JPH0338277B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 7-substituted-3-vinylcephalosporanic acids and salts thereof. More specifically, the present invention provides novel 7-substituted-3-vinylcephalosporanic acid derivatives having antibacterial activity, which are intermediates for producing novel 7-acylamino-3-vinylcephalosporanic acid derivatives and salts thereof. It relates to sporanic acid and its salts. Therefore, an object of the present invention is to provide an antibacterial agent that exhibits excellent antibacterial activity against a large number of pathogenic microorganisms.
A novel 7-substituted-3-vinylcephalosporanic acid derivative, which is an intermediate for producing a novel 7-acylamino-3-vinylcephalosporanic acid derivative and its pharmaceutically acceptable salts, which are particularly useful as drugs for oral administration. An object of the present invention is to provide sporanic acid and its salts. 7-Substituted-3-vinylcephalosporanic acid, which is the object of the present invention, is a new compound and can be represented by the following general formula. [In the formula, R ¹ is the formula

[Formula] or R ³ -CH=N- (wherein, R ³ is an aryl group, R ⁴ is a lower alkyl group or a lower alkyl group substituted with carboxy or protected carboxy, and R ^a is a protected amino group) , R ^b means a protected carboxy group, R ^c and R ^d are combined to form an oxo group or a protected oxo group, X ¹ means a halogen), R ² is a group represented by means a carboxy group or a protected carboxy group] In the target compound () and the corresponding starting compound () in Methods 1 to 4 below, optical isomerism is determined based on the asymmetric carbon atom and double bond in these compounds. There may be one or more pairs of stereoisomers, such as stereoisomers and geometric isomers, and any of these isomers are intended to be encompassed by this invention. Suitable salts of the object compound () include pharmaceutically acceptable salts, especially the customary non-toxic salts, salts with bases and acid addition salts, i.e. salts with inorganic bases, such as sodium salts, potassium salts. Alkali metal salts such as calcium salts, alkaline earth metal salts such as magnesium salts, ammonium salts,
Salts with organic bases, such as triethylamine salts,
Pyridine salt, picoline salt, ethanolamine salt,
Organic amine salts such as triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, formate, acetic acid salt,
trifluoroacetate, maleate, tartrate,
Methanesulfonate, benzenesulfonate, p
- Organic carboxylic acid or sulfonic acid addition salts such as toluene sulfonate, salts with basic or acidic amino acids such as arginine, aspartic acid, glutamic acid, etc. are included. In the description above and below, suitable examples included in the various definitions will be explained in detail as follows. The term lower is used to include groups having 1 to 7 carbon atoms, unless otherwise specified. Suitable lower alkyls include straight chain or branched groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, etc.
Among them, alkyl having 1 to 4 carbon atoms is preferred. Suitable protected aminos include the conventional amino protecting groups used in penicillin and cephalosporin compounds, such as the acyls described below, such as alkyls such as mono(or di- or tri)phenyl(lower) alkyls such as benzyl, benzhydryl, trityl, etc. Substituted with (lower) alkyl, lower alkoxycarbonyl (lower) alkylidene such as 1-methoxycarbonyl-1-propen-2-yl or its enamine tautomer, di(lower) alkylamino methylene such as dimethylamino methylene, etc. Contains an amino group. Suitable acyls include aliphatic acyls, aromatic acyls, heterocyclic acyls, and aliphatic acyls substituted with aromatic or heterocyclic groups. The aliphatic acyl is saturated or unsaturated,
Includes acyclic or cyclic ones, such as lower alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, lower alkanesulfonyl such as mesyl, ethanesulfonyl, propanesulfonyl, and methoxycarbonyl. ,
These include lower alkoxycarbonyl such as ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and tertiary butoxycarbonyl, lower alkenoyl such as acryloyl, methacryloyl, and crotonoyl, _C3 - _C7 cycloalkanecarbonyl such as cyclohexanecarbonyl, amidino, and the like. Examples of the aromatic acyl include aroyl such as benzoyl, toluoyl and xyloyl, arenesulfonyl such as benzenesulfonyl and tosyl. Examples of the heterocyclic acyl include heterocyclic carbonyls such as furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolyl, carbonyl, and tetrazolylcarbonyl. As aliphatic acyl substituted with an aromatic group,
Al (lower) alkanoyl such as phenyl (lower) alkanoyl such as phenyl acetyl, phenylpropionyl, phenylhexanoyl, al(lower) alkanoyl such as phenyl (lower) alkoxycarbonyl such as benzyloxycarbonyl, phenyloxycarbonyl, etc. These include phenoxy (lower) alkanoyl such as lower) alkoxycarbonyl, phenoxyacetyl, and phenoxypropionyl. Aliphatic acyl substituted with a heterocyclic group includes thienyl acetyl, imidazolylacetyl,
Includes furylacetyl, tetrazolylacetyl, thiazolyl acetyl, thiadiazolyl acetyl, thienilipropionyl, thiadiazolylpropionyl, and the like. These acyl groups may be further substituted with one or more suitable groups. Suitable substituents include lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, halogen such as chlorine, bromine, iodine, fluorine, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyl. These include lower alkoxy such as oxy, hexyloxy, lower alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc., and suitable acyls having such substituents include chloroacetyl, Mono (or di or tri) halo (lower) alkanoyl such as bromoacetyl, dichloroacetyl, trifluoroacetyl, chloromethoxycarbonyl, dichloromethoxycarbonyl, 2,
Mono (or di or tri) halo (lower) alkoxy carbonyl such as 2,2-trichloroethoxycarbonyl, nitro (or halo or lower alkoxy) phenyl (lower) such as nitrobenzyloxy carbonyl, chlorobenzyloxy carbonyl, methoxybenzyloxy carbonyl, etc. )
Includes alkoxycarbonyl, etc. Suitable protected carboxys include those commonly esterified at the 3- or 4-position of penicillin or cefluorosporin compounds. Suitable ester moieties in the esterified carboxy include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary
Lower alkyl esters such as butyl esters, pentyl esters, tertiary pentyl esters, hexyl esters, lower alkenyl esters such as vinyl esters and allyl esters, lower alkynyl esters such as ethynyl esters and propynyl esters, methoxymethyl esters, and ethoxymethyl esters. , isopropoxymethyl ester, 1-
Lower alkoxy (lower) alkyl esters such as methoxyethyl ester and 1-ethoxyethyl ester, lower alkylthio (lower) alkyl esters such as methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, and isopropylthiomethyl ester, 2-amino -2-
