 8 In the same manner as Reference Example 5, from 5.0 g of 4-bromo-3-oxobutyric acid tert-butyl ester and 6.5 g of silver benzenesulfonate. 3.4 g of 4-benzenesulfonyloxy-3-oxobutyric acid tert-butyl ester was obtained as colorless needle crystals. melting point
94-96℃ Elemental analysis value C ₁₄ H ₁₈ O ₆ S Calculated value: C, 53.50; H, 5.78; S, 10.20 Actual value: C, 53.49; H, 5.70; S, 10.16 NMR (CDCl ₃ ) δ _ppn 1.43 (9H, s, t-Butyl) 3.43 (2H, s, -COCH ₂ = CO-) 4.63 (2H, s, -SO ₂ COH ₂ = CO-) 7.40-8.03 (5H, m, benzene ring - H = ) Reference Example 9 In the same manner as in Reference Example 2, 4-benzenesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid was prepared from 3.4 g of tertiary butyl 4-benzenesulfonyloxy-3-oxobutyric acid and 900 mg of sodium nitrite. 2.95 g of lebutyl ester was obtained as colorless needles. Melting point 93~95
°C (decomposition) Elemental analysis value C ₁₄ H ₁₇ NO ₇ S Calculated value: C, 49.02; H, 5.00; N, 4.08; S, 9.35 Actual value: C, 48.93; H, 5.06; N, 4.01; S, 9.41 NMR (CDCl ₃ ) δ _ppn 1.57 (9H, s, t-Butyl) 5.07 (2H, s, -SO ₂ OCH ₂ =CO-) 7.40-8.03 (5H, m, benzene ring -H =) 10.17 (1H, bs,

[Formula]) Reference Example 10 In the same manner as in Reference Example 3, 2.95 g of 4-benzenesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid tertiary butyl ester, 1.80 g of anhydrous potassium carbonate, and 0.8 ml of dimethyl sulfate were added to 4-
Benzenesulfonyloxy-3-oxo-2-
800 mg of (syn)-methoxyiminobutyric acid tertiary butyl ester was obtained as a colorless oil. NMR (CDCl ₃ ) δ _ppn 1.50 (9H, s, t-Butyl) 4.05 (3H, s,

[Formula]) 5.07 (2H, s, -SO ₂ OCH ₂ = CO-) 7.30-8.00 (5H, m, benzene ring -H =) Reference example 11 4-bromo-3-oxobutyric acid tert-butyl ester 6.0 g and 7.7 g of silver methanesulfonate in 40
ml of dry acetonitrile and stir and reflux for 30 minutes. Filter the reaction solution and concentrate under reduced pressure. The obtained oil is dissolved in benzene, washed with water, sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate, and the solvent is concentrated under reduced pressure to obtain a brown oil. The oil was separated and purified by silica gel column chromatography using benzene-ethyl acetate as a developing solvent to obtain 5.5 g of 4-methanesulfonyloxy-3-oxobutyric acid tert-butyl ester as a pale yellow oil. NMR (CDCl ₃ ) δ _ppn 1.47 (9H, s) 3.14 (3H, s) 3.47 (2H, s) 4.89 (2H, s) Reference example 12 4-methanesulfonyloxy-3-oxobutyric acid tert-butyl ester 1.0 g Dissolve in 10 ml of glacial acetic acid and add 386 mg of sodium nitrite and 1 drop of concentrated sulfuric acid while cooling on ice. After stirring the reaction solution at 10°C for 20 minutes, add 50 ml of ethyl acetate and wash with brine. When the ethyl acetate solution is dried over anhydrous magnesium sulfate and concentrated, yellowish brown crystals are obtained. Crystal as ether
Recrystallization from petroleum ether gives 4-methanesulfonyloxy-3-oxo-2- as colorless crystals.
730 mg of hydroxyiminobutyric acid tertiary butyl ester was obtained. Melting point 103-104℃ (decomposed) NMR (CDCl ₃ + CD ₃ COCD ₃ ) δ _ppn 1.56 (9H, s) 3.20 (3H, s) 5.23 (2H, s) 11.93 (1H, s) Elemental analysis value C ₉ H ₁₅ NO ₇ S Calculated value: C, 38.47; H, 5.38; N, 4.99; S, 11.41 Actual value: C, 38.41; H, 5.37; N, 4.87; S, 11.32 Reference example 13 4-methanesulfonyloxy-3- Oxo-2
-Dissolve 2.8 g of hydroxyiminobutyric acid tertiary butyl ester in 30 ml of dry acetone,
Add 2.07 g of anhydrous potassium carbonate and 1.6 ml of diethyl sulfate under ice-cooling, and stir at room temperature for 1 hour. reaction solution
Pour into 300ml of ice water and extract with ethyl acetate.
The extract is washed with brine, dried over anhydrous magnesium sulfate, and concentrated to give a brown oil. When this was separated and purified using silica gel column chromatography using benzene-ethyl acetate as the developing solvent, 1.31 g of 4-methanesulfonyloxy-3-oxo-2-(syn)-ethoxyiminobutyric acid tert-butyl ester was obtained as a colorless oil. It was done. NMR (CDCl ₃ ) δ _ppn 1.27 (3H, t, J = 7.0) 1.54 (9H, s) 3.19 (3H, s) 4.20 (2H, q, J = 7.0) 5.23 (2H, s) Reference example 14 4- Ethanesulfonyloxy-3-oxo-2
Dissolve 1.56 g of -(syn)-methoxyiminobutyric acid tertiary butyl ester in 5 ml of trifluoroacetic acid and stir at room temperature for 7 hours. Concentrating the reaction solution gives a brown oil. If the oil is left overnight, it will crystallize. Dissolve the crystals in acetone, treat with decolorizing charcoal, concentrate, and convert the resulting crystals into methylene chloride.
When recrystallized from petroleum ether, 4-ethanesulfonyloxy-3-oxo-
995 mg of 2-(syn)-methoxyiminobutyric acid was obtained. Melting point 85.5-89℃ NMR (heavy acetone) δ _ppn 1.40 (3H, t, J = 7.0, CH ₃ = CH ₂ SO ₂ O-) 3.34 (2H, q, J = 7.0, CH ₃ CH ₂ = SO ₂ O −) 4.13(3H,s,

