JPS64399B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula () The present invention relates to pivaloyloxymethyl ester of 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino[syn isomer]acetamido]desacetoxycephalosporanic acid. As a result of research, the present inventors found that pivaloyloxymethyl ester of the compound represented by the above formula () exhibits high antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria, and completed the present invention. Cephalosporanic acid represented by the formula () is Although it is thought to have a tautomeric structure of a 2-aminothiazole body and a 2-iminothiazoline body, the thiazole type is described in this specification. The carboxyl group at the 4-position of the compound represented by the formula () is a biologically active ester derivative that has the effect of increasing blood concentration and prolonging the effective time. Valoyloxymethyl is used. The pivaloyloxymethyl ester of the compound () of the present invention can be administered in the form of capsules, tablets, or granules, similar to known cephalosporin agents or penicillin agents. That is, the pivaloyloxymethyl ester of compound () is derived from Escherichia coli, Serratia marcescens, Proteus rettgeri, Enterobacter cloacae,
Citrobacter freundii
It is a new compound that exhibits excellent antibacterial activity against a wide range of bacteria, including Gram-negative bacteria such as A. freundii), and is resistant to β-lactamase. When pivaloyloxymethyl ester of compound () is used as a therapeutic agent for infectious diseases, it can be used in humans and mice against infectious diseases caused by the aforementioned microorganisms, such as intraperitoneal infections, respiratory infections, and urinary tract infections. , 0.5 to 80 mg/kg body weight of mammals including rats.
It can be safely administered in doses of 1 to 20 mg/day, more preferably 1 to 20 mg/day, divided into 3 to 4 times a day. The dosage form for administration includes, for example, capsules, powders, granules, and tablets manufactured by methods known per se, and can be administered parenterally or orally. When used as capsules, powders, granules, and tablets, for example, known pharmaceutically acceptable excipients (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (starch,
gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), lubricants (e.g. magnesium stearate,
talc, etc.) and a disintegrant (e.g. carboxymethylcalcium, talc, etc.). Compound () is produced according to a method known per se. That is, for example, cephalosporanic acid represented by the formula () is expressed by the formula () 7- represented by [in the formula, R ₁ has the same meaning as above]
Aminocephalosporin derivatives and formula () 2-aminothiazole-4 represented by [In the formula, R ₂ NH represents an optionally protected amino group]
-yl-2-methoxyimino (syn isomer) It is produced by reacting with acetic acid and acylating the amino group at the 7-position of the compound (). In this method, the compound () is used in its free form or its reactive derivative is used as an acylating agent for the amino group at the 7-position of the compound (). That is, as the free acid () or its salt with an alkali or alkaline earth metal such as sodium, potassium or calcium, or with an organic amine such as trimethylamine or pyridine, or as its acid halide (e.g. acid chloride, acid chloride, etc.). A carboxylic acid represented by the general formula () is subjected to an acylation reaction as a reactive derivative such as bromide), acid anhydride, mixed acid anhydride, activated amide, or active ester. Examples of activated esters include p-nitrophenyl ester, 2,4-dinitrophenyl ester,
Pentachlorphenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, etc. are used. As mixed acid anhydrides, mixed anhydrides with carbonic acid monoesters such as carbonic monomethyl ester and carbonic monoisobutyl ester, and mixed anhydrides with lower alkanoic acids which may be substituted with halogen such as pivalic acid and trichloroacetic acid are used. It will be done. carboxylic acid()
When used in the form of free acid or salt, a suitable condensing agent is used. Examples of condensing agents include N,
N,N'-substituted carbodiimides such as N'-dicyclohexylcarbodiimide, azolide compounds such as N,N'-carbonylimidazole, N,N'-thionyldiimidazole, N-ethoxycarbonyl-2-ethoxy-1, Dehydrating agents such as 2-dihydroquinoline, phosphorus oxychloride, and alkoxyacetylene, 2-halogenopyridinium salts (eg, 2-chloropyridinium methyl iodide, 2-fluoropyridinium methyl iodide), and the like are used. When these condensing agents are used, the reaction is thought to proceed via reactive derivatives of carboxylic acids (). The reaction is generally carried out in a suitable solvent. As such solvents, halogenated hydrocarbons such as chloroform and methylene dichloride, ethers such as tetrahydrofuran and dioxane, dimethylformamide, dimethylacetamide, acetone, water, etc., or mixtures thereof are often used. The amount of acylating agent () used is