Amino and carboxy-substituted lower alkyl esters such as carboxyethyl ester, 3-amino-3-carboxypropyl ester, 2-tertiary butoxycarbonylamino-2-benzhydryloxycarbonyl ethyl ester, 3-tertiary butoxycarbonylamino - Protected amino and protected carboxy-substituted lower alkyl esters such as lower alkoxycarbonylamino and mono (or di or tri)phenyl (lower) alkoxycarbonyl substituted lower alkyl esters such as 3-benzhydryloxycarbonylpropyl ester; , 2-mode ethyl ester, 2,
Mono (or di or tri) halo (lower) alkyl ester such as 2,2-trichloroethyl ester, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, isobutyryloxymethyl ester,
Lower alkanoyloxy (lower) alkyl esters such as valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, 1-acetoxypropyl ester, mesylmethyl ester, lower alkanesulfonyl (lower) alkyl ester such as 2-mesylethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-
nitrobenzyl ester, phenethyl ester,
Trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4
-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiary butylbenzyl ester, etc., mono (or di- or tri) phenyl ( (lower) alkyl esters which may have one or more substituents such as lower) alkyl esters, phenyl esters, tolyl esters, tertiary butyl phenyl esters, xylyl esters, mesityl Included are aryl esters which may have one or more suitable substituents, such as esters, cumenyl esters and salicyl esters, and heterocyclic esters such as phthalidyl esters. Suitable halogens include chloro, bromo, iodo, and the like. Suitable aryls include phenyl, tolyl,
Includes xylyl, naphthyl, etc. Suitable protected oxos include di(lower)alkoxy such as dimethoxy, diethoxy, dipropoxy, lower alkylenedioxy such as ethylenedioxy, trimethylenedioxy, propylenedioxy, tetramethylenedioxy, hexamethylenedioxy, etc. Includes bis(substituted oxy) such as. Particularly preferable examples of the lower alkyl group substituted with carboxy for ^R4 include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 3-carboxypropyl, 1-carboxy-1-methylethyl, and the like. Particularly preferred examples of lower alkyl groups in which (lower) alkyl is also substituted with protected carboxy include, for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-tert-butoxycarbonylethyl, 3
-tertiary butoxycarbonylpropyl, 1-tertiary
lower alkoxycarbonyl (lower) alkyl such as butoxycarbonyl-1-methylethyl, lower alkanoyloxy (lower) alkoxycarbonyl (lower) such as acetoxymethoxycarbonylmethyl, pivaloyloxymethoxycarbonylmethyl, hexanoyloxymethoxycarbonylmethyl, etc. Alkyl, amino- and carboxy-substituted lower alkoxycarbonyl (lower) alkyl such as 2-amino-2-carboxyethoxycarbonylmethyl, 2-tert-butoxycarbonylamino-2-
Examples include lower alkoxycarbonylamino and mono- or di- or triphenyl (lower) alkoxycarbonyl-substituted lower alkoxycarbonyl (lower) alkyl, such as benzhydryloxycarbonylethoxycarbonylmethyl. The target compound () and its salts according to the present invention are produced by the method shown in the following reaction formula. [wherein R ¹ , R ² , R ⁴ , R ^c , R ^d and X ¹ each have the same meaning as before, R ^c ′ and R ^d ′ are combined to form a protected oxo group, R ² _a means a protected carboxy group, R ⁵ means an aryl group] Methods 1 to 4 for producing the target compound () are explained in detail as follows. Method 1 Compound () or its salts are compound ()
Or, it is produced by reacting its salts with formaldehyde. Suitable salts for compound () include the same salts as exemplified for compound (). This reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, etc., which does not adversely affect the reaction, or a mixture thereof. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or with slight warming. Method 2 Compound (-b) or a salt thereof is produced by subjecting compound (-a) or a salt thereof to a carboxy-protecting group elimination reaction. This reaction is carried out by conventional methods such as hydrolysis. Hydrolysis is preferably carried out in the presence of an acid. Suitable acids include salts, inorganic acids such as hydrobromic acid and sulfuric acid, organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; An ion exchange resin or the like is used. In this reaction, when using an organic acid such as trifluoroacetic acid or p-toluenesulfonic acid, it is desirable to carry out the reaction in the presence of a cation scavenger such as anisole. The acid suitable for this hydrolysis is selected depending on the type of protecting group to be removed. The hydrolysis is usually carried out in a conventional solvent that does not adversely affect the reaction, such as water, methanol, ethanol, propanol, tertiary butyl alcohol, tetrahydrofuran, N,N-dimethylformamide, dioxane, or a mixture thereof;
When the above acid is liquid, it can also serve as a solvent. The reaction temperature for hydrolysis is not particularly limited, but the reaction is usually carried out under cooling or with slight heating. Method 3 Compound (-d) or a salt thereof is obtained by reacting compound (-c) or a reactive derivative thereof at an amino group or a salt thereof with compound (-c) or a reactive derivative thereof at a carboxyl group or a salt thereof. Manufactured by. Suitable salts for starting compound () include the same salts as mentioned for compound (). Suitable reactive derivatives at the amino group of compound (-c) include those commonly used,
For example, bis(trimethylsilyl)acetamide,
Silyl derivatives obtained by reaction with silyl compounds such as trimethylsilylacetamide, isocyanates, isothiocyanates, amino groups and acetaldehyde, isopentaldehyde, benzaldehyde, salicylaldehyde, phenyl acetaldehyde, p-nitrobenzaldehyde, m-chlorobenzaldehyde, p- Schiff bases obtained by reaction with aldehyde compounds such as chlorobenzaldehyde, hydroxynaphthaldehyde, furfural, and thiophenecarbaldehyde, and carbonyl compounds such as ketone compounds such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone, and ethyl acetoacetate; Contains mutants. Suitable reactive derivatives at the carboxy group of compound () include acid halides, acid anhydrides, active amides, active esters, etc., among which preferred are acid chlorides, acid bromides, substituted phosphoric acids (e.g. dialkyl phosphoric acids), etc. , phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid) mixed anhydride, dialkyl phosphorous mixed anhydride, sulfite mixed anhydride, thiosulfuric acid mixed anhydride,
Sulfuric acid mixed anhydride, alkyl carbonate (e.g. methyl carbonate, ethyl carbonate, propyl carbonate, etc.) mixed anhydride,
Mixed acid anhydrides such as mixed anhydrides of aliphatic carboxylic acids (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid, etc.), mixed anhydrides of aromatic carboxylic acids (e.g. benzoic acid, etc.), symmetrical type Active amides, p-nitrophenyl esters with imino group-containing heterocyclic compounds such as acid anhydrides, imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole, etc.