[Formula]) 5.33 (2H, s, -SO ₂ OCH ₂ = CO-) 11.10 (1H, bs, -CO ₂ H =) Elemental analysis value C ₇ H ₁₁ O ₇ NS Calculated value: C, 33.23; H, 4.38; N, 5.54; S, 12.67 Actual value: C, 33.16; H, 4.29; N, 5.49; S, 12.67 Reference example 15 4-benzenesulfonyloxy-3-oxo-2-( From 800 mg of syn)-methoxyiminobutyric acid tertiary butyl ester and 5 ml of trifluoroacetic acid, 600 mg of 4-benzenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid was obtained as crystals. NMR (heavy acetone) δ _ppn 4.06 (3H, s,

[Formula]) 5.17 (2H, s, -SO ₂ -O-CH ₂ =CO-) 7.37-8.03 (5H, m, benzene ring-H=) 10.33 (1H, s, -CO ₂ H=) Reference example 16 In the same manner as in Reference Example 14, 4-methanesulfonyloxy-3-oxo- 980 mg of 2-(syn)-ethoxyiminobutyric acid was obtained as a light brown oil. NMR (heavy acetone) δ _ppn 1.30 (3H, t, J=7.0,

[Formula]) 3.14 (3H, s, CH ₃ ==SO ₂ O−) 4.20 (3H, t, J = 7.0,

[Formula]) 5.20 (2H, s, -SO ₂ OCH ₂ ==CO-) 10.28 (1H, s, -CO ₂ H=) Example 1 4-paratoluenesulfonyloxy-3-oxo-2-(syn ) - Suspend 464 mg of methoxyiminobutyric acid in 20 ml of methylene chloride and cool to -5℃0.204
Add ml of triethylamine and stir for 5 minutes to form a solution. Add 0.71 ml of oxalyl chloride and 1 drop of dimethylformamide to this solution and heat at -5℃.
Stir for 20 minutes. When the solvent is distilled off, 4-paratoluenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid chloride is obtained. Meanwhile, 530 mg of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester paratoluenesulfonate was dissolved in 20 ml of methylene chloride and 0.394 ml of diethylaniline was added at -5°C. Furthermore, a solution prepared by dissolving the above acid chloride in 10 ml of methylene chloride is added. After stirring for 5 minutes at −5° C., the solvent is concentrated. The resulting residue was dissolved in ethyl acetate and washed with diluted hydrochloric acid. Dry over magnesium sulfate and concentrate to give a brown oil.
When this was separated and purified using silica gel column chromatography using cyclohexane-ethyl acetate as the developing solvent, 7-(4-p-toluenesulfonyloxy-
510 mg of 3-oxo-2-(syn)-methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester was obtained as a colorless foam. NMR (CDCl ₃ ) δ _ppn : 1.22 (9H, s, tert-Butyl) 2.43 (3H, s,