The amount is usually about 1 to several mol per 1 mol of the compound (). The reaction is generally carried out at a temperature of -50°C to 40°C. Note that R ₂ represents a hydrogen atom or a protecting group for an amino group, and as the protecting group for the amino group, any known protecting group that is generally used as a protecting group for an amino group can be used, such as phthaloyl, benzoyl, Chlorobenzoyl, p-
Benzoyl substituted with halogen, nitro or lower alkyl having 1 to 4 carbon atoms such as nitrobenzoyl, p-tert-butylbenzoyl, toluoyl, naphthoyl, phenylacetyl, phenoxyacetyl, benzenesulfonyl, p-tert-butyl Aromatic acyl groups such as lower alkyl substituted benzenesulfonyl having 1 to 4 carbon atoms such as benzenesulfonyl and toluenesulfonyl, camphorsulfonyl, methanesulfonyl, acetyl, valeryl, caprylyl, n-decanoyl, acryloyl, pivaloyl, halogenoacetyl (e.g. , monochloroacetyl, monobromoacetyl, dichloroacetyl,
aliphatic or halogenated aliphatic carboxylic acid acyl groups such as (trichloroacetyl), ethoxycarbonyl, tert-butyloxycarbonyl, isobornioxycarbonyl, phenyloxycarbonyl,
Esterified carboxyl groups such as trichloroethoxycarbonyl and benzyloxycarbonyl, carbamoyl groups such as methylcarbamoyl, phenylcarbamoyl, and naphthylcarbamoyl, or similar thiocarbamoyl groups are used, but after the main acylation reaction, if necessary, The protective group can be removed by Removal of the protecting group for the amino group is generally carried out by methods known per se (for example, the method disclosed in Japanese Patent Application Laid-Open No.
50−52083, Pure and Applied
Chemistry Vol. 7, p. 335 (1963) [Pure
and Applied Chemistry, 7 , 335 (1963)] or a method analogous thereto). Further, the reaction for separating a monohalogenoacetyl group from an amino group is carried out by reacting a compound of general formula () whose amino group is protected with a monohalogenoacetyl group, thiourea, and a basic substance. This reaction is usually carried out in a solvent at around room temperature and is often completed within one to several hours. Any solvent may be used as long as it does not inhibit this reaction. For example, ethers such as ethyl ether, tetrahydrofuran, and dioxane, lower alcohols such as methanol and ethanol, halogenated hydrocarbons such as chloroform and methylene dichloride, esters such as ethyl acetate and butyl acetate, acetone,
Examples include ketones such as methyl ethyl ketone, water, etc., or mixtures thereof. As the basic substance, an alkali or alkaline earth metal salt of a lower aliphatic carboxylic acid and an inorganic or organic base having a pka of 9.5 or more, more preferably a pka of 9.8 to 12.0 are used for the purpose of this reaction. Examples of lower aliphatic carboxylates include sodium acetate, potassium acetate, calcium acetate, barium acetate, sodium formate,
Lower aliphatic carboxylates having 1 to 6 carbon atoms such as sodium propionate and potassium hexanoate; Examples of inorganic bases include alkali metal salts of carbonic acid such as sodium carbonate and potassium carbonate; Examples of organic bases include trimethylamine and triethylamine. , ethylamine, methylamine, diethylamine, dimethylamine, tributylamine,
Dibutylamine, butylamine, etc. with 1 or more carbon atoms
4 lower alkyl mono-, di- or tri-substituted amines, and 5-6 N-lower alkyl substituted with 1 to 2 carbon atoms, such as N-methylpyrodine, N-ethylpyrrolidine, N-methylpiperazine, N-ethylpiperazine, etc. Examples include cyclic amines. Thiourea is used in this reaction as described above, but N- or N,N-substituted thiourea, such as methylthiourea, N,N-diethylthiourea,
It is also possible to use N,N-hexamethylenethiourea. The cefem compound () obtained by the production method detailed above can be purified by known processing means such as column chromatography, extraction method, precipitation method, recrystallization method, etc. It can be converted into baloyloxymethyl ester by methods known per se. The 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) derivative (2), which is the raw material compound of the present invention, can be produced, for example, by the method of the following reference example. The compound of the general formula () of the present invention is, for example,
West German Patent Application No. 2461478, West German Patent Application No. P2607064.4 (Dutch Application No.
7601902), West German Patent Application No. P2619243.8,
Japanese Patent Application Publication No. 50-52083, Japanese Patent Application No. 51-42885,
It can be produced by an appropriate method selected from the methods described in West German Application Nos. 2460331 and 2460332, or a method analogous to these methods. Reference Example 1 Add 10 g of ethyl 3-oxo-2-hydroxyiminobutyrate to a solution of 13.3 g of sodium carbonate dissolved in 120 ml of water, dissolve, add 30 ml of methanol, and cool on ice. Add 15.8g of dimethyl sulfate to this while stirring.
was added dropwise for 3 minutes, and after the addition was completed, the ice bath was removed and the mixture was left at room temperature.