2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester , pyridyl esters, piperidyl esters, 8-quinolyl thioesters, N-hydroxy compounds (e.g. N,
N-dimethylhydroxyamine, 1-hydroxy-2(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6
active esters such as esters with -chlorobenzotriazole, etc.). A suitable reactive derivative is appropriately selected depending on the type of compound (-c) or () actually used. This reaction is preferably carried out using alkali metals such as lithium, sodium and potassium, alkaline earth metals such as calcium, alkali metal hydrides such as sodium hydride, alkaline earth metal hydrides such as calcium hydride, sodium hydroxide, etc. Alkali metal hydroxides such as potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, sodium methoxide, sodium ethoxide, potassium tertiary butoxide, etc. The reaction is carried out in the presence of an alkali metal alkoxide, an alkali metal alkanoate such as sodium acetate, a trialkylamine such as triethylamine, a pyridine compound such as pyridine, lutidine, picoline, or an organic or inorganic base such as quinoline. In this reaction, when using the compound () in the form of a free acid or its salt, for example, N,
N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl) ) Carbodiimide compounds such as carbodiimide, N,N'-carbonylbis(2-methylimidazole), pentamethyleneketene-N-
Cyclohexylimine, diphenylketene-N-
Ketenimine compounds such as cyclohexylimine,
Olefin or acetylene ether compounds such as ethoxyacetylene and β-chlorovinylethyl ether, N-hydroxybenzotriazole compounds such as 1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, sulfonic acid esters, trialkyl phos Phite or triphenylphosphine with carbon tetrachloride, disulfide or diazenedicarboxylate (e.g. diazenedicarboxylic acid diethyl ester)
Combinations with phosphorus compounds such as ethyl polyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorus trichloride,
N,N-di(lower) alkylformamide such as thionyl chloride, oxalyl chloride, N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3-sulfonic acid, dimethylformamide, N - It is preferable to carry out the reaction in the presence of a condensing agent such as the so-called Vilsmeier reagent obtained by the reaction of an amide compound such as methylformamide with a halogen compound such as thionyl chloride, phosphoryl chloride, or foscene. This reaction usually involves water, acetone, dioxane,
It is carried out in a customary solvent that does not adversely affect the reaction, such as acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, hexamethylphosphoramide, or a mixture thereof. . In these solvents,
Hydrophilic solvents can be used in combination with water. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating. Method 4 Compound (-f) or its salts are compound (-f) or its salts.
-e) or a salt thereof to an oxo-protecting group elimination reaction. This reaction is carried out by conventional methods such as hydrolysis. The hydrolysis method and reaction conditions (reaction temperature, solvent, etc.) are the same as those described for Method 2, so the above description is incorporated. In the above methods 1 to 4 and the post-treatment of the reaction mixture, if the starting compound or the target compound contains an optical or geometric isomer, this may change to another optical or geometric isomer;
This case is also included in this invention. When the target compound () has a free carboxy group at the 4-position, this group can be converted into a salt by a conventional method. 7-Acylamino-3-vinylcephalosporanic acid, which is useful as an antibacterial agent, can be produced from the target compound () of the present invention, for example, by the method shown in Reference Examples, and the compound () of the present invention is an intermediate in the synthesis of the antibacterial agent. It is useful for the body. In order to demonstrate the usefulness of the target compound (), we tested the antibacterial activity of representative 7-acylamino-3-vinylcephalosporanic acids produced using the compound () of the present invention as a raw material. The measured results are shown below. (1) Test 1: In vitro antibacterial activity [Test compound] No. 1 7-[2-(3-methanesulfonamidophenyl)-D-glycinamide]-3-vinyl-3
-Cefem-4-carboxylic acid (compound A) No. 2 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-
Vinyl-3-cephem-4-carboxylic acid (syn isomer) (compound B) No. 3 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamide]-3-vinyl- 3-Cefem-4-carboxylic acid (syn isomer) (Compound C) No. 4 7-[2-(2-aminothiazol-4-yl)-2-(3-carboxypropoxyimino)
Acetamide]-3-vinyl-3-cephem-
4-Carboxylic acid (syn isomer) (Compound D) [Test method] In vitro antibacterial activity was measured by the agar plate multiple dilution method described below. Trypticase Soy Broth (Bacterial count 10 ⁸ /
One loopful of the test strain cultured overnight in ml) was inoculated onto heart infusion agar (HI agar) containing each concentration of the test compound, and after culturing at 37°C for 20 hours, the lowest inhibitory concentration (MIC) μg/
Measured in ml.

【table】

【table】

[Table] (2) Test 2: Measurement of serum level after oral administration of antibiotics to rats [Test compound] Compound A [Test animal] 6-week old male rats, SD strain, weight 160 to 230 g each [Test method] Test compound A (100mg/
Kg) was administered orally. Rats were anesthetized with chloroform at specified time intervals, and blood samples were collected from the heart.
The antibiotic level in each serum sample was measured by the disk method using a standard solution made from rat serum. [Test results]

[Table] (3) Test 3: Protective effect against experimental mouse infection [Test compound] Compound A [Test animal] 4-week old male mouse, ICR strain, body weight 20.0 ± each
1.5g [Test method] Pathogenic microorganisms (1.3 x ¹⁰⁴⁾ suspended in 2.5% mucin were injected intraperitoneally. 1 hour after injection
Compound A was administered orally. The mice were determined to be alive or dead after 4 days, and the _ED50 value was calculated. [Test results]

[Table] 7- obtained from the object compound of this invention ()
When administering acylamino-3-vinylcephalosporanic acid for therapeutic purposes, it contains the above-mentioned compound as a main ingredient, and a pharmaceutically acceptable carrier, such as a pharmaceutically acceptable carrier suitable for oral, parenteral, or external use, is used. They can be administered in the form of conventional preparations with organic or inorganic, solid or liquid excipients. Such preparations include solids such as tablets, granules, powders, and capsules, as well as liquids, suspensions, syrups, emulsions,
Includes liquids such as lemonade. Furthermore, if necessary, adjuvants,
Stabilizers, wetting agents, and other commonly used additives such as lactose, magnesium stearate, terra alba, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, and ethylene glycol. can be contained. The dosage of 7-acylamino-3-vinyl-cephalosporanic acid varies depending on the patient's age, condition, type of disease, and type of compound administered, but is generally administered to the patient in an amount of 1 mg to about 4000 mg or more per day. Can be administered. The average dose for one time is about 50 mg, 100 mg, 250 mg, 500 mg,
1000mg, 2000mg can be used to treat diseases caused by pathogenic microorganisms. Next, the present invention will be explained in detail using examples. Production example of raw material compound 1 7-(5-amino-5-carboxypentanamide)-3-hydroxymethyl-3-cephem-
Benzoyl chloride (42.1 g) was added to a solution of sodium 4-carboxylate (118.6 g) in water (1000 ml) and acetone (600 ml) at 10°C with stirring under ice cooling, and the reaction mixture was diluted with 20% sodium carbonate aqueous solution to pH 6. Drop while adjusting to .5 to 7.5.