[Formula]) 3.30 (3H, s, 3rd position - OCH ₃ =) 3.51 (2H, s, 2nd position - CH ₂ = -) 4.10 (3H, s, N - OCH ₃ ) 4.27 (2H, s, 3rd position _-CH2 =-) 4.97 (1H, d, J=5.0, 6th position -H=) 5.07 (2H, s, _-SO2OCH2 =CO-) 5.53~ _5.97 (3H, m, 7th position -H= and ester -OCH ₂ O-) 7.20 to 7.93 (5H, m, 7-position -NH=- and benzene ring) Example 2 7-(4-paratoluenesulfonyloxy-3
-oxo-2-(syn)-methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (510 mg) was dissolved in 5 ml of ethanol to dissolve 76 mg of thiourea and 84 mg of acetic acid. Add sodium, add 3 ml of water little by little, and stir at room temperature for 3 hours and 30 minutes.
Ethanol was distilled off, and the residue was dissolved in ethyl acetate and washed with brine. Dry over magnesium sulfate and concentrate to give a pale brown foam. When this was separated and purified using silica gel column chromatography, 7-[2-(2
-aminothiazol-4-yl)-2-(syn)
-Methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester as a colorless foam 392
mg obtained. NMR (CDCl ₃ ) δ _ppn : 1.22 (9H, s, tert-Butyl) 3.30 (3H, s, 3rd position - OCH ₃ =) 3.53 (2H, s, 2nd position - CH ₂ =) 4.00 (3H, s,