Stir for 40 minutes. The reaction product (PH8 or higher) was extracted twice with ethyl acetate, the combined extracts were washed with water, dried, and then the solvent was distilled off under reduced pressure.The residue was subjected to vacuum distillation.
Boiling point of ethyl oxo-2-methoxyiminobutyrate
Obtained as a pale yellow oil, 0.3-0.4 mmHg, 56-61°C. 9g Elemental analysis value C ₇ H ₁₁ NO ₄ Calculated value C48.54; H6.40; N8.08 Actual value C48.41; H6.51; N7.96 NMR spectrum (60MHz, in CDCl ₃ ): 2.40ppm (3H , singlet,
CH ₃ CO), 4.10ppm (3H, singlet, = NOCH ₃ ) Reference example 2 (1) Ethyl 3-oxo-2-methoxyiminobutyrate
Dissolve 27.3 g in 120 ml of chloroform, warm to 40°C, and dropwise add a solution of 25.3 g of bromine dissolved in 30 ml of chloroform over 30 minutes. Thereafter, the mixture is stirred at room temperature for 1 hour to react. The reaction product was washed with a 5% aqueous sodium hydrogen carbonate solution and then with water, and the organic layer was dried. The solvent was distilled off under reduced pressure and 4-
Ethyl bromo-3-oxo-2-methoxyiminobutyrate is obtained as an oil. 36.2g NMR spectrum (60MHz, in CDCl ₃ ): 4.16ppm (3H, singlet,
OCH ₃ ), 4.36 ppm (2H, singlet, BrCH ₂ CO) (2) Dissolve 5 g of this product in 20 ml of ethanol, add 1.8 g of thiourea, and heat under reflux for 3 hours.
After cooling, the precipitate is collected by filtration, added to 20 ml of water and sodium bicarbonate, and the oily substance separated is extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the ethyl acetate is distilled off to obtain white crystals. Recrystallization from ethanol gives ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (anti-isomer) in the form of white crystals.
2.6g (57.2%) Melting point 114-115℃ Elemental analysis value C ₈ H ₁₁ N ₃ O ₃ S Calculated value C41.91; H4.84; N18.33 Actual value C41.71; H4.75; N18.07 NMR Spectrum (60MHz, in CDCl ₃ ): 4.07ppm (3H, singlet, OCH ₃ ),
5.80ppm (2H, broad singlet, NH ₂ ), 7.43ppm (1H, singlet, thiazole) 5-
H) (3) First, the precipitate was collected by filtration, the filtrate was concentrated under reduced pressure, sodium hydrogen carbonate was added to the residue, extracted with ethyl acetate, and the oil obtained from the ethyl acetate layer was purified by silica gel chromatography. 2-(2
Ethyl -aminothiazol-4-yl)-2-methoxyiminoacetate (syn isomer) is obtained in the form of white crystals. 59mg (1.3%) Melting point 163-164℃ Elemental analysis value C ₈ H ₁₁ N ₃ O ₃ S Calculated value C41.91; H4.84; N18.33 Actual value C41.57; H4.76; N18.07 NMR spectrum (60MHz, CDCl ₃ ): 4.02ppm (3H, singlet, OCH ₃ ),
5.80ppm (2H, broad singlet, NH ₂ ), 6.74ppm (1H, singlet, thiazole 5-H) Reference example 3 Ethyl 4-chloro-3-oxo-2-hydroxyiminoacetate 121g, thiourea Add 47.6 g to 600 ml of ethanol and stir at room temperature for 3 hours. Ethanol was distilled off under reduced pressure, 350 ml of water was added, and the aqueous layer was washed with ether, neutralized with sodium hydrogen carbonate (PH7.5), and extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1). After washing the organic layer with water and drying, the solvent was distilled off to obtain 45 g of a crystalline substance. Take 1 g of this product and purify it by silica gel chromatography (developing solution: ethyl acetate, n-hexane mixture). 650 mg of the anti-isomer of ethyl acetate and 150 mg of the syn-isomer of the same compound are obtained from the latter part. Anti isomer White crystals, melting point 145.3℃ Syn isomer Slightly yellowish white crystals, melting point 185.5℃ Elemental analysis C ₇ H ₉ N ₃ O ₃ S Calculated value C39.06; H4.21; N19.52 Actual value Anti isomer C38.81; H4.20; N19.62 Syn form C39.28; H4.10; N19.63 NMR spectrum (60 MHz, d _{6 -} in DMSO): Anti isomer; 7.10 ppm (2H, broad singlet, NH ₂ ), 7.50ppm (1H, singlet thiazole 5-H), 12.5ppm (1H, singlet, OH); syn isomer 6.80ppm (1H, singlet, thiazole 5-H), 7.12ppm
(2H, broad singlet, NH ₂ ),
11.6ppm (1H, singlet, OH) Reference example 4 Dissolve 10.6g of sodium carbonate in 150ml of water, add 2-(2-aminothiazol-4-yl)-
A solution of 10.7 g of ethyl 2-hydroxyiminoacetate (syn isomer) dissolved in a mixture of 150 ml of tetrahydrofuran and 50 ml of methanol was added, and 12.6 g of dimethyl sulfate was added dropwise over 5 minutes under ice-cooling. After the addition was complete, the ice bath was removed and the temperature was left at room temperature. Stir with During this time, a white crystalline substance begins to precipitate. After 3 hours, most of the organic solvent was distilled off under reduced pressure, the residue was cooled with ice, and the precipitate was collected by filtration.