After continuing to stir at the same temperature for 1 hour, the reaction mixture was adjusted to pH 6.0 with concentrated hydrochloric acid, the acetone was distilled off, and the mixture was washed with ethyl acetate (500 ml). Add ethyl acetate (300 ml) to the aqueous solution, add a solution of diphenyldiazomethane and ethyl acetate until the starting compound disappears on thin layer chromatography, and PH with concentrated hydrochloric acid.
Adjust to 3.0. The ethyl acetate layer is separated, washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Dissolve the residue in acetone (400 ml) and drop the solution into diisopropyl ether (4000 ml). When the precipitated crystals are collected by filtration and dried, 7-(5-benzamido-5-benzhydryloxycarbonylpentanamide)-3-hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl ester (mp100-110°C) is obtained. 224.8g). IR (Nujiyor): 3270, 1770, 1730, 1660,
1640cm ^-1 NMR δppm (DMSO-d ₆ ): 1.3-2.7 (6H, m),
3.38 (1H, s), 3.63 (2H, m), 4.27 (2H, d,
J = 5Hz), 4.67 (1H, m), 5.15 (1H, d, J
= 5Hz), 5.77 (1H, dd, J = 5Hz, 8Hz),
6.87 (1H, s), 6.95 (1H, s), 7.43 (25H,
m), 7.97 (1H, m), 8.87 (1H, m) Production example 2 Pyridine (10.3 g) was added dropwise to a suspension of 5-phosphorus chloride (27.0 g) and methylene chloride (200 ml) at 0°C. Stir for 20 minutes at 5°C. 7 for this
-(5-Benzamide-5-benzhydryloxycarbonylpentanamide)-3-hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl ester (21.0 g) was added in one portion at -40°C, and at -30°C. Stirring is continued for 1 hour and at -10°C for a further 1 hour. Methanol (100 ml) cooled to -40°C was added to the reaction mixture at -40°C in one portion, and the mixture was stirred at -10°C for 1 hour. The solvent was distilled off, methylene chloride (100 ml), water (30 ml) and diisopropyl ether (100 ml) were added to the residue, and the mixture was stirred for a while under ice cooling. Collect the precipitated crystals by filtration, suspend in ethyl acetate (300 ml), and adjust the pH to 8.0 with an aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed with an aqueous sodium chloride solution, and dried over magnesium sulfate. When the solvent is distilled off, mp135-140℃
(Decomposition) of 7-amino-3-chloromethyl-3-
Cefem-4-carboxylic acid benzhydryl ester (2.8 g) is obtained. IR (nujiol): 3400, 1760, 1725, 1650 cm ^-1 NMR δppm (DMSO-d ₆ ): 3.60 (2H, q, J=
17Hz), 4.38 (2H, s), 4.85 (1H, d, J=5
Hz), 5.05 (1H, d, J=5Hz), 6.95 (1H,
s), 7.4 (10H, m), 8.8 (2H, m) Production Example 3 7-Amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (8.0
Molecular sieve (10 g) and benzaldehyde (2.1 g) were added to a solution of g) in N,N-dimethylformamide (40 ml), and the mixture was heated at 40°C.
Stir for 40 minutes. Add sodium iodide (2.9
g) and triphenylphosphine (10.1 g) and stirred at 40°C for 1 hour. The reaction mixture was mixed with diisopropyl ether (200 ml) and ethyl acetate (100 ml).
ml), the precipitated crystals are collected by filtration and dried, resulting in [4-benzhydryloxycarbonyl-7-benzylideneamino-3-cephem-3-yl]methyl at mp150-158℃ (decomposition). Root-triphenylphosphonium iodide (16.9 g) is obtained. IR (nujiol): 1780, 1705, 1635 cm ^-1 NMR δppm (DMSO-d ₆ ): 3.67 (2H, m), 5.2
(2H, m), 5.58 (1H, d, J=5Hz), 5.82
(1H, d, J=5Hz), 6.30 (1H, s), 7.2−
8.3 (30H, m), 8.70 (1H, s) Production example 4 7-(5-benzamido-5-benzhydryloxycarbonylpentanamide)-3-hydroxymethyl-3-cephem-4-carboxylic acid benzhydryl ester To a solution of (100 g) dissolved in methylene chloride (600 ml), phosphorus pentachloride (25.6 g) was added all at once at -30°C, and pyridine (9.8
g was added dropwise at the same temperature. The reaction mixture was heated at -20℃ for 1
Stir for an hour and pour into a mixture of methylene chloride (500 ml) and water (300 ml). The organic layer was separated, washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to dryness.
7-(5-benzamide-5-benzhydryloxycarbonylpentanamide) at 110°C (decomposition)
-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (114.5 g) is obtained. IR (nujiol): 1780, 1725, 1640 cm ^-1 NMR δppm (DMSO-d ₆ ): 1.3-2.5 (6H, m),
3.67 (2H, m), 4.43 (2H, m), 4.67 (1H, m),
5.22 (1H, d, J=5Hz), 5.83 (1H, m),
6.83 (1H, s), 7.00 (1H, s), 7.4 (25H, m),
7.92 (1H, m), 8.90 (1H, m) Production example 5 7-(5-benzamido-5-benzhydryloxycarbonylpentanamide)-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (102 g) in N,N-dimethylformamide (150 ml) were added triphenylsulfosphine (48.5 g) and sodium iodide (18.4 g), and the mixture was stirred at room temperature for 1.5 g.
Stir for an hour. The reaction mixture was dropped into isopropyl alcohol (5000ml), the precipitate was collected by filtration, and washed with diisopropyl ether, resulting in mp165-175.