[Formula]) 4.30 (2H, s, 3rd position -CH ₂ =-) 5.05 (1H, d, J = 5.0, 6th position -H=) 5.70-6.30 (5H, m, 7th position -H= and side chain -N
H ₂ = and -OCH ₂ =O- of the ester) 6.63 (1H, s, aminothiazole ring 5th position -
H=) 8.27 (1H, d, J=9.0, 7th position -NH=) Example 3 7-(4-paratoluenesulfonyloxy-3-oxo-2-(syn)) according to the method of Example 2
From 490 mg of methoxyiminobutyryl amino)-3-methoxymethyl-3-cephem-4-carboxylic acid propionyloxymethyl ester, 7-
370 mg of [2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide)-3-methoxymethyl-3-cephem-4-carboxylic acid propionyloxymethyl ester was obtained. NMR (CDCl ₃ ) δ _ppn 1.17 (3H, t) 2.41 (2H, q) 3.28 (3H, s) 3.51 (2H, q) 4.02 (3H, s) 4.27 (2H, s) 5.08 (1H, d) 5.6 ~6.2 (5H, m) 6.67 (1H, s) 8.10 (1H, d) Example 4 The following compound was obtained by the same reaction as in Example 2. A 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-
4-Carboxylic acid 1-ethoxycarbonyloxyethyl ester NMR (CDCl ₃ ) δ _ppn 1.30 (3H, t) 1.61 (3H, d) 3.32 (3H, s) 3.57 (2H, s) 4.03 (3H, s) 4.30 ( 2H, s) 4.21 (2H, q) 5.10 (1H, d) 5.6-6.2 (3H, m) 6.70 (1H, s) 6.92 (1H, q) 8.20 (1H, d) B 7-[2-(2 -aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-
4-Carboxylic acid isobutyloxymethyl ester NMR (CDCl ₃ ) δ _ppn 1.20 (6H, d) 2.66 (1H, septet) 3.21 (3H, s) 3.40 (2H, q) 4.01 (3H, s) 4.16 (2H, s ) 5.05 (1H, d) 5.6-6.2 (5H, m) 6.65 (1H, s) 8.06 (1H, d) C 7-[2-(2-aminothiazol-4-yl)-2-(syn)- Methoxyiminoacetamide]-3-ethoxymethyl-3-cephem-
4-Carboxylic acid pivaloyloxymethyl ester NMR (CDCl ₃ ) δ _ppn 1.19 (3H, t) 1.24 (9H, s) 3.49 (2H, q) 3.58 (2H, s) 4.06 (3H, s) 4.37 (2H , s) 5.07 (1H, d) 5.57 (2H, s) 5.88 (2H, s) 6.04 (1H, dd) 6.76 (1H, s) 7.90 (1H, d) D 7-[2-(2-aminothiazole -4-yl)-2-(syn)-ethoxyiminoacetamide]-3-methoxymethyl-3-cephem-
4-Carboxylic acid pivaloyloxymethyl ester NMR (CDCl ₃ ) δ _ppn 1.22 (9H, s) 1.31 (3H, t) 3.30 (3H, s) 3.53 (2H, s) 4.28 (2H, q) 4.30 (2H , s) 5.01 (1H, d) 5.7-6.2 (5H, m) 6.76 (1H, s) 7.70 (1H, d) Example 5 4-ethanesulfonyloxy-3-oxo-2
Dissolve 480 mg of -(syn)-methoxyiminobutyric acid in 20 ml of methylene chloride, cool to -5°C, add 0.263 ml of triethylamine, 0.22 ml of oxalyl chloride, and 1 drop of dimethylformamide, and stir at -5°C for 20 minutes. When the solvent is distilled off, 4-ethanesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid chloride is obtained. Separately, 690 mg of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester paratoluenesulfonate was dissolved in 20 ml of methylene chloride, and 0.51 ml of diethylaniline was added at -5°C. A solution of the above acid chloride dissolved in 10 ml of methylene chloride is added. After stirring for 10 minutes at -5°C, the solvent is concentrated. The resulting residue was dissolved in ethyl acetate and washed with diluted hydrochloric acid and water. Dry over magnesium sulfate and concentrate to give a brown foam. When this was separated and purified using silica gel column chromatography using cyclohexane-ethyl acetate as the developing solvent, a colorless foam was obtained.
632 mg of -oxo-2-(syn)-methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester was obtained. NMR (CDCl ₃ ) δ _ppn 1.22 (9H, s, t-Butyl) 1.43 (3H, t, J = 7.0, CH 3 CH ₂ SO ₂ O-) 3.27 ( _2H , q, J = 7.0, CH ₃ CH ₂ ==SO ₂ O-) 3.30 (3H, s, 3rd position - OCH ₃ ==) 3.54 (2H, bs, 2nd position - CH ₂ = -) 4.13 (3H, s, N-OCH ₃ =) 4.26 (2H , s, 3rd position -CH ₂ =-) 5.00 (1H, d, J = 5.0, 6th position -H) 5.27 (2H, s, -SO ₂ OCH ₂ =CO-) 5.60 - 5.97 (3H, m, 7 -H position and -OCH ₂ =O-) of ester 7.55 (1H, d, J = 9.0, 7th position -NH=-) Example 6 7-(4-ethanesulfonyloxy-3-oxo-2-(syn) )-methoxyiminobutyrylamino)-3-methoxymethyl-3-cefem-4-
Carboxylic acid pivaloyloxymethyl ester 632
Dissolve mg in 8 ml of ethanol and add 91 mg of thiourea.
Add 146 mg of sodium acetate, add 3 ml of water little by little, and stir at room temperature for 5 hours and 30 minutes. Ethanol was distilled off, and the residue was dissolved in ethyl acetate and washed with brine. Dry over magnesium sulfate and concentrate to give a brown foam. When this was separated and purified using silica gel column chromatography, the same compound as the compound obtained in Example 2, 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3, was obtained. 440 mg of -methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester was obtained as a colorless foam. Example 7 350 mg of 4-benzenesulfonyloxy-3-oxo-2-(syn)methoxyiminobutyric acid and pivaloyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate were prepared in the same manner as in Example 1. Oxymethyl ester paratoluene sulfonate
From 530 mg, 7-(4-benzenesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrylamino)-3-methoxymethyl-3-
510 mg of cefem-4-carboxylic acid pivaloyloxymethyl ester was obtained as a pale yellow foam. NMR (CDCl ₃ ) δ _ppn 1.22 (9H, s, t-Butyl) 3.30 (3H, s, 3rd position - OCH ₃ =) 3.52 (2H, bs, 2nd position - CH ₂ = -) 4.10 (3H, s,

[Formula]) 4.27 (2H, s, 3rd position - CH ₂ = -) 4.98 (1H, d, J = 5.0, 6th position - H =) 5.08 (2H, s, -SO ₂ OCH ₂ CO -) 5.60 ~ 5.90 (3H, m, 7-position -H= and ester -OCH ₂ O-) 7.40-8.03 (5H, m, bezene ring -H=) Example 8 7-(4-benzene) in the same manner as Example 2 From 510 mg of sulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester and 76 mg of thiourea.
7-[2-(2-aminothiazol-4-yl)
-2-(syn)-methoxyiminoacetamide)
-3-Methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester is 360mg
Obtained. Example 9 In the same manner as in Example 1, 440 mg of 4-methanesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyric acid and 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1 -isopropyloxycarbonyloxyethyl ester
From 370mg, 1-isopropyloxycarbonyloxyethyl 7-(4-methanesulfonyloxy-3-oxo-2-(syn)-methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid 480 mg of the ester was obtained as a pale yellow powder. NMR (CDCl ₃ ) δ _ppn 1.28 (6H, d, J = 6.0, ester