Washed with water, dried and 2-(2-aminothiazole-4)
-yl)-2-methoxyiminoacetate (syn isomer) is obtained in the form of white crystals. 5.7g The NMR spectrum of this product matched that of ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (syn isomer) obtained in Reference Example 2. Reference example 5 2-(2-aminothiazol-4-yl)-2
-Ethyl methoxyiminoacetate (syn isomer, melting point
163-164℃) was dissolved in 10 ml of N,N-dimethylacetamide, and diluted with chloroacetic acid chloride under ice cooling.
Drop 1.27g. Cool on ice for 30 minutes, then at room temperature for 30 minutes.
After stirring for a minute, add 50ml of water and add 100ml each of ethyl acetate.
Extract twice with ml. The combined extracts were washed with a 5% aqueous sodium hydrogen carbonate solution and then with saturated saline.
The mixture is dried and the solvent is distilled off to obtain ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetate (syn isomer) in crystal form.
2.04g Melting point 111-112℃ Elemental analysis value C ₁₀ H ₁₂ N ₃ O ₄ SCl Calculated value C39.29; H3.96; N13.74 Actual value C39.15; H3.91; N13.69 NMR spectrum (60MHz, (in CDCl ₃ ): 4.00ppm (3H, singlet, = NOCH ₃ ),
4.24ppm (2H, singlet, ClCH ₂ CO),
7.15ppm (1H, singlet, thiazole 5-
H) Reference example 6 2-(2-chloroacetamidothiazole-4
Add 9.62 g of ethyl)-2-methoxyiminoacetate (syn isomer) to a solution of 9 g of potassium hydroxide in a mixture of 85 ml of water and 452 ml of ethanol.
Stir at room temperature for 2 hours. Ethanol was distilled off under reduced pressure, 85 ml of water was added, and the mixture was washed with 100 ml of ethyl acetate. The aqueous layer was adjusted to pH 2 with 10% hydrochloric acid and extracted twice with 200 ml of ethyl acetate each. The combined extracts are washed with saturated brine, dried, and the solvent is distilled off to obtain 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) in crystal form. 7.63
g Melting point 170-171℃ Elemental analysis value C ₈ H ₃ N ₃ O ₄ SCl Calculated value C34.60; H2.90; N15.13 Actual value C34.97; H3.03; N14.74 NMR spectrum (60MHz, d ₆ - in DMSO): 3.95ppm (3H, singlet, = _NOCH3 ),
4.40ppm (2H, singlet. ClCH ₂ CO),
7.57ppm (1H, singlet, thiazole 5
-H) Reference example 7 2-(2-aminothiazol-4-yl)-2
2-(2-chloroacetamidothiazol-4-yl) obtained by chloroacetylating 2.38 g of the syn- and anti-isomer mixture (7:8) of ethyl methoxyiminoacetate (7:8) with chloroacetic acid chloride in the same manner as in Reference Example 5. ) Add 30 ml of ether to the syn- and anti-isomer mixture of ethyl 2-methoxyiminoacetate and filter the precipitated crystals [Product (A)]. This product is 2-(2-chloroacetamidothiazole-4
-yl)-2-methoxyiminoacetate ethyl isomer obtained in Reference Example 5 and the NMR spectrum etc. matched. 600 mg The oil obtained by concentrating the filtrate (2.42 g, syn-anti isomer mixture) was mixed with 5 ml of water and 80 ml of ethanol.