[7-(5-benzamido-5-benzhydryloxycarbonylpentanamide)] at °C (decomposition)
-4-benzhydryloxycarbonyl-3-cephem-3-yl]methyltriphenylphosphonium iodide (123.5 g) is obtained. IR (nujiol): 1780, 1730, 1710, 1650cm ^-1 NMR δppm (DMSO-d ₆ ): 1.3-2.6 (6H, m),
4.33 (2H, m), 4.67 (2H, m), 5.13 (1H, m),
5.33 (1H, d, J=5Hz), 5.75 (1H, m),
6.33 (1H, s), 6.83 (1H, s), 7.0−8.3 (41H,
m), 8.92 (1H, m) Production Example 6 To a solution of N-hydroxyphthalimide (70.08 g) in acetonitrile (300 ml), triethylamine (48 g) and 4-bromocrotonic acid tertiary butyl ester (96.0 g) were added. is added under stirring and the mixture is heated to reflux for 1.5 hours. The reaction mixture is poured into water (600ml) and extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, concentrated to dryness under reduced pressure, and the residue is triturated with n-hexane. The resulting material was subjected to column chromatography on silica gel, and a mixture of n-hexane, ethyl acetate and diisopropyl ether (volume ratio 5:0.5:
4.5) and collect the fraction containing the target compound. The solvent was distilled off, and the residue was powdered with n-hexane and collected by filtration to obtain 4-phthalimidoxycrotonic acid tertiary butyl ester (41.7 g). NMR δppm (DMSO-d ₆ ): 1.45 (9H, s), 4.90
(2H, m), 6.09 (1H, m), 6.66−7.19 (1H,
m), 7.86 (4H, s) Production Example 7 Hydrazine monohydrate (5.0 g) was dissolved in methanol ( 10 ml) of the solution under stirring, and continued stirring at room temperature for 15 minutes. Insoluble matter is filtered and washed with methylene chloride. The washing liquid and filtrate are combined and extracted three times with 5% hydrochloric acid. Combine the extracts, wash with diethyl ether, add methylene chloride, and adjust the pH to 7.5 with 28% ammonium hydroxide aqueous solution. The methylene chloride solution is separated, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off to obtain oily 4-aminooxycrotonic acid tertiary butyl ester (11.03 g). IR (liquid film): 3340, 3250, 2980, 2940, 1720,
1660cm ^-1 NMR δppm (DMSO-d ₆ ): 1.43 (9H, s), 4.18
(2H, m), 5.85 (1H, m), 6.14 (2H, broad s), 6.52-7.06 (1H, m) Production example 8 Ethanol ( 150 ml) and water (150 ml) were added, and (2-formamidothiazol-4-yl)glyoxylic acid (11.0 g) was gradually added with stirring. During the addition, the PH of the mixture is adjusted to 5 to 5.5 with 10% aqueous sodium hydroxide solution and stirring is continued for 2 hours at room temperature. Ethanol is distilled off, ethyl acetate is added to the remaining aqueous solution, and the pH is adjusted to 7.5 with a 10% aqueous sodium hydroxide solution. Separate the aqueous layer and wash with ethyl acetate. Add ethyl acetate to this and adjust the pH to 2.0 with 10% hydrochloric acid. The organic layer is separated, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off, and the residue was pulverized with n-hexane and tetrahydrofuran and collected by filtration. Add ethanol (50ml) and water (30ml) to this, and add 10% sodium hydroxide aqueous solution.
Adjust to PH7.5. The precipitate is collected by filtration, washed with a mixture of water and ethanol (volume ratio 1:1), water and ethyl acetate are added, and the pH is adjusted to 2.0 with 10% hydrochloric acid.
The organic layer is separated, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off and the residue was triturated with n-hexane and tetrahydrofuran to give 2-(trans-3-tert-butoxycarbonylallyloximino)-2-(2
-formamidothiazol-4-yl)acetic acid (syn isomer) (12.01 g) is obtained. IR (nujiol): 3150, 1720, 1650cm ^-1 NMR δppm (DMSO-d ₆ ): 1.47 (9H, s), 4.89
(2H, m), 5.96 (1H, m), 6.69−7.16 (1H,
m), 7.60 (1H, s), 8.57 (1H, s), 12.72
(1H, broad s) Production example 9 2-(trans-3-tertiary-butoxycarbonylallyloxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (8.0
g) in ethyl acetate (60 ml) and ethanol (60 ml).
ml), 10% palladium on carbon (4.0 g) moistened with water (3 ml) was added in a nitrogen stream, and catalytic reduction was carried out at 1 atm for 4 hours. The catalyst is filtered off and the filtrate is concentrated. Water and ethyl acetate were added to the residue, and the pH was adjusted with saturated aqueous sodium bicarbonate solution.
Adjust to 7.5. Separate the aqueous layer, wash with ethyl acetate, add more ethyl acetate, and PH with 10% hydrochloric acid.
Adjust to 2.0. The organic layer is separated, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was removed by filtration, and the residue was crystallized from n-hexane and collected by filtration to give 2-(tert-butoxycarbonylpropoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer).
(1.80g) is obtained. NMR δppm (DMSO-d ₆ ): 1.44 (9H, s), 1.93
(2H, m), 2.33 (2H, t, J=6.0Hz), 4.20
(2H, t, J=6.0Hz), 7.61 (1H, s), 8.61
(1H, s), 12.63 (1H, broad s) Production example 1 of target compound [4-benzhydryloxycarbonyl-7-
benzylideneamino-3-cephem-3-yl]
To a solution of methyl-triphenylphosphonium iodide (16.9 g) in methylene chloride (200 ml) and water (100 ml) was added 36% formaldehyde aqueous solution (48 ml), and the mixture was diluted with sodium carbonate.
Adjust to PH9.0. After stirring the mixture at room temperature for 1 hour,
The organic layer is separated, washed with an aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off to obtain 7-benzylideneamino-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (8.6 g), mp 124-132°C. IR (nujiol): 1770, 1710, 1630 cm ^-1 NMR δppm (DMSO-d ₆ ): 3.75 (2H, q, J=
18Hz), 5.1-5.8 (4H, m), 6.75 (1H, dd, J
=10Hz, 18Hz), 6.93 (1H, s), 7.1−8.0
(15H, m), 8.58 (1H, s) Example 2 7-(5-benzamido-5-benzhydryloxycarbonylpentanamide)-4-benzhydryloxycarbonyl-3-cephem-3-
] Methyl-triphenylphosphonium iodide (123.5g) and methylene chloride (1000ml)
Add 36% formaldehyde aqueous solution (300 ml) to the dissolved solution, and adjust the pH to 9.0 with 20% sodium bicarbonate aqueous solution. After stirring the mixture at 25°C for 2 hours, the pH was adjusted to 5.0 with concentrated hydrochloric acid. Separate the organic layer,
Concentrate and add ethyl acetate to the concentrate. When the precipitated crystals are filtered and dried, mp180-184℃ (decomposition)
7-(5-benzamido-5-benzhydryloxycarbonylpentanamide)-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (63.5 g) was obtained. IR (Nujiyor): 3300, 1770, 1730, 1710,
1650cm ^-1 NMR δppm (DMSO-d ₆ ): 1.3-2.6 (6H, m),
3.72 (2H, m), 4.67 (1H, m), 5.1−5.6 (2H,
m), 5.7−5.9 (2H, m), 6.83 (1H, dd, J=
12Hz, 18Hz), 6.86 (1H, s), 7.0 (1H, s),
7.42 (25H, m), 7.98 (1H, m), 8.92 (1H, m) Example 3 7-amino-3-vinyl-3-cephem-4-
4-Bromo-3,3 was added to a solution of carboxylic acid benzhydryl ester (6.4 g), trimethylsilylacetamide (9.8 g) and ethyl acetate (80 ml).