【formula】) 1.55 (3H, d, J=6.0, of ester)

[Formula]) 3.17 (3H, s, CH ₃ = SO ₂ O-) 3.30 (3H, s, 3rd position - OCH ₃ = -) 3.53 (2H, bs, 2nd position - CH ₂ = -) 4.13 (3H, s,

[Formula]) 4.24 (2H, s, 3rd position -CH ₂ = O-) 4.60 - 5.10 (2H, m, 6th position -H= and ester

[Formula] 5.23 (2H, s, -SO ₂ OCH ₂ = CO-) 5.77 (1H, dd, J = 5.0, J = 9.0, 7th position -
H=) 6.83 (1H, m, ester -CO ₂ CH= (CH ₃ )
O-) 7.58 (1H, d, J = 9.0, 7th position -NH = -) Example 10 In the same manner as in Example 2, 7-(4-methanesulfonyloxy-3-oxo-2-(syn)- methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid 1-isopropyloxycarbonyloxyethyl ester
From 480 mg and 152 mg of thiourea, 7-[2-(2-
Aminothiazol-4-yl)-2-(syn)-
390 mg of methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4-carboxylic acid 1-isopropyloxycarbonyloxyethyl ester was obtained as a colorless powder. NMR (CDCl ₃ ) δ _ppn 1.28 (6H, d, J = 6.0, − of ester
OCOOCH (CH ₃ =) ₂ ) 1.55 (3H, d, J = 6.0, − of ester
CO ₂ CH (CH ₃ =) O-) 3.27 (3H, s, 3rd position - OCH ₃ =) 3.53 (2H, bs, 2nd position - CH ₂ =) 3.97 (3H, s,

[Formula]) 4.30 (2H, s, 3rd position -CH ₂ = O-) 4.60 ~ 5.15 (2H, m, 6th position -H= and ester

[Formula]) 5.70-6.40 (3H, m, -H= at the 7th position and -NH ₂ = on the side chain thiazole ring) 6.61 (1H, s, -H= on the side chain thiazole ring) 8.23 (1H, d, J=9.0, 7th position -NH=-) Test Example After orally administering 50 mg/Kg (corresponding free carboxylic acid equivalent amount) of the target compound of the present invention to mice, the urinary recovery rate was measured for up to 24 hours. and obtained the following results.

【table】

Claims (1)

[Claims] 1 formula [In the formula, R ₁ is a phenyl group or a lower alkyl group that may have a substituent, R ₂ is a lower alkyl group, R ₃ is a formula -CH ₂ R ₅ (wherein, R ₅ is a lower alkoxy ), R ₄ is -CHR ⁶ OCOR ⁷ group (wherein R ⁶ represents a hydrogen atom or a methyl group, R ⁷
When R ⁶ is a hydrogen atom, it represents a lower alkyl group or a lower alkoxy group, and when R ⁶ is a methyl group, it represents a lower alkoxy group. ) is shown. ] A formula characterized by reacting a compound represented by ] with thiourea [In the formula, R ₂ R ₃ and R ₄ have the same meanings as described above. ] A method for producing a cephalosporin derivative represented by 2 formulas [In the formula, R ₁ represents a phenyl group or a lower alkyl group which may have a substituent, and R ₂ represents a lower alkyl group. ] Alkoxyiminobutyric acid or its reactive derivative in the carboxyl group and the formula [In the formula, R ₃ is the formula -CH ₂ R ₅ (in the formula, R ₅ represents a lower alkoxy group), R ₄ is the -CHR ⁶ OCOR ⁷ group (in the formula, R ⁶ is a hydrogen atom or a methyl group) and R ⁷
When R ⁶ is a hydrogen atom, it represents a lower alkyl group or a lower alkoxy group, and when R ⁶ is a methyl group, it represents a lower alkoxy group. ) is shown. ] by reacting with a 7-aminocephalosporin derivative represented by the formula [In the formula, R ₁ , R ₂ , R ₃ and R ₄ have the same meanings as described above. ] to produce a compound represented by
A formula characterized by reacting the compound with thiourea [In the formula, R ₂ , R ₃ and R ₄ have the same meanings as described above. ] A method for producing a cephalosporin derivative represented by