Add 879 mg of potassium hydroxide to a solution of 879 mg of potassium hydroxide under ice-cooling, and stir at that temperature for 15 minutes. Ethanol was distilled off under reduced pressure, 50 ml of water was added to the residue, and the mixture was extracted twice with 100 ml each of ethyl acetate. After washing the ethyl acetate layer with water and drying, ethyl acetate was distilled off to give 2-(2
-Chloroacetamidothiazol-4-yl)-
Ethyl 2-methoxyiminoacetate (syn isomer) is obtained [product (B)]. 577mg The NMR spectrum of this product matched that of the syn isomer obtained in Reference Example 5. The total of products (A) and (B) was 1076 mg, and the recovery rate was
96.8% Reference Example 8 Dissolve 1.5 g of ethyl 4-bromo-3-oxo-2-methoxyiminobutyrate in 10 ml of tetrahydrofuran, add 7 ml of water, add 2.4 g of sodium acetate trihydrate and 0.9 g of thiourea, and leave at room temperature. Stir for 17 hours. Add dilute hydrochloric acid to the concentrated solution under reduced pressure to adjust the pH to approx.
1.5, washed with ethyl acetate, neutralized by adding sodium bicarbonate to the aqueous layer, extracted with ethyl acetate, washed the ethyl acetate layer with water, dried and concentrated under reduced pressure to obtain yellowish crystals. 0.8g This product is the syn isomer of ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate. The NMR spectrum of this product matched that of the syn isomer obtained in Reference Example 2. Reference example 9 4-bromo-3- in 10ml of dimethylformamide
Dissolve 2 g of ethyl oxo-2-methoxyiminobutyrate, add 1.2 g of thiourea, and react at room temperature for 5 hours. Add 20ml of saturated saline to the reaction solution,
Then, dilute hydrochloric acid was added to adjust the pH to about 1.5, and the following treatment was carried out in the same manner as in Reference Example 8 to obtain yellowish crystals. 1.1g This product is found to be a mixture of 87 syn isomers and 13 anti-isomers of ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate based on NMR spectra. By washing this product with a small amount of ether, the syn isomer containing substantially no anti isomer can be obtained. Reference example 10 Add 38 g of sodium nitrite and 53 g of methyl acetoacetate to 200 ml of water, and add 4N-sulfuric acid to this while stirring on ice.
Add 200ml dropwise over approximately 1 hour. During this time, the temperature of the reaction solution is maintained at 5 to 8°C. After further stirring in this temperature range for 2.5 hours, the mixture was extracted twice with 300 ml of ethyl acetate each time, and the extract was washed twice with saturated brine. Next, a solution prepared by dissolving 96.7 g of sodium carbonate in 1 part water is divided into 3 parts, and methyl 3-oxo-2-hydroxyiminobutyrate is extracted from the ethyl acetate layer (3 times). Add 200ml of methanol to the aqueous layer (1), cool on ice, and add 150g of dimethyl sulfate to this while stirring.
Drop for 10 minutes. After completing the dropwise addition, stir at room temperature for 1.5 hours, extract twice with 300 ml each of ethyl acetate, wash with water,
After drying, ethyl acetate is distilled off and the residue solidifies when cooled with ice. This is collected by filtration and washed with a small amount of water to obtain methyl 3-oxo-2-methoxyiminobutyrate in the form of white crystals. 52.3g Melting point 64.4℃ Elemental analysis value C ₆ H ₉ NO ₄ Calculated value C45.28; H5.70; N8.80 Actual value C44.93; H5.61; N8.71 NMR spectrum (60MHz, in CDCl ₃ ): 2.40ppm (3H, singlet

[Formula]), 3.86ppm (3H, singlet, COOCH ₃ ),
4.10ppm (3H, singlet, = NOCH ₃ ) Reference example 11 Methyl 3-oxo-2-methoxyiminobutyrate 40
Dissolve g in 150 ml of chloroform, heat to 40℃,
A solution prepared by dissolving 40 g of bromine in 50 ml of chloroform is added dropwise to this solution over an hour. Thereafter, the mixture is stirred at room temperature for 1 hour to react. The reaction product was washed with a 5% aqueous sodium hydrogen carbonate solution and then with water, and the organic layer was dried. The solvent was distilled off under reduced pressure to obtain methyl 4-bromo-3-oxo-2-methoxyiminobutyrate as an oil. 52.1g NMR spectrum (60MHz, in _CDCl3 ); 3.82ppm (3H, singlet, _COOCH3 ),
4.09ppm (3H, singlet, =N- _OCH3 ),
4.27ppm (2H, singlet, BrCH ₂ CO) 4-Brom-3- in 350ml of tetrahydrofuran
Dissolve 52 g of methyl oxo-2-methoxyiminobutyrate, add 250 ml of water, then add 89.1 g of sodium acetate trihydrate and 33.2 g of thiourea and let it cool at room temperature.