-Diethoxy-2-methoxyiminobutyryl chloride (syn isomer) (5.0 g) is added under stirring at -20°C and stirring is continued at -20 to -5°C for 1 hour.
Ethyl acetate and water are added to the reaction mixture, and the ethyl acetate layer is separated, washed with a saturated aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. When the solvent is distilled off, 7-
(4-bromo-3,3-diethoxy-2-methoxyiminobutyramide)-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (10.1 g) is obtained. IR (nujiol): 1780, 1720, 1610, 1510 cm ^-1 NMR δppm (DMSO-d ₆ ): 1.13 (3H, t, J=
7Hz), 3.60 (2H, q, J=7Hz), 3.76 (2H,
m), 3.83 (3H, s), 5.22 (1H, d, J=5
Hz), 5.24 (1H, d, J = 11Hz), 5.60 (1H, d,
J=17Hz), 5.82 (1H, dd, J=5Hz, 8Hz),
6.70 (1H, dd, J = 11Hz, 17Hz), 6.93 (1H,
s), 7.17-7.60 (10H, m), 9.00 (1H, d, J
=8Hz) Example 4 7-(4-bromo-3,3-diethoxy-2-
methoxyiminobutyramide)-3-vinyl-3
-To a solution of cefem-4-carboxylic acid benzhydryl ester (syn isomer) (6.5 g) in methylene chloride (60 ml) was added concentrated hydrochloric acid (6 ml) at 3 to 5°C, and the mixture was cooled on ice or at room temperature. Stir for 8 hours. Add methylene chloride (100 ml) to the reaction mixture, wash with water, and dry over anhydrous magnesium sulfate. The solvent was distilled off and the residue was washed with diethyl ether to give 7-(4-bromo-2-
3.5 g of methoxyiminoacetoacetamide)-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) is obtained. IR (Nujiyor): 3280, 1770, 1710, 1700,
1660, 1600, 1560 cm ^-1 NMR δppm (DMSO−d ₆ ): 3.78 (2H, q, J=
18Hz), 4.07 (3H, s), 4.63 (2H, s), 5.27
(1H, d, J=5Hz), 5.30 (1H, d, J=11
Hz), 5.63 (1H, d, J=17Hz), 5.93 (1H, dd,
J = 5Hz, 8Hz), 6.78 (1H, dd, J = 11Hz,
17Hz), 6.98 (1H, s), 7.17-7.67 (10H, m),
9.57 (1H, d, J=8Hz) Example 5 7-(4-bromo-3,3-diethoxy-2-
methoxyiminobutyramide)-3-vinyl-3
-Cefem-4-carboxylic acid benzhydryl ester (syn isomer) (3.36g), anisole (2.1
Add trifluoroacetic acid (8.0 g) to a solution of g) and methylene chloride (20 ml) under ice-cooling and stirring, and continue stirring at room temperature for 1 hour. The solvent is evaporated and the residue is dissolved in a mixture of ethyl acetate and water.
Separate the ethyl acetate layer, add water, and adjust the pH to 7 with saturated aqueous sodium hydrogen carbonate solution. Separate the aqueous layer, add ethyl acetate, and adjust the pH to 2 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 7-(4-bromo-2-methoxyiminoacetamide)-3-vinyl-3-cephem- 4-carboxylic acid (syn isomer) (1.6 g) is obtained. IR (Nujiyor): 3300-3200, 1780, 1700,
1675 (shoulder), 1540 cm ^-1 Example 6 Vilsmeier's reagent prepared from N,N-dimethylformamide (0.48 g) and phosphorus oxychloride (1.0 g) was suspended in ethyl acetate (20 ml), and 4-bromo- 2-Methoxyiminoacetoacetic acid (syn isomer) (1.34 g) was added under ice cooling and stirred at the same temperature for half an hour to obtain an activated acid solution. This solution was added to 7-amino-3-vinyl-3-cephem-4.
-To a solution of carboxylic acid benzhydryl ester hydrochloride (2.15 g) and trimethylsilylacetamide (3.93 g) in ethyl acetate (30 ml) was added at -20°C, and the mixture was heated at -20 to 0°C for 1.5
Stir for an hour. Ethyl acetate (100ml) to the reaction mixture
and water (100 ml) are added, and the ethyl acetate layer is separated, washed with a saturated aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was washed with diethyl ether to give 7-(4-bromo-2-methoxyiminoacetoacetamide)-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer). (2.5g) is obtained. IR (Nujiyor): 3280, 1770, 1710, 1700,
1660, 1600, 1560 cm ^-1 NMR δppm (DMSO−d ₆ ): 3.78 (2H, q, J=
18Hz), 4.07 (3H, s), 4.63 (2H, s), 5.27
(1H, d, J=5Hz), 5.30 (1H, d, J=11
Hz), 5.63 (1H, d, J=17Hz), 5.93 (1H, dd,
J = 5Hz, 8Hz), 6.78 (1H, dd, J = 11Hz,
17Hz), 6.98 (1H, s), 7.17-7.67 (10H, m),
9.57 (1H, d, J = 8 Hz) Reference example of manufacturing an antibacterial agent using the target compound as a raw material 1 7-benzylideneamino-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (8.6 g) and anisole ( 10ml) of suspension liquid,
Trifluoroacetic acid (10 ml) is added dropwise at −20° C., the reaction mixture is gradually brought to room temperature under stirring and stirred at room temperature for half an hour. The reaction mixture was poured into a mixture of ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (100 ml) and diluted with 20% aqueous sodium carbonate.
Adjust to PH7.5. The aqueous layer is separated, washed with ethyl acetate (100 ml), adjusted to pH 7.2 with concentrated hydrochloric acid, and subjected to column chromatography on alumina (10 ml). Elute with 15% aqueous sodium chloride solution, collect fractions containing the target compound, and dilute to pH3.3 with concentrated hydrochloric acid.
Adjust to. The precipitated crystals are collected by filtration, washed with acetone, and dried.
-Amino-3-vinyl-3-cephem-4-carboxylic acid (2.0 g) is obtained. IR (nujiol): 1800, 1605 cm ^-1 NMR δppm (D ₂ O + NaHCO ₃ ): 3.67 (2H, s),
4.8−5.8 (5H, m), 6.88 (1H, dd, J=12Hz,
18Hz) Reference example 2 2-(3-methanesulfonamidophenyl)-D
- Glycine (2.44g) and methylene chloride (25g)
ml) of suspension, add 5 to 10 ml of hydrogen chloride gas.
Bubble for 5 minutes at °C. Add phosphorus pentoxide (3.1g),
The mixture is stirred for 5 hours at 0-10°C. The precipitated solid was collected by filtration, washed with methylene chloride (5 ml) and dried to give a residue (2.7 g). This residue was added to a solution of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (1.8 g) and trimethylsilylacetamide (6.3 g) in methylene chloride (30 ml) at -15°C with stirring. Add and continue stirring at -5 to 0°C for 3 hours. Add water (30 ml) to the reaction mixture and shake briefly. The aqueous layer was separated, adjusted to pH 5 with a 20% aqueous sodium carbonate solution, concentrated to dryness under reduced pressure, and the resulting solid was collected using a nonionic adsorption resin "Diaion HP-20" (120
ml) for chromatography. After washing with water, 30%
Elute with isopropyl alcohol, collect fractions containing the target compound, and concentrate under reduced pressure. The residue was lyophilized to give 7-[2-(3-methanesulfonamidophenyl)-D-glycinamide]-3-vinyl-3-cephem-4-carboxylic acid (0.47 g).
get. IR (Nujiyor): 3300-3150, 1760, 1685,
1605cm ^-1 Reference Example 3 Add pyridine (5.9g) dropwise to a suspension of 5-phosphorus chloride (15.5g) and methylene chloride (200ml) under stirring at 5 to 10°C, and continue stirring at 5°C for 20 minutes. . To this, 7-(5-benzamide-5
-benzhydryloxycarbonylpentanamide)-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (20 g) is added in one portion at 5°C and the mixture is stirred at the same temperature for 2 hours. Methanol (120 ml) was gradually added to the reaction mixture at -40°C, and the mixture was stirred at -20 to -10°C for 1 hour. The solvent was distilled off, and ethyl acetate (300 ml) and water (50 ml) were added to the residue. The mixture was stirred briefly under ice cooling,
The precipitated crystals were collected by filtration and washed with isopropyl alcohol to obtain 7-amino-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester hydrochloride (8.4 g) with a mp of 180-195°C (decomposed). IR (nujiol): 1760, 1705, 1580 cm ^-1 NMR δppm (DMSO-d ₆ ): 3.88 (2H, q, J=
18Hz), 5.1-5.4 (2H, m), 5.58 (1H, d, J
=6Hz), 5.93 (1H, m), 6.97 (1H, s), 7.0
(1H, dd, J=12Hz, 18Hz), 7.42 (10H, m),
9.17 (2H, m) Reference example 4 2-tertiary butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)
Acetic acid (syn isomer) (13.8g) N,N-dimethylformamide (3.66g), phosphorus oxychloride (7.7g)
7-amino-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester hydrochloride (15 g) and trimethylsilylacetamide (32 g) were added to an activated acid prepared in a conventional manner from Ethyl (150ml)
Add to the stirred solution at -20°C while stirring, and continue stirring at the same temperature for half an hour. After adding water (100ml),
Separate the ethyl acetate layer, add sodium chloride aqueous solution,
Wash sequentially with an aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution, and dry over anhydrous magnesium sulfate. When the solvent was distilled off and the resulting oil was powdered and washed with diisopropyl ether, mp101
7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (decomposition) at °C (decomposition). isomer) (23.1 g) is obtained. IR (Nujiyor): 3250, 1780, 1720, 1680,
1540cm ^-1 NMR δppm (DMSO-d ₆ ): 1.45 (9H, s), 3.77
(2H, q, J=18Hz), 4.64 (2H, s), 5.32
(1H, d, J=5Hz), 5.2−6.0 (2H, m),
5.97 (1H, dd, J=5Hz, 8Hz), 6.5-7.6
(1H, m), 6.98 (1H, s), 7.2−7.8 (11H,
m), 8.55 (1H, s), 9.68 (1H, d, J=8
Hz), 12.71 (1H, broad s) Reference example 5 7-[2-tertiary butoxycarbonylmethoxyimino)-2-(2-formamidothiazole-4
-yl)acetamide]-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (2 g) and anisole (8.0 ml) in dioxane (8 ml) and tertiary butyl alcohol (8.0 ml). Add p-toluenesulfonic acid (2.2 g) to the solution and stir at 60°C for 5 hours.
Add ethyl acetate and water to the reaction mixture, and adjust the pH to 7.5 with saturated aqueous sodium hydrogen carbonate solution. Separate the aqueous layer, wash with ethyl acetate, add ethyl acetate and tetrahydrofuran, and adjust the pH to 2.2 with 10% hydrochloric acid. The aqueous layer is saturated with sodium chloride, and the organic layer is separated, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off, the residue is washed with diisopropyl ether and filtered.
Add water to this and use 2N sodium hydroxide aqueous solution.
Adjust to PH5.5. The aqueous layer is subjected to column chromatography using a nonionic adsorption resin "Diaion HP-20" (20 ml) and eluted with water (40 ml). Add ethyl acetate and tetrahydrofuran to the eluent,
Adjust the pH to 2.2 with 10% hydrochloric acid. The aqueous layer is saturated with sodium chloride, and the organic layer is separated, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off, and the residue was powdered with diisopropyl ether and collected by filtration to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamide]-3-vinyl-3-cephem- 4-Carboxylic acid (syn isomer) (0.31g)
get. IR (nujiol): 3350, 1770, 1680, 1640 cm ^-1 NMR δppm (DMSO-d ₆ ): 3.70 (2H, q, J=
18Hz), 4.62 (2H, s), 5.21 (1H, d, J=5
Hz), 5.82 (1H, dd, J=5Hz, 8Hz), 5-6
(2H, m), 6.82 (1H, s), 7.22 (2H, broad s), 6.5−7.5 (1H, m), 9.5 (1H, d, J=
8Hz) Reference example 6 7-amino-3-vinyl-3-cephem-4-
Carboxylic acid benzhydryl ester hydrochloride (2.3
Dissolve g) in dry ethyl acetate (50 ml) and trimethylsilylacetamide (4.9 g) at 40°C. On the other hand, Tetrahydrofuran (20 ml) and 2
-(3-tert-butoxycarbonylpropoxyimino)-2-(2-formamidothiazole-4-
yl) acetic acid (syn isomer) (2.1 g) was added, -3
The activated acid solution is obtained by stirring briefly at a temperature of 3°C to 3°C. This solution is added to the above ethyl acetate solution at -10°C with stirring, and stirring is continued at -10 to -5°C for half an hour. Water is added to the reaction mixture, and the separated organic layer is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off and the residue was triturated with diisopropyl ether to give 7-[2-(3-tert-butoxycarbonylpropoxyimino)-2-(2-
Formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (3.63
g) is obtained. IR (Nujiyor): 3280, 3150, 1780, 1720,
1660cm ^-1 NMR δppm (DMSO-d ₆ ): 1.43 (9H, s), 1.97
(2H, m), 2.38 (2H, t, J=6.0Hz), 3.79
(2H, q, J = 18.0Hz) 4.18 (2H, t, J = 6.0
Hz), 5.33 (1H, d, J = 11.0Hz), 5.34 (1H,
d, J = 5.0Hz), 5.67 (1H, d, J = 17.0Hz),
5.97 (1H, dd, J=5.0Hz, 8.0Hz), 6.82 (1H,
dd, J=11.0Hz, 17.0Hz), 7.00 (1H, s),
7.19−7.73 (11H, m), 8.57 (1H, s), 9.77
(1H, d, J=8.0Hz) Reference example 7 7-[2-(3-tertiary butoxycarbonylpropoxyimino)-2-(2-formamidothiazol-4-yl)acetamide]-3-vinyl-3
-Cefem-4-carboxylic acid benzhydryl ester (syn isomer) was treated in the same manner as in Reference Example 5 to obtain 7-[2-(2-aminothiazol-4-yl)-
2-(3-carboxypropoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) is obtained. IR (Nudiyol): 3300, 1760, 1660 cm ^-1 Reference example 8 7-(4-bromo-2-methoxyiminoacetamide)-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer)
(1.2 g), thiourea (0.5 g) and sodium acetate (trihydrate) (0.7 g) were dissolved in water (20 ml) and tetrahydrofuran (20 ml) at 30°C.