Stir and react for 18 hours. Add 200 ml of 5% aqueous sodium hydrogen carbonate solution to the reaction mixture, and extract with ethyl acetate. After washing the organic layer with water and drying, the solvent is distilled off under reduced pressure. 200 ml of ether is added to the resulting residue, and the precipitated crystals are collected by filtration. Methyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (syn isomer) is obtained in crystalline form. 24.8g melting point
164.9℃ Elemental analysis value C ₇ H ₉ N ₃ O ₃ S Calculated value C39.06; H4.21; N19.52 Actual value C38.78; H4.15; N19.33 NMR spectrum (60MHz, in CDCl ₃ ); 3.84ppm (3H, singlet, COOCH ₃ ),
4.02ppm (3H, singlet, = _NOCH3 ),
5.74ppm (2H, broad singlet,
NH ₂ ), 6.74ppm (1H, singlet, thiazole 5-H) Reference example 12 2-(2-aminothiazol-4-yl)-2
-Methyl methoxyiminoacetate (syn isomer) 21.5
g was dissolved in 90 ml of N,N-dimethylacetamide, and 13.6 g of chloroacetic acid chloride was added dropwise thereto under ice cooling. After stirring for 30 minutes under ice cooling and then for 30 minutes at room temperature, 500 ml of water was added and extracted twice with ethyl acetate. The extracted layer is washed with a 5% aqueous sodium bicarbonate solution, then with water, and then dried. The solvent was distilled off to give 2-(2-chloroacetamidothiazole-4-
Methyl)-2-methoxyiminoacetate (syn isomer) is obtained in crystalline form. 25g Melting point 130.8℃ Elemental analysis value C ₉ H ₁₁ N ₃ O ₄ SCl Calculated value C37.05; H3.45; N14.40 Actual value C37.30; H3.40; N14.35 NMR spectrum (60MHz, in CDCl ₃ ); 3.90ppm (3H, singlet, COOCH ₃ ),
4.02ppm (3H, singlet, = _NOCH3 ),
4.26ppm (2H, singlet, ClCH ₂ CO),
7.24ppm (1H, singlet, thiazole 5
-H) Reference example 13 2-(2-chloroacetamidothiazole-4
Add 20g of methyl 2-methoxyiminoacetate (syn isomer) to a solution of 19.2g of potassium hydroxide in a mixture of 170ml of water and 900ml of ethanol,
Stir at room temperature for 2 hours. Ethanol was distilled off under reduced pressure, 170 ml of water was added, and the mixture was washed with 200 ml of ethyl acetate. The aqueous layer was adjusted to pH 2 with 10% hydrochloric acid and extracted twice with 300 ml of ethyl acetate each. The combined extracts are washed with saturated brine, dried, and the solvent is distilled off to obtain 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) in crystal form. 16.8
gThe NMR spectrum of this product matched that obtained in Reference Example 6. Reference example 14 (1) 833 mg of 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) in 10 ml of tetrahydrofuran, N-
Add 380 mg of hydroxysuccinimide and 630 mg of dicyclohexylcarbodiimide, and stir at room temperature for 45 minutes. Remove the precipitated urea and heat at 5°C.
Cool to 7-aminodesacetoxycephalosporanic acid 650mg, bis(trimethylsilyl)
2 ml of acetamide are dissolved in 12 ml of methylene dichloride and poured into the cooled solution. After stirring overnight at room temperature, the solvent was distilled off under reduced pressure. To the resulting oil, 50 ml of water and 50 ml of ethyl acetate were added, and the mixture was diluted with 1N hydrochloric acid.
After adjusting the pH to approximately 2.5 and separating the two layers, the mixture is further extracted twice with 50 ml each of ethyl acetate. The ethyl acetate layer was washed with water and dried, and the ethyl acetate was distilled off to give 7-
[2-(2-chloroacetamidothiazole-
4-yl)-2-methoxyiminoacetamido]desacetoxycephalosporanic acid (syn isomer) is obtained as an oil. 1.1g (2) Dissolve the entire amount of this product in 25ml of tetrahydrofuran, add thiourea, then sodium acetate trihydrate.
Add 632 mg and stir at room temperature for 4 hours. The precipitate was collected by filtration, washed with ether, dissolved in 10 ml of water, added with sodium bicarbonate to adjust the pH to approximately 7.0, and purified by passing through an Amberlite XAD-2 column. Sodium aminothiazol-4-yl)-2-methoxyiminoacetamide]desacetoxycephalosporanate (syn isomer) is obtained in the form of a white powder. 120mg Elemental analysis value C ₁₄ H ₁₄ N ₅ O ₅ S ₂ Na・1.5H ₂ O Calculated value C37.67; H3.84; N15.68 Actual value C37.37; H3.98; N15.38 NMR spectrum (60MHz , in D ₂ O): 1.94 ppm (3H, singlet, 3-CH ₃ ),
3.46ppm (2H, quartet, 2-CH ₂ ),
4.00ppm (3H, singlet, = NOCH ₃ ),
5.17ppm (1H, double rate 6-H),
5.76ppm (1H, doublet, 7-H),
6.99ppm (1H, singlet, thiazole 5
-H) Reference example 15 (1) 2-(2-chloroacetamidothiazole-
277 mg of 4-yl)-2-methoxyiminoacetic acid (syn isomer) and 270 mg of 7-aminodesacetoxycephalosporanic acid t-butyl ester were dissolved in 20 ml of tetrahydrofuran, 206 mg of dicyclohexylcarbodiimide was added thereto, and the mixture was stirred at room temperature for 6 hours. Stir and react. The filtrate obtained by filtering off the precipitated urea is poured into 50 ml of water and extracted with ethyl acetate. The ethyl acetate layer was treated with 0.5N hydrochloric acid,
After washing with water and saturated saline, dry and concentrate.
[2-(2-chloroacetamidothiazole-
4-yl)-2-methoxyiminoacetamide]desacetoxycephalosporanic acid t-butyl ester (syn isomer) is obtained as an oil. 320mg NMR spectrum (60MHz, in CDCl ₃ ): 1.53ppm (9H, singlet, t-C ₄ H ₉ ),
2.13ppm (3H, singlet, 3-CH ₃ ),
3.39ppm (2H, quartet, 2-CH ₂ ),
4.06ppm (3H, singlet, = _NOCH3 ),
4.29ppm (2H, singlet, ClCH ₂ CO),
5.06ppm (1H, doublet, 6-H),
5.86ppm (1H, doublet of doublet, 7-
H), 7.20ppm (1H, singlet, thiazole 5-H), 8.14ppm (1H, doublet,
7-CONH) (2) Dissolve the entire amount of this product in 12 ml of tetrahydrofuran, add 100 mg of thiourea, and 200 mg of sodium acetate trihydrate.
mg was added to this and stirred at room temperature for 8 hours. Add 30 ml of water to the reaction solution and extract with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated, and the resulting oil was purified by silica gel chromatography to obtain 7-
[2-(2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] desacetoxycephalosporanic acid t-butyl ester (syn isomer) is obtained in powder form. 128mg NMR spectrum (60MHz, in CDCl ₃ ): 1.52ppm (9H, singlet, t-C ₄ H ₉ ),
2.10ppm (3H, singlet, 3-CH ₃ ),
3.40ppm (2H, quartet, 2-CH ₂ ),
4.00ppm (3H, singlet, = NOCH ₃ ),
5.05ppm (1H, doublet, 6-H),
5.98ppm (1H, doublet of doublet, 7-
H), 6.66ppm (1H, singlet, thiazole 5-H), 8.28ppm (1H, doublet,
7-CONH) (3) Dissolve the entire amount of this product in a mixture of 1 ml of trifluoroacetic acid and 0.1 ml of anisole, stir at room temperature for 1.5 hours, add ether, collect the precipitated powdery substance by filtration, wash with ether, and prepare 7-CONH). [2-(2-
aminothiazol-4-yl)-2-methoxyiminoacetamide] desacetoxycephalosporanic acid trifluoroacetate (syn isomer)
is obtained in powder form. 70mg The NMR spectrum of this product (60MHz, in D ₂ O containing NaHCO ₃ ) matched that obtained in Reference Example 14. MIC (μg/ml) of the compound obtained in Reference Example 14
For example:

【table】

[Table] Reference example 16 (1) Suspend 5.54 g of 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) in 70 ml of methylene chloride, and add 2.42 g of triethylamine to this. Comb it.
Add 4.16 g of phosphorus pentachloride to this solution all at once while stirring on ice. After 5 minutes, remove the ice bath and continue stirring at room temperature for 20 minutes, then concentrate under reduced pressure. To the resulting residue, add 150 ml of hexane and decant (2
times). Add 90 ml of anhydrous tetrahydrofuran and filter off the precipitated triethylamine hydrochloride.
A solution of (2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid chloride in tetrahydrofuran is obtained. Separately, 4.28 g of 7-aminodesacetoxycephalosporanic acid (7-ADCA) is suspended in a mixture of 50 ml of water and 50 ml of tetrahydrofuran, and 4.44 g of triethylamine is added thereto under ice cooling to completely dissolve. Add the acid chloride solution obtained earlier to this under ice cooling.
It was added dropwise over 15 minutes, and after further stirring at room temperature for 2 hours, saturated saline was added, and diluted hydrochloric acid was added to adjust the pH to about 2.
and extract with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to obtain 8 g of a yellowish white powder. Add 50ml of methanol to this, wash it, filter out the insoluble matter, and
-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]desacetoxycephalosporanic acid (syn isomer) is obtained in the form of a white powder. 4.6g. NMR spectrum (60MHz, _d6- in DMSO): 2.04ppm (3H, singlet, 3H- _CH3 ),
3.50ppm (2H, broad singlet, 2
―CH ₂ ), 3.92ppm (3H, singlet,
OCH ₃ ), 4.40ppm (2H, singlet,
ClCH ₂ CO), 5.18ppm (1H, doublet, 6
-H), 5.78ppm (1H, doublet x 2.7-
H), 7.50ppm (1H, singlet, thiazole 5-H) (2) This product was subjected to the same reaction treatment as described in Reference Example 14-(2) to obtain 7-[2-(2-aminothiazole 5-H). -4-yl)-2-methoxyiminoacetamide] sodium desacetoxycephalosporanate (syn isomer) is obtained in the form of a white powder. The NMR spectrum of this product matched that obtained in Reference Example 14. Example 1 2.8 g of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide] desacetoxycephalosporanate (syn isomer) was suspended in 25 ml of dimethylformamide and cooled on ice. Add to this 3.75g of iodomethyl pivalate.
and wash with 3 ml of dimethylformamide. 17
After a few minutes, 100 ml of ethyl acetate was added to the reaction solution, insoluble materials were removed by filtration, and the filtrate was washed with water, a 5% aqueous sodium bicarbonate solution, and then saturated brine, and then dried over magnesium sulfate. The oil (2.4 g) obtained by distilling off ethyl acetate was purified by silica gel chromatography to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]desacetoxy. Pivaloyloxymethyl cephalosporanate (syn isomer) is obtained in the form of a white powder. 1g. Elemental analysis value C ₂₀ H ₂₅ N ₅ O ₇ S ₂ Calculated value C, 46.95; H, 4.92; N, 13.69 Actual value C, 46.92; H, 4.88; N, 13, 13 NMR spectrum (60 MHz, in CDCl ₃ ) : 1.24ppm (9H, singlet, -C( _CH3 ) ₃ ),
2.16ppm, 3.44ppm (2H, doublet, 2-
CH ₂ ), 4.10ppm (3H, singlet,
OCH ₃ ), 5.16ppm (1H, doublet, 6-
H), 5.94ppm (2H, singlet, -
OCH ₂ O), 6.86ppm (1H, singlet, thiazole, 5-H) Example 2 7- obtained by the method described in Reference Example 16-(1)
[2-(2-chloroacetamidothiazole-4
-yl)-2-methoxyiminoacetamide] desacetoxycephalosporanic acid (syn isomer)
Add 0.7 g to ice-cooled dimethylformamide (7 ml) containing 149 mg of triethylamine and dissolve. Add 715 mg of iodomethyl pivalate to this and stir for 15 minutes to react. Add 40 ethyl acetate to this
ml, water, 5% sodium bicarbonate aqueous solution,
Then, it is washed with saturated saline and dried over magnesium sulfate. Ethyl acetate was distilled off to obtain crude 7-[2-
(2-chloroacetamidothiazol-4-yl)
-2-methoxyiminoacetamide] pivaloyloxymethyl desacetoxycephalosporanate (syn isomer) is obtained as a brown oil. 0.8g. Dissolve this product in 3 ml of dimethylacetamide, add 206 mg of thiourea, and stir at room temperature overnight. Add 40 ml of ethyl acetate to this, and add 30 ml each of saturated saline to
After washing twice, dry with magnesium sulfate. The brown oil (0.4 g) obtained by distilling off ethyl acetate was purified by silica gel chromatography to give 7-[2-
(2-Aminothiazol-4-yl)-2-methoxyiminoacetamide] desacetoxycephalosporanate pivaloyloxymethyl (syn isomer) is obtained in the form of a white powder. 0.2g. The NMR spectrum of this product matched that obtained in Example 1.

Claims (1)

[Claims] 1 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]desacetoxycephalosporanate pivaloyloxymethyl (syn isomer).