Stir for 3.5 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was triturated with diethyl ether to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-vinyl-3-cephem-4-carvone. Acid benzhydryl ester (syn isomer)
(1.05g) is obtained. IR (Nujiyor): 3230, 1780, 1710, 1650,
1620, 1580, 1540 cm ^-1 NMR δppm (DMSO−d ₆ ): 3.78 (2H, q, J=
17Hz), 3.87 (3H, s), 5.28 (1H, d, J=5
Hz), 5.32 (1H, d, J = 11Hz) 5.65 (1H, d,
J = 17Hz), 5.72 (1H, dd, J = 5Hz, 8Hz),
6.80 (1H, s), 6.80 (1H, dd, J=11Hz, 17
Hz), 6.97 (1H, s), 7.20−7.67 (10H, m),
9.67 (1H, d, J = 8Hz) Reference example 9 7-[2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (0.9 g), methylene chloride (10 ml) and anisole (0.66 g) in a suspension, Add trifluoroacetic acid (2.5 g) under ice-cooling, and stir at room temperature for 1 hour. The reaction mixture was added dropwise to diisopropyl ether (100ml) and
The precipitate was collected by filtration, suspended in a mixture of ethyl acetate and water, and the pH was adjusted to 7 with saturated aqueous sodium hydrogen carbonate solution. The separated aqueous layer is saturated with sodium chloride, and a mixed solvent of ethyl acetate and tetrahydrofuran (volume ratio 8:2) is added thereto. PH with 10% hydrochloric acid
3.2, separate the organic layer, wash with saturated aqueous sodium chloride solution, and dry over magnesium sulfate. The solvent was distilled off and the residue was washed with diisopropyl ether to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-vinyl-3-cephem-4-carboxylic acid. (Syn isomer) (0.4 g) is obtained. IR (Nujiyor): 3400-3100, 1780, 1660,
1630, 1540cm ^-1 NMR δppm (DMSO−d ₆ ): 3.72 (2H, q, J=
18Hz), 3.87 (3H, s), 5.20 (1H, d, J=5
Hz), 5.33 (1H, d, J = 11Hz), 5.58 (1H, d,
J = 18Hz), 5.78 (1H, dd, J = 5Hz, 8Hz),
6.77 (1H, s), 6.95 (1H, dd, J=11Hz, 18
Hz), 9.62 (1H, d, J=8Hz) Reference example 10 7-(4-bromo-2-methoxyiminoacetoacetamide)-3-vinyl-3-cephem-4
- Carboxylic acid (syn isomer) (1.5 g) and thiourea (0.8 g) were reacted in the same manner as in Reference Example 8, and 7-
[2-(2-aminothiazol-4-yl)-2-
methoxyiminoacetamide]-3-vinyl-3
-Cefem-4-carboxylic acid (syn isomer) (0.8
g) is obtained. IR (Nujiyor): 3400-3100, 1780, 1660,
1630, 1540cm ^-1 NMR δppm (DMSO−d ₆ ): 3.72 (2H, q, J=
18Hz), 3.87 (3H, s), 5.20 (1H, d, J=5
Hz), 5.33 (1H, d, J = 11Hz), 5.58 (1H, d,
J = 18Hz), 5.78 (1H, dd, J = 5Hz, 8Hz),
6.77 (1H, s), 6.95 (1H, dd, J=11Hz, 18
Hz), 9.62 (1H, d, J = 8Hz) Reference example 11 7-amino-3-vinyl-3-cephem-4-
Carboxylic acid benzhydryl ester hydrochloride (48
g), methanol (250ml) and anisole (70ml)
p-Toluenesulfonic acid (85 g) was added to the suspension (ml) and the mixture was stirred at 50°C for 2 hours. The reaction mixture was poured into a 10% aqueous sodium bicarbonate solution (600 ml) and ethyl acetate (700 ml). ,
Adjust the pH to 7.5 with 20% sodium carbonate aqueous solution.
Separate the aqueous layer, wash with ethyl acetate (500ml),
Adjust the pH to 2.5 with concentrated hydrochloric acid and stir for 1 hour under ice cooling. The precipitated crystals were collected by filtration and washed with acetone, resulting in 7-amino-3-
Vinyl-3-cephem-4-carboxylic acid (15.4
g) is obtained. IR (nujiol): 1800, 1605 cm ^-1 NMR δppm (D ₂ O + NaHCO ₃ ): 3.67 (2H, s),
4.8−5.8 (5H, m), 6.88 (1H, dd, J=12Hz,
18Hz)

Claims (1)

[Claims] 1 formula [In the formula, R ¹ is the formula [Formula] or R ³ -CH=N- (wherein, R ³ is an aryl group, R ⁴ is a lower alkyl group or a lower alkyl group substituted with carboxy or protected carboxy, and R ^a is a protected amino group) , R ^b means a protected carboxy group, R ^c and R ^d are combined to form an oxo group or a protected oxo group, X ¹ means a halogen), R ² is a group represented by meaning a carboxy group or a protected carboxy group] or salts thereof. 2 R ¹ is the formula (In the formula, R ⁴ and X ¹ have the same meanings as above.) The compound according to claim 1, represented by the formula: