JPH0357107B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to 3-cephem compounds, which are novel intermediates of cephalosporin compounds with antibacterial activity. More specifically, the present invention provides cephalosporin compounds, such as 7-
[2-(2-aminothiazol-4-yl)-2-
Methoxyiminoacetamide]-3-Cefem-
The object of the present invention is to provide a novel 3-cephem compound for use in producing 4-carboxylic acid (syn isomer) or a pharmaceutically acceptable salt thereof, and a method for producing the novel 3-cepheme compound. The 3-cephem compound () of this invention is represented by the following general formula. (In the formula, R ¹ is a lower alkyl group, R ² is a carboxy group or a protected carboxy group, X″ is hydrogen or a halogen, Y′ is a carbonyl group or a protected carbonyl group, and Y′ is a carbonyl group. (X'' shall be hydrogen) The 3-cephem compound and its salts of the present invention are produced by the following method. (In the formula, R ¹ and R ² each have the same meaning as before,
X' means hydrogen or halogen, Y means a protected carbonyl group) The compound () used in the above method [A] includes a new compound, and the new compound is preferably represented by the following structural formula. (In the formula, R ¹ and X' have the same meanings as before, and A ¹ and A ² mean acetal residues that may be bonded to each other.) The above raw material compound (') is produced by the following method. . * Journal of Medicinal Chemistry Vol. 16, p. 978 (1973) ** German Patent Publication No. 2707565 (wherein R ¹ , A ¹ and A ² have the same meanings as before, X is halogen, (Z means an esterified carboxy group) The terms and definitions used in this specification are as follows. Substructure shown by the formula below means syn isomer. Lower level words are 1 to 6 unless otherwise specified.
includes groups containing up to 1 carbon atoms. Examples of the protected carboxy group include an esterified carboxy group, an amidated carboxy group, and the like. Suitable esters for the esterified carboxy group include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary
Lower alkyl esters such as butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester, 1-cyclopropylethyl ester, lower alkenyl esters such as vinyl ester and allyl ester, lower alkynyl esters such as ethynyl ester and propynyl ester, Lower alkoxy (lower) alkyl esters such as methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthio Lower alkylthio (lower) such as methyl ester
Alkyl ester, 2-iodoethyl ester,
Halo (lower) alkyl esters such as 2,2,2-trichloroethyl ester, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, lower alkanoyloxy (lower) alkyl ester such as 2-acetoxyethyl ester, 2-propionyloxyethyl ester, lower alkanoyloxy (lower) alkyl ester such as mesylmethyl ester, 2-mesylethyl ester, benzyl ester, 4- Methoxybenzyl ester, 4-
nitrobenzyl ester, phenethyl ester,
Trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4
Al(lower)alkyl (e.g. phenyl(lower)alkyl) which may have one or more suitable substituents such as -dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiary butylbenzyl ester, etc. Aryl esters optionally having one or more suitable substituents, such as esters, phenyl esters, tolyl esters, tertiary butyl phenyl esters, xylyl esters, mesityl esters, cumenyl esters, salicyl esters, Esters with silyl compounds such as tri(lower)alkylsilyl compounds, di(lower)alkylalkoxysilyl compounds, or tri(lower)alkoxysilyl compounds, such as trimethylsilyl esters,
Tri(lower)alkylsilyl esters such as triethylsilyl ester, di(lower)alkyl alkoxysilyl esters such as dimethylmethoxylyl ester, dimethylethoxysilyl ester, diethylmethoxysilyl ester, trimethoxysilyl ester, triethoxysilyl ester, etc. Examples include (lower) alkoxysilyl esters. Among them, 4-nitrobenzyl ester,
Nitrophenyl (lower) alkyl esters such as 4-nitrophenethyl esters, methyl esters,
Ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester,
Lower alkyl esters such as neopentyl ester and hexyl ester are preferred. Lower alkyl groups include straight-chain or branched alkyl containing 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, hexyl, heptyl, octyl, etc. groups, more preferably groups containing 1 to 4 carbon atoms. The protecting group for the protected carbonyl group includes commonly used removable groups, and preferable ones include lower alkylene glycols such as ethylene glycol, trimethylene glycol, ethanedithiol, and propanedithiol, methanol, ethanol, Lower alkanols such as propanol and isopropyl alcohol, acetals with lower alkanethiols such as methanethiol and ethanethiol, or methyl carbazate,
Examples include hydrazone type protecting groups such as hydrazine with carbazine esters such as ethyl carbazate. The acetal residues ^{of A 1 and A 2 that} may be bonded to each other include methyl, ethyl, propyl, isopropyl, butyl,
Examples include lower alkyl groups such as pentyl and hexyl, and cases where A ¹ and A ² combine to form a lower alkylene group such as ethylene and trimethylene. Halogens include chlorine, bromine, iodine and fluorine, preferably chlorine and bromine. A preferred example of the above definition is as follows. Preferred examples of R ¹ include methyl, ethyl,
Examples include lower alkyl groups such as propyl, isopropyl, butyl, pentyl, etc., more preferred are groups containing 1 to 4 carbon atoms, and most preferred is methyl. A preferred example of R ² is a carboxy group. Preferred examples of Z include esterified carboxy groups, more preferably lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and isopropoxycarbonyl. Preferred examples of A ¹ and A ² include when each is a lower alkyl group such as methyl, ethyl, propyl, isopropyl, etc., and when A ¹ and A ² combine to form a lower alkylene group such as ethylene or trimethylene. There are cases where Preferred examples of X include halogen, more preferably bromine or chlorine. Preferred examples of X' and Examples include di(lower) alkoxymethylene groups such as dioxymethylene group, dimethoxymethylene and diethoxymethylene, and lower alkoxycarbonylhydrazonomethylene groups such as methoxycarbonylhydrazonomethylene and ethoxycarbonylhydrazonomethylene. Preferred Y' Examples include carbonyl groups, lower alkylene dioxymethylene groups such as ethylenedioxymethylene and trimethylene dioxymethylene, di(lower) alkoxymethylene groups such as dimethoxymethylene and diethoxymethylene, or methoxycarbonylhydrazonomethylene and ethoxycarbonyl groups. Examples include lower alkoxycarbonylhydrazonomethylene groups such as carbonylhydrazonomethylene. Salts include commonly used salts, including alkali metal salts such as sodium salts and potassium salts, alkaline earth salts such as calcium salts, and magnesium salts. Salts with inorganic bases or acids such as metal salts such as metal salts, inorganic acid salts such as ammonium salts, hydrochlorides, hydrobromides, sulfates, phosphates, carbonates, bicarbonates; and trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, N-methyleneglucamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamine) Amine salts such as methane salts, phenethylbenzylamine salts, organic carboxylic acids or sulfones such as acetates, maleates, lactates, tartrates, methanesulfonates, benzenesulfonates, toluenesulfonates. Examples include salts with organic bases or organic acids, such as basic or acidic amino acid salts such as acid salts, arginine salts, aspartate salts, glutamate salts, lysine salts, and serine salts, and these salts are suitable for the compounds of the present invention. Each method of the present invention will be described in detail.Method [A] Compound (-a) or a salt thereof is a compound (-a) or a reactive derivative thereof at an amino group or a reactive derivative thereof. For salts, general formula (In the formula, R ¹ , X' and Y have the same meanings as above.) It is produced by reacting a compound represented by the following formula, a reactive derivative thereof at the carboxy group, or a salt thereof. Reactive derivatives at the amino group of compound () include isocyanato, isothiocyanato, reaction products of compound () with silyl compounds such as trimethylsilylacetamide and bis(trimethylsilyl)acetamide, acetaldehyde, isopentaldehyde, benzaldehyde, salicylaldehyde, Reaction products with aldehyde compounds such as phenylacetaldehyde, p-nitrobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, hydroxynaphthaldehyde, furfural, thiophenecarbaldehyde, or the corresponding hydrates, acetals, hemiacetals or enolates reaction products with ketone compounds such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone, ethyl acetoacetate or the corresponding ketals, hemiketals, or enolates, phosphorus oxychloride,
Included are reactive derivatives commonly used in a wide range of amidation reactions, such as reaction products with phosphorus compounds, such as phosphorus trichloride, and reaction products with sulfur compounds, such as thionyl chloride. Examples of reactive derivatives at the carboxy group of the compound () include acid halides, acid anhydrides, active amides, active esters, etc., but particularly preferred are acid halides such as acid chlorides and acid bromides, substituted phosphoric acids, etc. (e.g. dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.) mixed anhydride, dialkyl phosphorous mixed anhydride, sulfurous mixed anhydride, thiosulfuric acid mixed anhydride, sulfuric acid mixed anhydride, alkyl carbonic acid mixed anhydride mixed anhydrides such as aliphatic carboxylic acids (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid, etc.) mixed anhydrides, aromatic carboxylic acids (e.g. benzoic acid, etc.) mixed anhydrides, symmetrical type acid anhydride, imidazole, 4
-Activated amides, cyanomethyl esters, methoxymethyl esters, dimethylaminomethyl esters, vinyl esters with substituted imidazoles, dimethylpyrazoles, triazoles, tetrazoles, etc.
Propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenyl azophenyl ester, phenyl thio ester, p
- Nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, N-hydroxy compounds (e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2 Active esters such as esters with -(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc.) are commonly used in amidation reactions. Examples include reactive derivatives. The reactive derivative of compound () is appropriately selected depending on the type of compound () used and reaction conditions. This reaction usually involves water, acetone, dioxane, acetonitrile, chloroform, benzene,
The reaction is carried out in a conventional solvent such as methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, other solvents that do not adversely affect the reaction, or mixtures thereof. In this reaction, when the compound () used as an acylating agent is used in the form of a free acid or its salt, examples of N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-
N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylamino carbodiimide compounds such as N,N-carbonylbis(2-methylimidazole), imine compounds such as pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, ethoxyacetylene, β−
Olefinic or acetylenic ether compounds such as chlorovinylethyl ether, 1-(4-chlorobenzenesulfonyloxy)-6-chloro-
1H-benzotriazole, N-ethylbenzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide inner salt, polyphosphoric acid, trialkyl phosphite, polyphosphoric acid ethyl ester, poly Phosphorus compounds such as phosphoric acid isopropyl ester, phosphorus oxychloride, phosphorus trichloride, diethylchlorophosphite, orthophenylenechlorophosphite, thionyl chloride, oxalyl chloride, N,N-dimethylformamide and thionyl chloride, phosphorus oxychloride, phosgene, etc. It is preferable to carry out the reaction in the presence of a condensing agent such as Vilsmeier's reagent obtained by reaction with. Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction under cooling or heating. Method [B] Compound (-c) or a salt thereof is produced by subjecting compound (-b) or a salt thereof to an elimination reaction of a protecting group on a carbonyl group. This elimination reaction can be carried out by a conventional method, for example, treating the compound (-b) or its salts with an acid such as a mineral acid such as hydrochloric acid or sulfuric acid, or an inorganic peracid such as perchloric acid or periodic acid. This is done by The reaction usually involves water, methanol, ethanol,
acetone, chloroform, methylene chloride,
It is carried out in a solvent such as diethyl ether, benzene, dioxane, or tetrahydrofuran. Although the reaction temperature is not particularly limited, it is often carried out under cooling or heating. Methods [C] and [D] Compounds (-a) and (-c) or salts thereof are prepared by preparing the corresponding compounds () and (), respectively.
or its salts, by subjecting it to a dehydration reaction. This dehydration reaction is preferably performed on compound (-a)
Alternatively, it is carried out by treating (-c) or a salt thereof with a dehydrating agent. As a dehydrating agent,
Alkanesulfonic acids such as methanesulfonic acid, p-
Organic sulfonic acids such as arenesulfonic acids such as toluenesulfonic acid, organic carboxylic acids such as haloalkanoic acids such as trifluoroacetic acid, organic carboxylic acid anhydrides such as acetic anhydride, trifluoroacetic anhydride, formic acid and acetic anhydride. Acid halides such as combinations of acids and acid anhydrides, organic sulfonic acid halides such as mesyl chloride and tosyl chloride, organic carboxylic acid halides such as acetyl chloride, and inorganic acid halides such as phosphorous oxychloride and thionyl chloride. Can be mentioned. The dehydration reaction, particularly when using an acid halide or acid anhydride type dehydrating agent, is preferably carried out in the presence of a base. As the base, trimethylamine, triethylamine, N-methylpiperazine,
Organic bases such as N,N-dimethylaniline, pyridine, anisole, thioanisole, etc.; inorganic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate, sodium acetate, potassium acetate, etc. Examples include Lewis bases. When the dehydrating agent is an acylating agent in this reaction, a compound in which the 3-hydroxy group of the starting compound () or () is acylated may be produced during the reaction, but these 3-acyloxy A cephalic compound can be isolated or without isolation, for example, treated with a base to lead to the corresponding target compound (-a) or (-c). This reaction is preferably carried out under anhydrous conditions and is usually carried out in a conventional solvent such as tedrahydrofuran, dioxane, chloroform, methylene chloride, benzene, or other solvents that do not adversely affect the reaction. . The reaction temperature is not particularly limited, but it is preferably carried out at room temperature or under heating. Method [E] Compound (a) or (b) is produced by subjecting the corresponding compound (a) or (b) to an acetal-forming reaction. This acetal-forming reaction is preferably carried out by reacting compound (a) or (b) with an alcohol or orthoformate. Examples of alcohols include lower alkanols such as methanol, ethanol, and propanol, and lower alkylene glycols such as ethylene glycol and propylene glycol. Examples of orthoformate esters include orthoformates such as methyl orthoformate and ethyl orthoformate. Examples include lower alkyl esters. When using alcohol in this reaction, p
- in a solvent such as benzene, toluene, cyclohexane, 1,2-dichloroethane, 1,2- It is preferable to carry out the reaction under heating in an azeotropic solvent such as dichloropropane while distilling off water produced during the reaction. When using orthoformic acid ester in this reaction, in the presence of a Lewis acid such as the one mentioned above, in a lower alkanol such as methanol, ethanol, or other solvent that does not adversely affect this reaction, at room temperature or It is desirable to carry out the reaction under heating. Method [F] Compound (a) or (b) is added to the corresponding compound (a) or (b) by adding a group to the hydroxy group of these compounds (a) or (b), respectively.
It is produced by reacting a lower alkylating agent capable of introducing R ¹ (R ¹ has the same meaning as before). Examples of lower alkylating agents include mono (or di) (lower) alkyl sulfates such as mono (or di) methyl sulfate and mono (or di) ethyl sulfate;
Examples include halo (lower) alkanes such as methyl iodide, and diazo lower alkanes such as diazomethane and diazoethane. This reaction is preferably carried out in a conventional solvent such as acetone, methyl isobutyl ketone, ethyl acetate, or other solvents that do not adversely affect the reaction. Mono(or di)(lower) alkyl sulfate or halo(lower) as the lower alkylating agent in this reaction.
When using an alkane, it is desirable to carry out the reaction in the presence of a base such as sodium carbonate or potassium carbonate. Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction under cooling or under heating. Method [G] Compound (a) or (b) is produced by subjecting the corresponding compound (a) or (b), respectively, to an acetal-forming reaction. Since this reaction is carried out in substantially the same manner as reaction [E], the description regarding method [E] is cited for the reaction conditions. Method [H] Compound (b) is produced by reacting compound (a) with a halogenating agent. Examples of halogenating agents include halogens such as chlorine, bromine, and iodine, sulfuryl halides such as sulfuryl chloride and sulfuryl bromide, N-haloid compounds such as N-bromosuccinimide and N-chlorosuccinimide, and pyridinium hydrobromide peroxide. Complex compounds of halogen and pyridine such as bromide,
Mention may be made of the conventional halogenating agents used for the halogenation of so-called active methylene groups, such as 2-pyrrolidone hydrotribromide. This reaction usually involves chloroform, methylene chloride, 1,2-dichloroethane, 1,2-dichloropropane, diethyl ether, diisopropyl ether, tedrahydrofuran, dioxane,
or in any other solvent that does not adversely affect the reaction. The reaction temperature is not particularly limited, but it is preferably carried out at room temperature or under heating. Method [I] Compound (a) or its salt, or compound (b) or its salt is produced by hydrolyzing the corresponding compound (a) or (b), respectively. This reaction may be carried out in the presence of a base such as an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, or an organic base such as trimethylamine, triethylamine, picoline, N-methylmorpholine. is preferable, and it is particularly preferable to carry out the reaction in the presence of a strong base. Among the above bases, liquid ones can also be used as a solvent. This reaction is preferably carried out in a solvent such as water or a lower alkanol such as methanol or ethanol, or any other solvent that does not adversely affect this reaction. Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction under cooling or under heating. The 3-cephem compound of the present invention can be prepared by, for example, the method shown in the Examples, and has antibacterial activity.
-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-cephem-4-
It can lead to carboxylic acid (syn isomer). In order to clarify the usefulness of the above-mentioned compound having antibacterial activity, the test results for this compound are as follows. 1 In vitro antibacterial activity test (1) Test method In vitro antibacterial activity was measured by the agar plate multiple dilution method described below. One loopful of the test strain, cultured overnight in trypticase soy broth and diluted 1:100, was inoculated onto heart infusion agar (HI agar) containing each concentration of compound and incubated at 37°C for 20 hours. After incubation, the minimum inhibitory concentration (MIC) was determined in μg/ml. (2) Test results

【table】

[Table] 2 Infection protection test in mice (1) Test method Ten ICR male mice, 4 weeks old and weighing 18.5-21.5 g, were used in the test as one group. The test bacterial strains were cultured overnight at 37°C on trypticase soy agar, and then suspended in 5% mucin to prepare suspensions of viable bacteria for each test. This Kendaku liquid
0.5 ml was inoculated intraperitoneally into mice. Test compound vehicles were injected subcutaneously into mice at various doses 1 hour after the above inoculation. After 4 days, the ED ₅₀ value was calculated from the number of surviving mice at each dose. (2) Test results

[Table] 3 Acute toxicity test (1) Test method 6 weeks old, 10 ICL-SD male rats and female rats
10 animals were used as one group. Test compounds were dissolved in distilled water and injected subcutaneously and intravenously to rats. Seven days after injection, Richfield was determined from the number of dead rats.
LD ₅₀ values were calculated by Wilcoxon method. (2) Test results

[Table] Next, this invention will be explained in more detail with examples.
I will clarify. Example 1 2-methoxyimino-3,3-ethylenedioxy
Production of butyric acid (syn isomer) (1) Ethyl 2-methoxyimino-3-oxobutyrate
Ethylene ester (syn isomer, 200g)
Dry base is added to the solution dissolved in Recall (179g).
(3) and p-toluenesulfonic acid
(6g) and the resulting mixture was azeotroped with water.
Heat to reflux for 20 hours while removing with water. reaction mixture
Cool the mixture to room temperature, add water, sodium bicarbonate
Saturated aqueous solution, water, sodium chloride saturated aqueous solution
Washed sequentially, dried with magnesium sulfate, and filtered.
do. Concentrate the liquid and evaporate the remaining oil under reduced pressure.
bp (0.6mmHg) 89.5~91℃
Toxiimino-3,3-ethylenedioxybutyric acid
Ethyl ester (syn isomer, yield 85.5%)
obtain. (2) 2-methoxy-3,3-ethylenedioxybutyric
Acid ethyl ester (syn isomer, 180g) and
and 1N hydroxide in a solution of ethanol (1080ml).
Add sodium aqueous solution (1660ml) and mix
Stir at room temperature for 2 hours and 10 minutes. The reaction mixture is
Adjust the pH to 7.3 with 6N hydrochloric acid and add ethanol under reduced pressure.
and diluted with diethyl ether (500ml x 2).
Wash. Add diethyl ether (1) to this
Add, adjust the pH to 1.5 with 6N hydrochloric acid, and add diethyl ethyl ether.
Separate the ether layer. Remove the aqueous layer from diethyl ether
(350ml), adjusted to PH1.3 with 6N hydrochloric acid,
Further extraction with diethyl ether (350ml x 2)
do. Combine the diethyl ether layer and the extract,
Wash with saturated sodium chloride solution and sulfuric acid mug.
Dry with nesium and strain. concentrate the liquid
and 2-methoxyimino in oil form (155.6g)
3,3-ethylenedioxybutyric acid (syn isomer,
99.3%). IR spectrum (nujiol) 3700−2200, 1740, 1640, 1470, 1450,
1400, 1380, 1260, 1240, 1210, 1150,
1130, 1080, 1030, 1055, 870, 820cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 1.55 (3H, s) 3.85 (3H, s) 3.97 (4H, s) Example 2 2-Methoxyimino-3,3-ethylenedioxy
Production of butyric acid (syn isomer) (1) Ethyl 2-methoxyimino-3-oxobutyrate
Ester (syn isomer, 17.3g), ethylene
Recall (12.4g) and p-toluene sulfonate
acid (0.5g) was dissolved in benzene (260ml).
The solution is heated to reflux while removing the water. obtained
The solution is diluted with saturated aqueous sodium bicarbonate solution and
Wash sequentially with saturated aqueous sodium chloride solution and sulfuric acid.
Dry with magnesium. After distilling off the solvent,
When the residue is distilled under reduced pressure, bp (4 mmHg) 97 ~
2-methoxyimino-3,3-ethyle at 102℃
dioxybutyric acid ethyl ester (syn isomer,
15.2g). NMR spectrum (CDCl ₃ , δppm) 1.34 (3H, t, J = 7Hz) 1.64 (3H, s) 3.92 (3H, s) 4.02 (4H, s) 4.33 (2H, q, J = 7Hz (2) 2-methoxyimino-3, 3-ethylenedio
Xybutyric acid ethyl ester (syn isomer, 25.7
g) and 1N in a solution of ethanol (150ml).
Add sodium hydroxide aqueous solution (130ml) and
Stir overnight at warm temperature. The resulting solution was concentrated under reduced pressure.
Dissolve the residue in saturated aqueous sodium chloride solution.
Dissolve and wash with diethyl ether. water layer
Add ethyl ether (100ml) and dilute with 10% hydrochloric acid.
Adjust the pH to 1 and separate the diethyl ether layer.
Ru. The aqueous layer was extracted twice with diethyl ether (50ml).
put out Combine the diethyl ether layer and extract.
washed with saturated aqueous sodium chloride solution and sulfurized.
Dry with magnesium acid. Distill the solvent and leave the residue
Crystallize the residue and wash it with n-hexane.
Ru. When the precipitate is collected and dried, 2-methoxy
-3,3-ethylenedioxybutyric acid (synisomer
body, 17.7 g). IR spectrum (nujiol) 2650−2200, 1735, 1630cm ^-1 NMR spectrum (CDCl ₃ , δppm) 1.66 (3H, s) 3.94 (3H, s) 4.05 (4H, s) Example 3 2-Methoxyimino-3,3-ethylenedioxy
Production of ci-4-chlorobutyric acid (syn isomer) (1) 2-methoxyimino-3-oxo-4-chloro
Lobutyric acid ethyl ester (syn isomer), 41g),
Ethylene glycol (24.6g), p-toluene
Sulfonic acid (2.0g) and toluene (250ml)
Heat the mixture to reflux for 20 hours while removing the water.
Ru. The reaction mixture was cooled to room temperature and diluted with sodium bicarbonate.
Lium saturated aqueous solution and sodium chloride saturated aqueous solution
solution, dry with magnesium sulfate, and remove the solution.
Distill the medium. Distillation of the residue under reduced pressure yields bp
(2mmHg) 2-methoxyimino at 103-110℃
3,3-ethylenedioxy-4-chlorobutyric acid
The thyl ester (syn isomer, 24.4 g) is obtained. IR spectrum (liquid film) 1735, 1625, 1600cm ^-1 NMR spectrum (CDCl ₃ , δppm) 1.37 (3H, t, J = 7Hz) 3.92 (2H, s) 3.97 (3H, s) 4.17 (4H, s) 4.37 (2H, q, J = 7Hz) (2) 2-methoxyimino-3 ,3-ethylenedio
xy-4-chlorobutyric acid ethyl ester (syn-4-chlorobutyric acid ethyl ester)
(7.3 g) and ethanol (35 ml).
Add 1N aqueous sodium hydroxide solution (35ml) to the solution.
and stir the mixture for 2 hours at 40-45°C. decrease
Concentrate under pressure and add saturated sodium chloride water to the residue.
solution (50 ml) and diethyl ether (60 ml) was added.
ml). Separate the aqueous layer and add diethyl ether.
Add tel (100ml) and adjust the pH to 1 with 10% hydrochloric acid.
do. Separate the diethyl ether layer and dilute the aqueous layer.
Extract with ethyl ether (50 ml x 2). Jie
Combine the methyl ether layer and extract solution, and add sodium chloride.
Wash with magnesium sulfate solution and rinse with magnesium sulfate.
Dry and evaporate the solvent. Apply the base to any remaining oily matter.
Add bezene and distill off besezene. can get
Wash the solid with ligroin, remove and dry.
and 2-methoxyimino-3, with mp80−81℃.
3-ethylenedioxy-4-chlorobutyric acid (syn
isomer, 5.4 g, yield 83.3%). IR spectrum (nujiol) 2500−2200, 1720, 1655, 1625cm ^-1 NMR spectrum (CDCl ₃ , δppm) 3.92 (2H, s) 4.02 (3H, s) 4.20 (4H, s) Example 4 2-Methoxyimino-3,3-ethylenedioxy
Production of cy-4-chlorobutyric acid (syn isomer) (1) 2-methoxyimino-3,3-ethylenedio
Xybutyric acid ethyl ester (syn isomer, 30g)
and lithium chloride in a solution of acetic acid (150 ml)
(7 g) and stir the mixture for 15 minutes at room temperature.
Ru. Add sulfuryl chloride (22.4g) dropwise to the mixture.
Stir for 1 hour at room temperature and leave overnight. reaction
Add water (600 ml) to the mixture under ice-cooling and stirring.
Add diisopropyl ether (400ml) and stir.
Stir. Separate the diisopropyl ether layer,
The aqueous layer is extracted with diisopropyl ether. Ji
Combine the isopropyl ether layer and the extract,
water, saturated aqueous sodium bicarbonate solution, water and
Wash sequentially with saturated aqueous sodium chloride solution and sulfuric acid.
Dry with magnesium and filter. concentrate the liquid
and distill the remaining oil (31.2g) under reduced pressure.
and 2-method of bp (0.32-0.35mmHg) 104-106℃.
Toxiimino-3,3-ethylenedioxy-4
-Chlorobutyric acid ethyl ester (syn isomer)
obtain. IR spectrum (nujiol) 2970, 2930, 2900, 2820, 1730, 1620,
1460, 1445, 1420, 1375, 1300, 1280,
1260, 1210, 1200, 1140, 1040cm ^-1 NMR spectrum (CDCl ₃ , δppm) 1.33 (3H, t, J = 7Hz) 3.90 (2H, s) 3.97 (3H, s) 4.17 (4H, s) 4.34 (2H, q, J = 7Hz) (2) 2-Methoxyimino-3 ,3-ethylenedio
xy-4-chlorobutyric acid ethyl ester (syn-4-chlorobutyric acid ethyl ester)
(10.4 g) and ethanol (30 ml).
Water with sodium hydroxide (3.3g) dissolved in the liquid
The solution (10 ml) was added under ice cooling and the mixture was kept at room temperature.
Stir for 30 minutes. The reaction mixture was cooled on ice with 20% sulfuric acid.
Adjust the pH to 7 while stirring, add water (30ml) and dissolve.
Distill the medium. Add water (30 ml) to the residue and obtain
Diisopropyl ether (50ml)
Wash with Diisopropyl ether in aqueous solution
(100ml) and stirred with 20% sulfuric acid to pH 2.
Adjust to saturate the sodium chloride. Diiso
Separate the propyl ether layer and separate the aqueous layer in diisopropylene.
Extract with lopylether. Diisopropyle
Combine the ether layer and extract and add sodium chloride.
Wash with aqueous solution and dry with magnesium sulfate
treated with activated carbon and filtered. concentrate the liquid
and leave the remaining oil under vacuum for 1 hour.
and mp80−81℃, crystalline 2-methoxyimide
No-3,3-ethylenedioxy-4-chlorobutyric
The acid (syn isomer, yield 99.6%) is obtained. IR spectrum (nujiol) 2650, 2500, 1720, 1655, 1620, 1465,
1430, 1400, 1300, 1255, 1215, 1050,
1020cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 3.80 (2H, s) 3.83 (3H, s) 4.00 (4H, d) Example 5 2-Methoxyimino-3,3-ethylenedioxy
Production of cy-4-bromobutyric acid (syn isomer) (1) 2-methoxyimino-3,3-ethylenedio
Xybutyric acid ethyl ester (syn isomer, 20g)
and bromine in a solution of chloroform (200 ml)
(14.72g) and chloroform (30ml) solution
was added at room temperature and stirred at the same temperature for 1 hour. Obtained
5% sodium thiosulfate aqueous solution
(100ml) and stir for 10 minutes at room temperature. organic
Separate the layers and add 5% sodium thiosulfate aqueous solution.
(100ml), water (100ml), sodium bicarbonate
water solution and saturated sodium chloride solution.
Then wash and dry with magnesium sulfate. solution
was concentrated under reduced pressure to obtain the remaining oil (33.4g).
When distilled under reduced pressure, bp (0.95mmHg) 115−118
°C, oily 2-methoxyimino-3,3-ethyl
Dioxy-4-bromobutyric acid ethyl ester
(syn isomer, yield quantitative) is obtained. IR spectrum (liquid film) 3000, 2960, 1745, 1630, 1300, 1265,
1200, 1040cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 1.33 (3H, t, J = 6Hz) 3.78 (2H, s) 3.93 (3H, s) 4.17 (4H, s) 4.35 (2H, q, J = 6Hz) (2) 2-methoxyimino-3 ,3-ethylenedio
xy-4-bromobutyric acid ethyl ester (syn-4-bromobutyric acid ethyl ester)
(26.6 g) and methanol (60 ml).
Add sodium hydroxide (8.64g) and water to the liquid.
(20 ml) solution was added under ice-cooling and kept at room temperature for 2 hours.
Stir. Add water (100ml) to the resulting solution,
Adjust the pH to 7.0 with 20% sulfuric acid under ice cooling. under reduced pressure
After distilling off the methanol, the solution was diluted with diethyl ethyl ethyl ether.
Wash with water (100ml). Diethyl in the aqueous layer
Add ether (100ml) and keep at below 10℃.
Adjust the pH to 2.0 with 20% sulfuric acid. Separate the organic layer,
Extract the aqueous layer twice with diethyl ether (100ml)
do. Collect the organic layer, add water and sodium chloride
Washed sequentially with saturated aqueous solution and then with magnesium sulfate.
dry. Concentrate the solution under reduced pressure and cool the residue.
If left overnight in a warehouse, 2-methoxyimino-
3,3-ethylenedioxy-4-bromobutyric acid
(Syn isomer, 18.0 g. Yield 74.7%) was obtained. IR spectrum (nujiol) 2600, 1755, 1650, 1290, 1230, 1170,
1060, 1035, 1015cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 3.73 (2H, s) 3.8 (3H, s) 4.03 (4H, d, J = 2Hz) Example 6 2-Methoxyimino-3,3-ethylenedioxy
Production of cibutyric acid ethyl ester (syn isomer) (1) Ethyl 2-hydroxyimino-3-oxobutyrate
ester (syn isomer, 10g). Ethylene
Recall (19.75g), p-toluenesulfonic acid
(0.3g) and dry benzene (150ml).
Heat the product to reflux for 2 hours while removing water azeotropically.
do. The reaction mixture was dissolved in water (50 ml) and sodium bicarbonate.
Lium saturated aqueous solution (50ml), water (50ml) and
Wash sequentially with saturated aqueous sodium chloride solution (50 ml)
, dried over magnesium sulfate, and filtered.
When the liquid is concentrated, an oily 2-hydroxyimino
-3,3-ethylenedioxybutyric acid ethyl ester
(syn isomer, 7.12 g, yield 55.1%) was obtained.
Ru. IR spectrum (liquid film) 3350, 2960, 2880, 1730, 1370, 1280,
1200, 1060, 1030, 960, 945, 880cm ^-1 NMR spectrum (CCl _Four , δppm) 1.33 (3H, t, J = 7Hz) 1.58 (3H, s) 3.97 (4H, s) 4.33 (2H, q, J = 7Hz) 9.67 (1H, broad s) (2) 2-Hydroxyimino- 3,3-ethylenedi
Oxybutyric acid ethyl ester (syn isomer, 5
g) and dry ethyl acetate (20ml),
Add potassium carbonate (5.78g) and dimethyl sulfate.
(3.96 ml) was added dropwise at room temperature under stirring, and the mixture was
Stir at 43-45°C for 2 hours. water to the reaction mixture
(10 ml) and ethyl acetate (5 ml), and
Stir for 40 minutes at warm temperature. Mixture to PH7.2 with 6N hydrochloric acid
saturated with sodium chloride and ethyl acetate.
Separate the layer. Extract the aqueous layer with ethyl acetate
Ru. Combine the ethyl acetate layer and extract, add sodium chloride to
Wash with a saturated aqueous solution of magnesium sulfate
Dry and sieve. When the liquid is concentrated, 2-
Methoxyimino-3,3-ethylenedioxybutyric
Acid ethyl ester (syn isomer, quantitative) obtained
Ru. IR spectrum (liquid film) 2990, 2950, 2900, 1740, 1620, 1470,
1450, 1380, 1285, 1220, 1080, 1040cm ^-1 NMR spectrum (CDCl ₃ , δppm) 1.33 (3H, t, J = 7Hz) 1.67 (3H, s) 3.93 (3H, s) 4.03 (4H, s) 4.33 (2H, q, J = 7Hz) The obtained compound was obtained in Example 1. ,2,3,4 also
In the same manner as in 5, 2-methoxyimino-3,3
-ethylene dioxybutyric acid (syn isomer), 2-methane
Toximino-3,3-ethylenedioxy-4-
Chlorobutyric acid (syn isomer), or 2-methoxy
imino-3,3-ethylenedioxy-4-bromo
can lead to butyric acid (syn isomer). Example 7 2-methoxyimino-3,3-ethylenedioxy
Production of cy-4-chlorobutyric acid ethyl ester (1) 2-hydroxyimino-3-oxobutyric acid ethyl ester
ester (syn isomer, 31.8g) and chloroester (syn isomer, 31.8g) and
Sulfuryl chloride in a solution of loform (70 ml)
(29.7g) was added over 6 minutes under ice cooling, and mixed.
The mixture is stirred for 4.5 hours at room temperature. Mixture at 7℃
Cool to
Add. The mixture is stirred at room temperature overnight. reaction
The mixture was cooled with ice water and chloroform (50ml)
and water (40 ml) are added under stirring. into the mixture
Saturate the sodium chloride, separate the organic layer, and salt
Wash with saturated sodium chloride solution (40ml x 2)
, dried over magnesium sulfate, and filtered.
When the liquid is concentrated, 2-hydroxyimino-3-
Oxo-4-chlorobutyric acid ethyl ester (syn
isomers, quantitative). IR spectrum (liquid film) 3700−3100, 2980, 2875, 1720, 1630,
1480, 1455, 1400, 1380, 1335, 1280,
1200, 1100, 1030, 980cm ^-1 NMR spectrum (CCl _Four , δpppm) 1.37 (3H, t, J = 7Hz) 4.37 (2H, q, J = 7Hz) 4.52 (2H, s) 10.65 (1H, s) (2) 2-Hydroxyimino-3-oxo-4-k
lolobutyric acid ethyl ester (syn isomer, 10g),
Ethylene glycol (16g), p-toluene
Sulfonic acid (0.3g) and dry benzene (100g)
ml) mixture at 19:00 with azeotropic removal of water.
Heat to reflux for a while. Cool the reaction mixture to room temperature,
Add water (30ml) and benzene (20ml) to this.
I can do it. This mixture is saturated with sodium chloride,
Separate the benzene layer and add the aqueous layer to benzene (20ml)
Extract with Combine the benzene layer and extract.
Then, add saturated aqueous sodium chloride solution (30ml x 2).
Wash, dry with magnesium sulfate and filter
Ru. When the liquid is concentrated, an oily 2-hydroxy
Methoxyimino-3,3-ethylenedioxy-
4-chlorobutyric acid ethyl ester (syn isomer,
7.23 g, yield 58.9%). IR spectrum (liquid film) 3675−3125, 2980, 2910, 1730, 1455,
1430, 1380, 1290, 1190, 1095, 1030,
955cm ^-1 NMR spectrum (CCl _Four , δppm) 1.33 (3H, t, J = 7Hz) 3.77 (2H, s) 4.05 (4H, s) 4.28 (2H, q, J = 7Hz) 9.67 (1H, s) (3) 2-Hydroxyimino-3 ,3-ethylenedi
Oxy-4-chlorobutyric acid ethyl ester (syn
isomer, 0.5 g) and dry acetone (5 ml)
Add potassium carbonate (0.29g) to the solution and dilute
Add methyl sulfuric acid (0.265g) dropwise at room temperature while stirring.
do. The mixture was stirred at room temperature for 7 hours and filtered.
Ru. When the liquid is concentrated, 2-methoxyimino-
3,3-ethylenedioxy-4-chlorobutyric acid
The thyl ester (syn isomer) is obtained. IR spectrum (liquid film) 2970, 2930, 2900, 2820, 1730, 1620,
1460, 1445, 1420, 1375, 1300, 1280,
1260 (shoulder), 1210, 1200, 1140, 1040cm ^-1 NMR spectrum (CDCl ₃ , δppm) 1.33 (3H, t, J = 7Hz) 3.90 (2H, s) 3.97 (3H, s) 4.17 (4H, s) 4.34 (2H, q, J = 7Hz) The obtained compound was obtained in Example 3. (2) or same as 4(2)
2-methoxyimino-3,3-ethylene
dioxy-4-chlorobutyric acid (syn isomer)
You can Example 8 2-methoxyimino-3,3-dimethoxy-4
-Production of bromobutyric acid (syn isomer) (1) Ethyl 2-methoxyimino-3-oxobutyrate
Ester (syn isomer, 17.3g) and dry method
Methyl orthoformate in a solution of tanol (50 ml)
(31.8g) and Amberlyst 15 (trade name,
Add 1.7g) under stirring and heat at 50 to 60℃ for 2.5 hours.
Stir for a while. Add methoxy orthoformate to the resulting solution.
(10.6 g) and stir for 2 hours. This melt
Leave the liquid in the refrigerator overnight at 50 to 60℃.
Stir for 2 hours. Distill methanol under reduced pressure
Then add diethyl ether (100ml) and
Add water (50ml) and separate the organic layer. water layer
is extracted with diethyl ether. Organic layer and extraction
Combine the liquids and wash with saturated aqueous sodium chloride solution.
do. Dry the solution over magnesium sulfate and reduce pressure
Concentrate down to bp (0.35mmHg) 61-64℃ 2
-Methoxyimino-3,3-dimethoxybutyric acid
The thyl ester (syn isomer, 18 g) is obtained. IR spectrum (liquid film) 3000, 2950, 2920, 2850, 1750, 1640,
1480, 1460, 1400, 1380, 1310, 1250,
1205, 1195, 1160, 1120, 1085, 1060,
1040,890cm ^-1 NMR spectrum (CCl _Four , δpppm) 1.28 (3H, t, J = 7Hz) 1.47 (3H, s) 3.17 (6H, s) 3.85 (3H, s) 4.18 (2H, q, J = 7Hz) (2) 2-Methoxyimino-3 ,3-dimethoxybutyric
Acid ethyl ester (syn isomer, 1.0g) and
and dry tedrahydrofuran (10 ml).
Pyridinium hydromide perbromide
(1.82 g) and heated under reflux for 1 hour. Obtained
Pour the solution into water (30 ml) and add diethyl ethyl ether.
Extract with ether (10ml x 2). 5% extract
Sodium thiosulfate solution (5 ml x 5) and salt
Wash sequentially with a saturated aqueous sodium solution (10 ml x 1).
Purify. Dry the solution with magnesium sulfate and reduce
Concentration under pressure yields 2-methoxyimino-3,
3-dimethoxy-4-bromobutyric acid ethyl ester
(syn isomer, 2.02 g). IR spectrum (liquid film) 3700−2500, 1730, 1620, 1600, 1460,
1440, 1385, 1365, 1305, 1245, 1200,
1150, 1100, 1060, 1030cm ^-1 NMR spectrum (CDCl ₃ , δppm) 1.33 (3H, t, J = 7Hz) 3.33 (6H, s) 3.83 (2H, s) 3.97 (3H, s) 4.32 (2H, q, J = 7Hz) (3) 2-methoxyimino-3 ,3-dimethoxy-
4-bromobutyric acid ethyl ester (1.06g) and
Add 2N sodium hydroxide to a solution of water and methanol (1 ml).
Thorium methanol solution (6.5ml) was cooled on ice.
Add and stir at room temperature for 3 hours. the resulting solution
, diethyl ether (20ml) and water (20ml)
ml). Separate the organic layer and add diethyl to the aqueous layer.
Add ether (30ml) and keep at below 10℃.
Adjust pH to 1.6 with 6N hydrochloric acid. Separate the organic layer,
Extract the aqueous layer with diethyl ether (30ml).
Combine the organic layer and extract and add water and sodium chloride.
Wash sequentially with a saturated aqueous solution of magnesium sulfate.
Dry in a vacuum. The solution is concentrated under reduced pressure to form an oil.
2-methoxyimino-3,3-dimethoxy
-4-Bromobutyric acid (syn isomer, 0.4g) was obtained.
Ru. IR spectrum (liquid film) 3700−2700, 2700−2200, 1740, 1640,
1480, 1475, 1455, 1430, 1400, 1310,
1260, 1220, 1160, 1120, 1060, 1040,
970, 890, 835cm ^-1 NMR spectrum (CDCl ₃ , δppm) 3.33 (3H, s) 3.50 (3H, s) 3.70 (2H, s) 4.00 (3H, s) Example 9 2-methoxyimino-3,3-diethoxy-4
-Production of bromobutyric acid (syn isomer) (1) Ethyl 2-methoxyimino-3-oxobutyrate
Ester (syn isomer, 0.5g), orthoformate
Chill (1.71g), Amberlyst 15 (trade name,
200 mg) and dry ethanol (ml), carried out
When treated in the same manner as Example 8 (1), 2-methoxyimide
Nor-3,3-diethoxybutyric acid ethyl ester
(Syn isomer, 0.35 g) is obtained. IR spectrum (liquid film) 2980, 2950, 2900, 1750, 1640, 1600,
1500, 1480, 1460, 1400, 1380, 1310,
1250, 1180, 1130, 1100, 1080, 1060,
1040cm ^-1 NMR spectrum (CCl _Four , δppm) 1.13 (6H, t, J = 7Hz) 1.28 (3H, t, J = 7Hz) 1.50 (3H, s) 3.50 (4H, q, J = 7Hz) 3.85 (3H, s) 4.18 (2H, q , J=7Hz) (2) 2-methoxyimino-3,3-diethoxybutyro
Acid ethyl ester (syn isomer, 10.0g), pi
Lysinium hydrobromide perbromide
(15.5g) and Tedrahydrofuran (100ml)
When treated in the same manner as in Example 8(2), 2-meth
xiimino-3,3-diethoxy-4-bromo
Butyric acid ethyl ester (syn isomer, 16.20g)
get. IR spectrum (liquid film) 3000−2900, 1730, 1620, 1600, 1440,
1390, 1360, 1300, 1250, 1190, 1150,
1110, 1090, 1040cm ^-1 NMR spectrum (CCl _Four , δppm) 1.10−1.42 (9H, m) 3.42 (4H, q, J=6.0Hz) 3.60 (2H, s) 3.92 (3H, s) 4.22 (2H, q, J=6.0Hz) (3) 2− Methoxyimino-3,3-diethoxy-
4-bromobutyric acid ethyl ester (syn isomer,
10.0g), aqueous solution of sodium hydroxide (3.68g)
liquid (70 ml) and ethanol (100 ml).
When treated in the same manner as in Example 8 (3), 2-methoxyi
Mino-3,3-diethoxy-4-bromobutyric acid
(Syn isomer, 4.97 g) is obtained. IR spectrum (liquid film) 3450, 3000−2900, 2600, 1730, 1620,
1440, 1420, 1390, 1290, 1240, 1190,
1150, 1110, 1090, 1040cm ^-1 NMR spectrum (CDCl ₃ , δppm) 1.17 (3H, t, J = 6Hz) 1.25 (3H, t, J = 6Hz) 3.49 (4H, q, J = 6Hz) 3.66 (2H, s) 3.91 (3H, s) 7.00 (1H, s ) Example 10 (1) 7-aminocephalosporanic acid (23.1 g, pure
86.4%), 2-mercaptobenzothiazole
(14.7 g) and water (800 ml), carbonated
Add sodium hydrogen (13.5g) little by little while stirring.
Add acetone (250ml). the mixture,
Stir at 73℃ for 4.5 hours, cool to below 20℃, and add 6N
Adjust the pH to 3.4 with hydrochloric acid. Take the precipitated crystals
washed sequentially with water and acetone and placed under reduced pressure.
When dried, 7-amino-3-(benzothiazo
(2-ylthiomethyl)-3-cephem-
4-carboxylic acid (18.7 g) is obtained. IR spectrum (nujiol) 3800−2800, 1800, 1620, 1540, 1425,
1410 (shoulder), 1350, 1020 (shoulder), 1010, 1000,
820, 800, 785, 755, 730cm ^-1 NMR spectrum (D ₂ O+NaHCO ₃ , δppm) 3.22, 3.62 (2H, d, d, J = 15Hz) 4.06, 4.4 (2H, d, d, J = 13Hz) 5.02 (1H, d, J = 5Hz) 5.55 (1H, d, J = 5Hz ) 7.0−7.88 (4H, m) (2) 7-amino-3-(benzothiazole-2-
ylthiomethyl)-3-cephem-4-carbo
Sudden acid (3.80g) and ethyl acetate (80ml)
Trimethylsilylacetamide (6.57
g) and stirred at room temperature for 1 hour. On the other hand,
N,N-dimethylformamide (0.92g), vinegar
Add thionichloride to a solution of ethyl chloride (10 ml) under stirring.
(1.5 g) and stir for 30 minutes under ice cooling.
Add 2-methoxyimino-3,3-ethyl to this solution.
Tyledioxybutyric acid (syn isomer, 2.27g)
Add and stir at 5 to 10°C for 2 hours. instructor
The activated acid solution obtained by
at -30℃ for 45 minutes, and then at the same temperature for 2 hours.
Stir for a while. The resulting mixture was mixed with water (100ml).
Dilute and stir for 10 minutes. remove insoluble matter from the mixture
and diluted the liquid with ethyl acetate:methanol (4:
1) Extract twice with mixed solvent (200ml). the above
Insoluble matter is ethyl acetate:methanol (4:1)
Dissolve in mixed solvent (200ml) and stir for 30 minutes.
and pass. Combine the liquid and the above extract.
washed with a saturated aqueous solution of sodium chloride, and washed with sulfuric acid.
Dry over magnesium and concentrate under reduced pressure. Residue
Add diisopropyl ether to the distillate and store in the refrigerator.
Leave it inside. Decant the solvent and remove the residue.
When triturated in n-hexane, 7-(2-methane)
Toxiimino-3,3-ethylenedioxybutylene
(benzothiazol-2-yl)-3-(benzothiazol-2-yl)
thiomethyl)-3-cephem-4-carboxylic acid
(Syn isomer, 3.7 g) is obtained. IR spectrum (nujiol) 3700−2000, 1780, 1720, 1685 (shoulder),
1670, 1620 (shoulder), 1520, 1430, 1240,
1200, 1165 (shoulder), 1100, 1080, 1040, 1000
cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 1.50 (3H, s) 3.3−4.0 (2H, broad s) 3.8 (3H, s) 3.93 (4H, s) 4.23, 4.83 (2H, d, d, J=12Hz) 5.1 (1H, d, J=5Hz) 5.71 (1H, d, d, J=5Hz, 8Hz) 7.27-7.67 (2H, m) 7.67-8.17 (2H, m) 9.37 (1H, d, J=8Hz) (3) Method A 7 -(2-methoxyimino-3,3-ethylene
dioxybutyramide)-3-(benzothiazole)
-2-ylthiomethyl)-3-cephem-4-ka
Rubonic acid (syn isomer, 2g) and N,N-di
Formic acid (10ml) was added to a solution of methylformamide (10ml).
ml), Tedrahydrofuran (40ml) and water (10
ml) and to this mixture, add zinc powder (1.4 g)
was added under stirring at 0 to 2℃ and kept at the same temperature for 1.5 hours.
Stir. The reaction mixture was filtered and the residue
Wash with hydrofuran. Combine the liquid and washing liquid,
Concentrate under reduced pressure. Dilute the residue with water (50ml)
and extract with ethyl acetate (150ml). extract liquid
Wash with water and extract with aqueous sodium bicarbonate solution.
Add ethyl acetate (50ml) to the extract and dilute with 6N hydrochloric acid.
Adjust to PH2. Separate the organic layer and remove the aqueous layer with acetic acid.
Extract with chill (50ml). Ethyl acetate layer and extract
were combined with water and a saturated aqueous solution of sodium chloride.
Washed sequentially, dried over magnesium sulfate, and dried under reduced pressure.
Concentrate into. Add n-hexane to the oily residue,
Leave in the refrigerator overnight to pulverize. precipitation
When taken, 7-(2-methoxyimino-3,3-
ethylenedioxybutyramide)-3-methylene
Cefem-4-carboxylic acid (syn isomer) and
7-(2-methoxyimino-3,3-ethylene di
Oxybutyramide)-3-methyl-3-cefe
Mu-4-carboxylic acid (syn isomer) (5:1)
A mixture (0.5 g) is obtained. 3-methylene cefem compound NMR spectrum (DMSO-d ₆ , δppm) 1.5 (3H, s) 3.5 (2H, s) 3.8 (3H, s) 3.9 (4H, s) 5.07 (1H, s) 5.27 (2H, s) 5.3 (1H, d, J=4Hz) 5.47 (1H, d, d, J = 4Hz, 8Hz) 9.3 (1H, d, J = 8Hz) B Method 7-(2-methoxyimino-3,3-ethylene
dioxybutyramide)-3-(benzothiazole)
-2-ylthiomethyl)-3-cephem-4-ka
Rubonic acid (syn isomer, 500mg) tedrahydrof
Acetic acid was added to a solution of run (6 ml) and water (2 ml).
(1 ml). Add zinc powder (500mg) to this solution.
and copper sulfate pentahydrate (50 mg) were added at room temperature.
Stir for 2 hours at 30°C. The resulting solution was subjected to the above procedure.
When processed in the same way as method A in Example 10(3), 7-(2-method)
Toximino-3,3-ethylenedioxybutyl
(amide)-3-methylenecepham-4-carvone
acid (syn isomer) and 7-(2-methoxyimi
No-3,3-ethylenedioxybutyramide)-
3-Methyl-3-cephem-4-carboxylic acid
A mixture (120 mg) of (5:1) is obtained. (4) The mixture obtained in Example 10(3) (346 mg) and
Add 70% perchloric acid to a solution of acetone (5 ml) and
Add solution (0.3 ml) and stir at room temperature for 1 hour.
Add ethyl acetate (50ml) and water to the resulting solution.
(30ml) and separate the organic layer. Vinegar the water layer
Extract with ethyl acid (30ml). organic layer and vinegar
Combine the ethyl acid extracts and add water and sodium chloride.
Wash sequentially with a saturated aqueous solution of magnesium sulfate.
Dry in a vacuum and concentrate under reduced pressure. remove the residue
Powder it with sopropyl ether and remove the precipitate.
Then, 7-(2-methoxyimino-3-oxy
sobutyramide)-3-methylenecefam-4
-carboxylic acid (syn isomer) and 7-(2-
methoxyimino-3-oxobutyramide)-
3-Methyl-3-cephem-4-carboxylic acid
(syn isomer) (5:1) mixture (290mg)
obtain. 3-methylenecephalic compound NMR spectrum (DMSO-d ₆ , δppm) 2.35 (3H, s) 3.53 (2H, s) 4.03 (3H, s) 5.1 (1H, s) 5.28 (2H, s) 5.32 (1H, d, J=5Hz) 5.55 (1H, d, d , J = 5Hz, 8Hz) 9.35 (1H, d, J = 8Hz) (5) The mixture (0.7g) obtained in Example 10 (4) and
Carbadic acid was added to a solution of methanol (10ml).
Add ethyl (256 mg) and acetic acid (0.1 ml),
Stir for 30 minutes at 50-60°C. resulting solution
Add ethyl acetate (50ml) and water (30ml) to
Then, adjust the mixture to pH 2.0 with 6N hydrochloric acid. organic
Separate the layers and extract the aqueous layer with ethyl acetate (30ml)
do. Combine the organic layer and ethyl acetate extract.
and then sequentially with water and saturated aqueous sodium chloride solution.
Washed, dried over magnesium sulfate and under reduced pressure.
Concentrate. Dilute the residue with diisopropyl ether.
After powdering and removing the precipitate, 7-(2-methane)
Toxiimino-3-ethoxycarbonylhydra
(zonobutyramide) -3-methylenecefam-
4-carboxylic acid (syn isomer) and 7-(2
-methoxyimino-3-ethoxycarbonyl
drazobutyramide)-3-methyl-3-se
Fem-4-carboxylic acid (syn isomer) (5:
A mixture of 1) (0.8 g) is obtained. 3-methylenecephalic compound NMR spectrum (DMSO-d ₆ , δppm) 1.2 (3H, t, J = 9Hz) 1.95 (3H, s) 3.47 (2H, broad s) 3.82 (3H, s) 4.10 (2H, q, J = 9Hz) 5.03 (1H, s) 5.20 ( 2H, s) 4.83-5.5 (2H, s) 9.17 (1H, d, J = 8Hz) 10.2 (1H, s) (6) The mixture (100 mg) obtained in Example 10 (5),
Methylene chloride (16ml) and methanol
(4 ml). Add acetal to this solution.
Dehyde (45 mg) was added, and the raw material was analyzed by TLC.
Apply ozone gas at -65℃ until no longer detected.
After passing through the chamber, excess ozone is removed through nitrogen gas.
Ku. FeCl ₃ water at -65°C until the reaction is negative.
Add sodium borohydride. Pour this solution into the chamber
After standing at room temperature, add ethyl acetate (30 ml) and water.
(20ml). The mixture was adjusted to pH 2.0 with 6N hydrochloric acid.
After conditioning, saturate with sodium chloride. water layer
Separate and extract with ethyl acetate (30ml). Yes
Combine the organic layer and ethyl acetate extract and add water and
and saturated aqueous sodium chloride solution, and
Dry over magnesium chloride and concentrate under reduced pressure.
Ru. Powder the residue with diisopropyl ether
After removing the precipitate, 7-(2-methoxyi
Mino-3-ethoxycarbonylhydrazonobuti
3-Hydroxycepham-4-ka
Rubonic acid (syn isomer), 42.8 mg) is obtained. IR spectrum (nujiol) 3700−2200, 3300, 1780 (shoulder), 1770,
1740, 1680, 1550 (shoulder), 1530, 1240,
1170, 1100, 1040cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 1.2 (3H, t, J = 7Hz) 1.95 (3H, s) 2.6-3.83 (3H, m) 3.83 (3H, s) 4.12 (2H, q, J = 7Hz) 4.42 (1H, d, J = 6Hz) 5.1 (1H, d, J = 4Hz) 5.43 (1H, d, d, J = 4Hz, 8Hz) 9.11 (1H, d, J = 8Hz) 10.4 (1H, s) (7) 7 - (2 -methoxyimino-3-ethoxyca
Rubonylhydrazonobutyramide)-3-hydro
Roxycefam-4-carboxylic acid (synisomer
body), 40 mg) and acetone (5 ml),
Add 70% perchloric acid (0.05ml) and incubate for 30 minutes at room temperature.
Stir. The reaction mixture was treated similarly to Example 10(4).
When processed, 7-(2-methoxyimino-3-o
xobutyramide)-3-hydroxycepham
-4-carboxylic acid (syn isomer, 26 mg) was obtained.
Ru. IR spectrum (nujiol) 3450, 3220, 1770 (shoulder), 1750 (shoulder), 1730,
1690, 1660, 1580, 1530, 1360, 1300,
1260, 1170, 1075, 1040cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 2.33 (3H, s) 2.67-4.0 (3H, m) 4.03 (3H, s) 4.47 (1H, d, J = 6Hz) 5.17 (1H, d, J = 4Hz) 5.49 (1H, d, d , J = 4Hz, 8Hz) 9.3 (1H, d, J = 8Hz) (8) 7-(2-methoxyimino-3-oxobuty
3-Hydroxycepham-4-ka
Rubonic acid (syn isomer, 100 mg) and dry
Triflu in a solution of trahydrofuran (10 ml)
Oroacetic anhydride (0.2ml) and triethyl acetate
Add Min (0.12ml) and leave at room temperature for 10 minutes.
Ru. Add ethyl acetate (30ml) and water to the reaction mixture.
(10ml) and adjust the pH to 2 with hydrochloric acid. acetic acid
Separate the ethyl layer, wash with water, and use magnesium sulfate.
and concentrate under reduced pressure. Remove the residue
When crystallized from thyl ether, 7-(2-methane)
Toxiimino-3-oxobutyramide)-3
-Cefem-4-carboxylic acid (syn isomer, 66
mg). IR spectrum (nujiol) 3250, 1780, 1710, 1685, 1650, 1620
(shoulder), 1600, 1540, 1310, 1285, 1260,
1210, 1160, 1100, 1080, 1050, 990cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 2.30 (3H, s) 3.60 (2H, s) 4.00 (3H, s) 5.06 (1H, d, J = 5Hz) 5.79 (1H, d, d, J = 5Hz, 8Hz) 6.48 (1H, s ) 9.34 (1H, d, J = 8Hz) (9) 7-(2-methoxyimino-3-oxobuty
Ruamido)-3-cephem-4-carboxylic acid
(syn isomer, 50 mg) and dry tetrahydro
Aluminum chloride in a solution of furan (10 ml)
(120mg). Add pyridinium to this solution.
Add hydrobromide perbromide (50mg)
Stir for 20 minutes at room temperature. In the resulting solution,
Add ethyl acetate (50ml) and water (10ml),
When the mixture was treated in the same manner as in Example 10(8), 7-
(2-methoxyimino-3-oxo-4-bro
Mobutyramide)-3-cephem-4-carbo
Obtain phosphoric acid (syn isomer, 52.5 mg). IR spectrum (nujiol) 3600−2200, 3240, 1780, 1700, 1690
(shoulder), 1650, 1620, 1590, 1540, 1280,
1230 (shoulder), 1210, 1050cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 3.48, 3.73 (2H, d, d, J = 9Hz) 4.07 (2H, s) 4.12 (3H, s) 5.12 (1H, d, J = 5Hz) 5.83 (1H, d, d, J = 5Hz , 8Hz) 6.5 (1H, s) 9.63 (1H, d, J = 8Hz) (10) 7-(2-methoxyimino-3-oxo-4
-bromobutyramide)-3-cephem-4-
Carboxylic acids (syn isomer, 42 mg) and ethano
Add thiourea (8.4 mg) to a solution of
Add and stir at room temperature for 1 hour, then at 50℃ for 30 minutes.
do. Distill ethanol from the reaction mixture under reduced pressure.
Add water (5 ml) to the residue and dilute with 6N hydrochloric acid.
Adjust to PH4.0. After removing the precipitate and drying it,
7-[2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide]-3-se
Fem-4-carboxylic acid (syn isomer, 8mg)
get. The liquid is mixed with non-ionic adsorption resin “Diamond”.
AEON HP-20” (trade name, manufactured by Mitsubishi Kasei, 5ml)
Column chromatography using
Wash with water (5 ml) and remove with 20% aqueous isopropyl alcohol.
Elute with alcohol. Eluent 1N sodium hydroxide
Adjust the pH to 6.5 with an aqueous solution of aluminum under ice cooling and reduce the pressure.
Concentrate below. Lyophilization of the residue results in 7-
[2-(2-aminothiazol-4-yl)-2
-Methoxyiminoacetamide]-3-cefe
Mu-4-carboxylic acid sodium salt (syn isomer
body, 15 mg). IR spectrum (nujiol) 3700−2200, 1765, 1650, 1620 (shoulder),
1520, 1290, 1245, 1220, 1040, 985cm ^-1 NMR spectrum (D ₂ O, δppm9 3.63 (2H, m) 3.99 (3H, s) 5.16 (1H, d, J=5Hz) 5.81 (1H, d, J=5Hz) 6.28 (1H, t) 6.96 (1H, s) Example 11 (1) N,N-dimethylformamide (0.92g)
and dry ethyl acetate (16 ml).
Add onil (1.52g) under ice-cooling, and stir at the same temperature for 30 minutes.
Stir for a minute. Add 2-methoxyimide to this solution.
No-3,3-ethylenedioxybutyric acid (synisomer
2.3 g) and stirred on ice for 1 hour.
7-amino-3(5-methyl-1,3,4-thi)
Diazole-2-ylthiomethyl)-3-se
Fem-4-carboxylic acid (3.44g), triethyl
Ruamine (4.9ml) and dry methylene chloride
(70 ml) of the above solution under stirring.
It took 30 minutes to drip, and the temperature was 1.5 at -20 to -30℃.
Stir for an hour. Add sodium bicarbonate to the resulting solution.
Add aqueous solution of aluminum, separate the aqueous layer, and add ethyl acetate.
Wash with Ethyl acetate in aqueous solution: ethanol
Add a mixed solvent (4:1) and add 20% sulfur under ice cooling.
Adjust the pH to 2.5 with acid and filter. acetic acid from liquid
Separate the ethyl layer and add the aqueous layer to ethyl acetate (50ml)
Extract twice. , ethyl acetate layer and extract
Combine water and saturated aqueous sodium chloride solution
washed sequentially with water, dried with magnesium sulfate,
Concentrate under reduced pressure. Dilute the residue with diisopropyl ether
When powdered with ether and removed the precipitate, it turns yellow.
Powdered 7-(2-methoxyimino-3,3-
ethylenedioxybutyramide)-3-(5-methane)
Thyl-1,3,4-thiadiazol-2-yl
thiomethyl)-3-cephem-4-carboxylic acid
(Syn isomer, 2.2 g) is obtained. IR spectrum (nujiol) 3700−2100, 3300, 1780, 1730, 1680,
1630, 1535, 1240, 1200, 1170 (shoulder),
1100, 1080, 1040, 1000 (shoulder) cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 1.53 (3H, s) 2.71 (3H, s) 3.73 (2H, broad s) 3.83 (3H, s) 3.97 (4H, s) 4.2, 4.57 (2H, d, d, J = 13Hz) 5.13 ( 1H, d, J = 5Hz) 5.77 (1H, d, d, J = 5Hz, 8Hz) 9.37 (1H, d, J = 8Hz) (2) 7-(2-ethoxyimino-3,3-ethyle
dioxybutyramide)-3-(5-methyl-
1,3,4-thiadiazol-2-ylthiome
Chyl)-3-cefem-4-carboxylic acid (syn)
isomer, 500 mg), tedrahydrofuran (6 ml),
Zinc in a solution of water (2 ml) and acetic acid (1 ml)
(500mg) and copper sulfate pentahydrate (50mg)
Add and stir at room temperature for 2 hours. the resulting mixture
and washed with tedrahydrofuran (5 ml).
do. Combine the liquid and washing liquid, and combine with Example 10(3).
When treated in the same way, 7-(2-methoxyimino
-3,3-ethylenedioxybutyramide)-
3-methylenecefam-4-carboxylic acid
isomer) and 7-(2-methoxyimino-3,
3-ethylenedioxybutyramide)-3-methane
Chil-3-cephem-4-carboxylic acid
to obtain a mixture (160 mg) of 3-methylenecephalic compound NMR spectrum (DMSO-d ₆ , δppm) 1.5 (3H, s) 3.5 (2H, s) 3.8 (3H, s) 3.9 (4H, s) 5.07 (1H, s) 5.27 (2H, s) 5.3 (1H, d, J=4Hz) 5.47 (1H, d, d, J = 4 Hz, 8 Hz) 9.3 (1H, d, J = 8 Hz) (3) The mixture obtained in (2) above was added to Example 10 (4) to (9).
When treated in the same manner as 7-(2-methoxyimine)
Nor-3-oxo-4-bromobutyramide)-
3-cephem-4-carboxylic acid (syn isomer)
get. IR spectrum (nujiol) 3600−2200, 3240, 1780, 1700, 1690 (shoulder)
1650, 1620, 1590, 1540, 1280, 1230
(shoulder), 1210, 1050cm ^-1 NMR spectrum (DMSO−d ₆ , δpppm) 3.48, 3.73 (2H, d, d, J = 9Hz) 4.07 (2H, s) 4.12 (3H, s) 5.12 (1H, d, J = 5Hz) 5.83 (1H, d, d, J = 5Hz , 8Hz) 6.5 (1H, s) 9.63 (1H, d, J = 9Hz) Example 12 (1) Method A 7-amino-3-(5-methyl-1,3,4-
Thiadiazol-2-ylthiomethyl)-3-se
Fem-4-carboxylic acid (3.44g), acetone
(60 ml) and 6N hydrochloric acid (25 ml).
(3.44g) under stirring and stirred at room temperature for 1 hour.
Ru. The resulting mixture is filtered and washed with water. liquid
Combine the washings and wash twice with ethyl acetate (30ml).
Ru. PH7.5 aqueous solution with 4N sodium hydroxide aqueous solution
When adjusted to 7-amino-3-methylenecephaly
mu-4-carboxylic acid and 7-amino-3-methy
A solution containing lu-3-cephem-4-carboxylic acid
obtain. On the other hand, N,N dimethylformamide (0.92
g) and a solution of dry ethyl acetate (16 ml)
Add thionyl (1.52g) under ice cooling,
Stir for 30 min at °C. This suspension contains 2-meth
Xiimino-3,3-ethylenedioxybutyric acid
isomer, 2.3 g). Add this solution to the above
Add to the solution under ice-cooling and add 4N sodium hydroxide solution.
While maintaining pH7.0 to PH7.5 with a solution, at the same temperature.
Stir for 2 hours. Remove the solvent from the resulting solution under reduced pressure.
was distilled off, and ethyl acetate (100ml) was added to the residue.
Ru. Adjust the solution to PH2.0 with 6N hydrochloric acid and separate the organic layer.
take. Extract the aqueous layer twice with ethyl acetate (50ml)
washed sequentially with water and sodium chloride, and washed with sulfuric acid.
Dry over magnesium and concentrate under reduced pressure. Residue
The distillate was powdered with diisopropyl ether and precipitated.
If you remove it, 7-(2-methoxyimino-3,
3-ethylenedioxybutyramide (3-methylene
ncefam-4-carboxylic acid (syn isomer) and
and 7-(2-methoxyimino-3,3-ethylene
dioxybutyramide)-3-methyl-3-cef
Mixture of em-4-carboxylic acids (syn isomers)
(1.59g) is obtained. 3-methylenecephalic compound NMR spectrum (DMSO-d ₆ , δppm) 1.5 (3H, s) 3.5 (2H, s) 3.8 (3H, s) 3.9 (4H, s) 5.07 (1H, s) 5.27 (2H, s) 5.3 (1H, d, J=4Hz) 5.47 (1H, d, d, J = 4Hz, 8Hz) 9.3 (1H, d, J = 8Hz) (2) Method B 7-Amino-3-(5-methyl-1,3,4-
Thiadiazol-2-ylthiomethyl)-3-se
Fem-4-carboxylic acid (3.44 g) and water (60
ml) of p-toluenesulfonic acid monohydrate.
(11.4g). Add zinc powder (3.4
g) is added and the mixture is stirred at room temperature for 1 hour. profit
Filter the mixture and wash with water (10 ml).
Combine the solution and washing solution and wash with ethyl acetate (90ml).
Then adjust the pH to 7.0 with 4N aqueous sodium hydroxide solution.
Ru. Add acetone (40ml) to this aqueous solution and mix.
Compound 2 obtained in the same manner as Example 12 (1) Method A
-methoxyimino-3,3-ethylenedioxybutyrolyte
Acid (syn isomer) reacts with an activated acid solution.
Ru. Add ethyl acetate (100ml) to the resulting reaction mixture
Add and adjust the pH to 2.0 with 6N hydrochloric acid. Ethyl acetate
Separate the layers and extract the aqueous layer twice with ethyl acetate (50ml).
put out Combine the ethyl acetate layer and extract, add salt
Wash with saturated aqueous sodium sulfate solution and rinse with magnesium sulfate solution.
and concentrate under reduced pressure. oily residue
When washed with diisopropyl ether, 7-
(2-methoxyimino-3,3-ethylenedioxy
Sibutyramide)-3-methylenecephaam-4-
Carboxylic acid (syn isomer) and 7-(2-meth
xiimino-3,3-ethylenedioxybutyla
mido)-3-methyl-3-cephem-4-carbo
A mixture of phosphoric acids (syn isomers) is obtained. 3-methylenecephalic compound NMR spectrum (DMSO-d ₆ , δppm) 1.5 (3H, s) 3.5 (2H, s) 3.8 (3H, s) 3.9 (4H, s) 5.07 (1H, s) 5.27 (2H, s) 5.3 (1H, d, J=4Hz) 5.47 (1H, d, d, J = 4 Hz, 8 Hz) 9.3 (1H, d, J = 8 Hz) (3) The mixture obtained in the above Example 12 (2) Method B was
Dissolved in setone (50 ml), 70% perchloric acid (0.3
ml) and stir at room temperature for 1.5 hours. acetic acid
Separate the chilled layer and dilute the aqueous layer with ethyl acetate (50ml).
Extract twice. Combine the ethyl acetate layer and extract.
and then with water and saturated aqueous sodium chloride solution.
Next washed and dried over magnesium sulfate under reduced pressure.
Concentrate into. Diisopropyl ether from the residue
After powdering, removing the precipitate and drying, 7
-(2-methoxyimino-3-oxobutyla
mido)-3-methylenecepham-4-carvone
acid (syn isomer) and 7-(2-methoxyi
Mino-3-oxobutyramide)-3-methyl
-3-cephem-4-carboxylic acid (synisomer
Obtain a mixture (2.1 g) of 3-methylenecephalic compound NMR spectrum) DMSO-d ₆ , δppm) 2.35 (3H, s) 3.53 (2H, s) 4.03 (3H, s) 5.1 (1H, s) 5.28 (2H, s) 5.32 (1H, d, J=7Hz) 5.55 (1H, d, d , J = 5 Hz, 8 Hz) 9.35 (1H, d, J = 8 Hz) (4) The mixture obtained in (3) above was prepared in Example 10 (5) to (9).
When treated in the same manner as 7-(2-methoxyimine)
Nor-3-oxo-4-bromobutyramide)-
3-cephem-4-carboxylic acid (syn isomer)
get. IR spectrum (nujiol) 3600−2200, 3240, 1780, 1700, 1690
(shoulder), 1650, 1620, 1590, 1540, 1280,
1230 (shoulder), 1210, 1050cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 3.48, 3.73 (2H, d, d, J = 9Hz) 4.07 (2H, s) 4.12 (3H, s) 5.12 (1H, d, J = 5Hz) 5.83 (1H, d, d, J = 5Hz , 8Hz) 6.5 (1H, s) 9.63 (1H, d, J = 8Hz) Example 13 (1) 7-Amino-3-(1,3,4-thiadiazo
(2-ylthiomethyl)-3-cephem-
4-carboxylic acid (29.1g) and 2-methoxy
Imino-3,3-ethylenedioxybutyric acid
isomer, 15.1 g) was treated in the same manner as in Example 10(2).
Then, 7-(2-method) of mp145-152℃(decomposition)
Toxiimino-3,3-ethylenedioxybutylene
(1,3,4-thiadiazole)-3-(1,3,4-thiadiazole)
-2-ylthiomethyl)-3-cephem-4-
Carboxylic acid (syn isomer, 32.5 g) is obtained. IR spectrum (nujiol) 3350, 1770, 1730, 1665, 1620, 1530cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 1.53 (3H, s) 3.72 (2H, broad s) 3.82 (3H, s) 3.95 (4H, s) 4.45 (2H, ABq, J = 13Hz) 5.15 (1H, d, J = 5Hz) 5.77 ( 1H, d, d, J = 5Hz, 8Hz) 9.38 (1H, d, J = 8Hz) 9.58 (1H, s) (2) The compound obtained in (1) above was subjected to Example 10 (3) to ( 9)
When treated in the same manner as 7-(2-methoxyimine)
Nor-3-oxo-4-bromobutyramide)-
3-cephem-4-carboxylic acid (syn isomer)
get. IR spectrum (nujiol) 3600−2200, 3240, 1780, 1700, 1690
(shoulder), 1650, 1620, 1590, 1540, 1280,
1230 (shoulder), 1210, 1050cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 3.48, 3.73 (2H, d, d, J = 9Hz) 4.07 (2H, s) 4.12 (3H, s) 5.12 (1H, d, J = 5Hz) 5.83 (1H, d, d, J = 5Hz , 8Hz) 6.5 (1H, s) 9.63 (1H, d, J = 8Hz) Example 14 (1) 7-Amino 3-(5-methyl-1,3,4-
Thiadiazol-2-ylthiomethyl)-3-
Cefem-4-carboxylic acid (1000g) and water
Add concentrated hydrochloric acid (2325ml) to the suspension in (10).
and zinc powder (585g) under ice-cooling,
Stir at 15°C for 1.5 hours. From the reaction mixture
Remove the lead powder, adjust the pH of the solution to 2.0, and add acetic acid ethyl chloride.
Wash with chill (5). Add the solution to 8N sodium hydroxide.
Adjust the pH to 7.0 with thorium aqueous solution and store in the refrigerator.
Leave it overnight. Remove insoluble matter from the mixture and make a liquid
Concentrate to 5 under reduced pressure. Solution with concentrated hydrochloric acid
Adjust to PH3.5. Take the precipitate, water (1),
Acetone (1), ethanol (700ml) and
After sequential washing with diethyl ether (1),
7-amino-3-methylenecephaam-4-cal
Bonic acid (423.7g) is obtained. NMR spectrum (D ₂ O+NaHCO ₃ , δppm) 3.37, 3.72 (2H, d, d, J = 14Hz) 5.00 (1H, s) 5.28, 5.35 (2H, s) 5.33 (1H, d, J = 3Hz) 5.42 (1H, d, J = 3Hz ) (2) 7-Amino-3-methylenecephaam-4-ka
Rubonic acid (10.7g) in methanol (300ml)
Add methanolic hydrochloric acid (300ml).
and dissolve. Add acetaldehyde to this solution.
(11.3 ml) at -65°C and passed through ozone.
Excess ozone is removed through nitrogen gas. obtained
Sodium borohydride (5.67g)
and a saturated aqueous solution of sodium chloride (400ml).
Add to the solution under cooling and leave overnight at 5°C. melt
Methanol is distilled off from the liquid, and water (100%
ml) and adjust the pH to 5.0. Remove the solution from
Ionic adsorption resin “Diaion HP-20” (commercial)
Column chromatograph
Attach to roughy. The eluent was concentrated under reduced pressure;
The residue was lyophilized and dissolved in methanol (50 ml).
to develop. Filter the suspension and concentrate the liquid
do. Washing the residue with acetone reveals 7-a
Mino-3-hydroxycepham-4-carvone
Obtain the acid sodium salt (3.1 g). IR spectrum (nujiol) 3700−2400, 1755, 1610cm ^-1 NMR spectrum (D ₂ O + DCl, δppm) 3.01 (1H, s) 3.10 (1H, d, J = 3Hz) 4.63 (1H, m) 4.78 (1H, d, J = 6Hz) 4.93 (1H, d, J = 4Hz) 5.37 (1H, d, J = 4Hz) Example 15 (1) 7-amino-3-methylenecephaam-4-ka
Rubonic acid (2.14g) and dry methanol
(100ml) of sulfur solution, 20% (W/W) meth
Noric hydrochloric acid (1.8g) and acetaldehyde
(1.76 g) and stir at room temperature. This melt
Add ozone to the solution until no raw material compounds are detected.
through the internet. Pass nitrogen gas through the resulting solution
to remove excess ozone. Hydrogenate this solution
Sodium boron (1.14g) and sodium chloride
um saturated aqueous solution (160 ml) and refrigerated.
Leave it in the refrigerator overnight, then add acetone (80ml) on ice.
(hereinafter, this solution will be referred to as solution A).
On the other hand, 2-methoxyimino-3,3-ethylene
Dioxybutyric acid (syn isomer, 1.89 g), N,
N-dimethylformamide (1.42ml), thiochloride
(1.32ml) and dry ethyl acetate (10ml)
Added under cooling to Vilsmeier reagent prepared from
Well, stir it for 30 minutes at pH 7.0 to 7.5 to activate it.
Make a solution of the acid. This solution was added to the above solution A.
Add to ice-cooling and stir for hours at pH 7.0 to 7.5.
Ru. Acetone is distilled off under reduced pressure and the remaining solution
Wash with ethyl acetate (50ml) and separate the aqueous layer.
Ru. Add ethyl acetate (100ml) to the aqueous layer and chlorinate
Saturate the sodium and adjust the pH to 2.0 with 6N hydrochloric acid.
Ru. Separate the ethyl acetate layer and saturated with sodium chloride.
Wash with aqueous solution and dry with magnesium sulfate.
Ru. The solution was concentrated under reduced pressure and the residue was purified by diisopropylene.
Powder with lopyl ether. Take the precipitate,
When dried, 7-(2-methoxyimino-3,
3-ethylenedioxybutyramide)-3-hyde
Droxycefam-4-carboxylic acid (synisomer
body, 210 mg). IR spectrum (nujiol) 3700−2200 (broad), 1760, 1660,
1520, 1200, 1040cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 1.5 (3H, s) 2.67-4.00 (3H, m) 3.77 (3H, s) 3.90 (4H, s) 4.43 (1H, d, J = 6Hz) 5.12 (1H, d, J = 4Hz) 5.42 (1H, d, d, J = 4Hz, 8Hz) 9.17 (1H, d, J = 8Hz) (2) 7-(2-methoxyimino-3,3-ethyl
dioxybutyramide)-3-hydroxy
Cepham-4-carboxylic acid (syn isomer, 50
mg) and tetrahydrofuran (5 ml) solution
, trifluoroacetic anhydride (0.1 ml) and
Add triethylamine (0.2 ml) and incubate at room temperature for 10
Stir for a minute. Add sodium bicarbonate to the resulting solution.
Add aqueous solution (2 ml) and heat for 2 minutes.
Ru. Add ethyl acetate and water to the solution and add 6N salt
Acidify with acid and separate the ethyl acetate layer. water layer
is extracted with ethyl acetate. ethyl acetate layer and
Combine the aqueous layers and add water and aqueous sodium chloride solution.
and dry with magnesium sulfate.
The solution was concentrated under reduced pressure and the residue was dissolved in diethyl ether.
When powdered with tel, 7-(2-methoxyimide
3,3-ethylenedioxybutyramide)
-3-cephem-4-carboxylic acid (synisomer
body, 30 mg). IR spectrum (nujiol) 3300, 1790, 1730, 1700, 1650, 1550,
1470cm ^-1 NMR spectrum (DMSO−d ₆ , ppm) 1.55 (3H, s) 3.50-3.73 (2H, broad s) 3.83 (4H, s) 3.97 (3H, s) 5.10 (1H, d, J = 4Hz) 6.83 (1H, d, d, J = 4Hz, 8Hz) 6.40−6.63 (1H, t) 9.35 (1H, d, J=8Hz) (3) 7-(2-methoxyimino-3,3-ethyle
dioxybutyramide)-3-cephem-4
-carboxylic acid (syn isomer, 10.9 g) and a
70% perchloric acid in a solution of setone (270ml)
(1.09g) and stirred at room temperature for 3 hours. profit
Add water (150ml) to the solution and add acetone.
is distilled off under reduced pressure. Ethyl acetate to the residue
(300ml) and separate the ethyl acetate layer. water
Extract the layers with ethyl acetate (400ml). acetic acid
Combine the chilled layer and extract and saturated with sodium chloride.
Wash with aqueous solution, leave in refrigerator overnight, and remove sulfuric acid.
Dry with magnesium. Concentrate the solution under reduced pressure
and powder the residue with diisopropyl ether.
Then, 7-(2-methoxyimino-3-oxy
sobutyramide)-3-cephem-4-carbo
phosphoric acid (syn isomer, 5.75 g) is obtained. IR spectrum (nujiol) 3250, 1780, 1710, 1685, 1650, 1620
(shoulder), 1600, 1540cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 2,30 (3H, s) 3.6 (2H, broad s) 4.0 (3H, s) 5.06 (1H, d, J = 5Hz) 5.79 (1H, d, d, J = 5Hz, 8Hz) 6.48 ( 1H, t, J = 4Hz) 9.34 (1H, d, J = 8Hz) Example 16 (1) 7-(2-methoxyimino-3-ethoxyca
Rubonylhydrazonobutyramide)-3-hydro
Roxycefam-4-carboxylic acid (synisomer
4.3 g) and dry tetrahydrofuran
(215 ml) of trifluoroacetic anhydride.
(6.8ml) and triethylamine (4.2ml)
Add under ice cooling and stir at the same temperature for 1 hour. Obtained
Add ethyl acetate (200 ml) and chloride to the solution.
Add saturated aqueous sodium solution (100ml) and add 6N salt.
Adjust the pH to 2.0 with acid. Separate the organic layer and remove the aqueous layer.
Extract with ethyl acetate (100ml). organic layer
Combine the extracts and extracts, and add a saturated aqueous solution of sodium chloride.
Wash with liquid and dry with magnesium sulfate. melt
Concentrate the liquid under reduced pressure and add diisopropyl to the residue.
Add ether (50ml). Remove the precipitate and dilute
Washing with isopropyl ether gives 7-(2
-methoxyimino-3-ethoxycarbonyl
drazobutyramide)-3-cephem-4-
Carboxylic acid (syn isomer, 3.85 g) is obtained. IR spectrum (nujiol) 3300, 1780, 1730, 1680, 1530cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 1.23 (3H, t, J = 7Hz) 2.00 (3H, s) 3.90 (3H, s) 4.18 (2H, q, J = 7Hz) 5.08 (1H, d, J = 4Hz) 5.83 (1H, d , d, J = 4Hz, 8Hz) 6.38-6.62 (1H, t) 9.22 (1H, d, J = 8Hz) 10.30 (1H, s) (2) 7-(2-methoxyimino-3-ethoxyca
Rubonylhydrazonobutyramide)-3-cef
Em-4-carboxylic acid (syn isomer, 4.1g)
and 70% oversalt in a solution of acetone (200ml)
Add basic acid (4.1ml) at room temperature and keep at the same temperature for 2 hours.
Stir. PH2.0 with 1N sodium hydroxide aqueous solution
After adjusting the temperature, remove the acetone from the solution under reduced pressure.
leave Ethyl acetate (100ml) and
Add saturated aqueous sodium chloride solution (50ml).
Separate the ethyl acetate layer, and add the aqueous layer to ethyl acetate.
(100ml). Ethyl acetate layer and extract
combined, washed with saturated aqueous sodium chloride solution,
Dry over magnesium sulfate and concentrate under reduced pressure.
Ru. Powder the residue with diisopropyl ether
When the precipitate was removed, 7-(2-methoxyi
Mino-3-oxobutyramide)-3-cefe
Mu-4-carboxylic acid (syn isomer, 3.25g)
obtain. IR spectrum (nujiol) 3250, 1780, 1710, 1685, 1650, 1620
(shoulder), 1600, 1540cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 2.30 (3H, s) 3.60 (2H, s) 4.00 (3H, s) 5.06 (1H, d, J = 5Hz) 5.79 (1H, d, d, J = 5Hz, 8Hz) 6.48 (1H, s ) 9.34 (1H, d, J = 8Hz) Example 17 7-Aminocephalosporanic acid (27.3g), concentrated
Zinc in a solution of hydrochloric acid (70 ml) and water (200 ml)
Add powder (40 g) at 5°C and stir for 1 hour. Obtained
Adjust the pH of the solution to 4.0 with 4N sodium hydroxide.
Adjust and concentrate to 100ml. Adjust the solution to PH4.0
and leave it to cool overnight. After removing the precipitate,
7-amino-3-methylenecefam-4-carbo
Obtain phosphoric acid (11.96 g). IR spectrum (nujiol) 3200−2000, 1770, 1620 (shoulder), 1540 (shoulder),
1460, 1220, 1140cm ^-1 NMR spectrum (D ₂ O-NaHCO ₃ , δppm) 3.37, 3.72 (2H, d, J=14Hz), 5.00
(1H, s), 5.28 (1H, s), 5.33 (1H, d,
J=3Hz), 5.35 (1H, s), 5.42 (1H, d,
J=3Hz) Example 18 7-(2-methoxyimino-3-oxo-4-
Bromobutyramide)-3-hydroxycepham
-4-carboxylic acid (syn isomer, 1 g) and dry
Add truffles to a solution of dry tetrahydrofuran (3 ml).
fluoroacetic anhydride (1 ml), anisole (1 drop)
and N,N-dimethylformamide (1 drop)
Add and stir for 4 hours. Add methane to the resulting solution.
of water (0.3 ml), stirred for 1 hour, and removed under reduced pressure.
Concentrate. Triturate the residue with diisopropyl ether.
After removing the precipitate and drying it with phosphorous pentoxide,
7-(2-methoxyimino-3-oxo-4-bu
lomobutyramide)-3-cephem-4-carbo
phosphoric acid (syn isomer, 0.82 g) is obtained. IR spectrum (nujiol) 3600−2200, 3240, 1780, 1700, 1690
(shoulder), 1650, 1620, 1590, 1540, 1280,
1230 (shoulder), 1210, 1050cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 3.57 (2H, d, J=4Hz), 4.05 (3H, s),
4.57 (2H, s), 5.05 (1H, d, J=5Hz),
5.78 (1H, d, d, J = 5Hz, 8Hz), 6.50
(1H, s), 9.63 (1H, d, J = 8Hz) Example 19 7-(2-methoxyimino-3-oxo-4-
Bromobutyramide)-3-hydroxycepham
-4-carboxylic acid (syn isomer, 1 g) and
Add trifluoro to a solution of trihydrofuran (3 ml).
Example 18
When treated in the same manner as 7-(2-methoxyimino
-3-oxo-4-bromobutyramide)-3-
Cefem-4-carboxylic acid (syn isomer, 0.65
g) is obtained. IR spectrum (nujiol) 3600−2200, 3240, 1780, 1700, 1690
(shoulder), 1650, 1620, 1590, 1280, 1230
(shoulder), 1210, 1050cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 3.57 (2H, d, J=4Hz), 4.05 (3H, s),
4.57 (3H, s), 5.05 (1H, d, J=5Hz),
5.78 (1H, d, d, J = 5Hz, 8Hz), 6.50
(1H, s), 9.63 (1H, d, J = 8Hz) Example 20 7-amino-3-methylenecephaam-4-cal
Bonic acid (107g), methanol (6.4) and
Dissolve in a solution of methanesulfonic acid (57.7 g).
Add the starting compound to this solution until it is no longer detected.
Then, ozone is passed at -70 to -75℃. obtained
After passing nitrogen gas through the mixture, add sodium meth
Add oxide (3.5 g) at -65°C. Separately, water
of sodium oxide (14.4g) and water (3.2)
Add sodium borohydride (56.7g) to the solution.
Stir for 20 minutes at room temperature, then cool. This melt
The above oxidizing solution was added to the solution over a period of 3 minutes, and -4
Stir at 0°C for 20 minutes. PH the solution with 6N hydrochloric acid
Adjust to 4.0 and leave at 5℃ overnight. remove the precipitate
After washing with methanol and drying, the 7-amino
Nor-3-hydroxycepham-4-carboxylic acid
(70.8g) is obtained. IR spectrum (nujiol) 3500, 2700-2000 (broad), 1760,
1620, 1580cm ^-1 NMR spectrum (D ₂ O + DCl, δppm) 3.01 (1H, s), 3.10 (1H, d, J = 3Hz),
4.63 (1H, m), 4.78 (1H, d, J=6Hz),
4.93 (1H, d, J = 4Hz), 5.37 (1H, d,
J=4Hz) Example 21 2-methoxyimino-3,3-ethylenedioxy
C-4-bromobutyric acid (syn isomer, 1.6g),
Phosphorus dichloride (0.54g), N,N-dimethylforma
Mido (438 mg), 7-amino-3-cephem-4-
Carboxylic acid (1g), trimethylsilylaceto
Mido (3.3 g) and dry ethyl acetate (21 ml),
When treated in the same manner as in Example 11(1), 7-(2-meth)
xiimino-3,3-ethylenedioxy-4-bu
lomobutyramide)-3-cephem-4-carbo
2.25 g of phosphoric acid (syn isomer) is obtained. IR spectrum (nujiol) 3350, 1780, 1730, 1680, 1640 (shoulder),
1540, 1295, 1220, 1170, 1100, 1040cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 3.6 (2H, d, J=4Hz), 3.83 (5H, s),
4.05 (4H, s), 5.1 (1H, d, J=4Hz),
5.8 (1H, d, d, J = 4Hz, 8Hz), 6.52
(1H, t, J = 4Hz), 9.47 (1H, d, J
=8Hz) Example 22 7-(2-methoxyimino-3-oxo-4-
Bromobutyramide)-3-hydroxycepham
-4-Carboxylic acid (syn isomer, 10g) was dried.
Add to tetrahydrofuran (100ml) at 30°C.
Add acetic anhydride (10 ml) to this solution and heat at the same temperature.
Stir for 30 minutes. Sodium acetate (3g) in solution
and stir at 30°C for 4 hours. into the reaction mixture
Add 6N hydrochloric acid (10ml) dropwise under ice cooling, and cool at below 30℃.
The solvent is removed under reduced pressure. Add water to the residue and mix.
The mixture is stirred for 30 minutes at 20-25°C. precipitation
When taken, washed with water and dried, 7-(2-methoxy
imino-3-oxo-4-bromobutyramide)
-3-cefem-4-carboxylic acid (syn isomer,
7g) is obtained. IR spectrum (nujiol) 3600−2200, 3240, 1780, 1700, 1690
(shoulder), 1650, 1620, 1590, 1540, 1280,
1230 (shoulder), 1210, 1050cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 3.57 (2H, d, J=4Hz), 4.57 (2H, s),
4.05 (3H, s), 5.05 (1H, d, J=5Hz),
5.78 (1H, d, d, J = 5Hz, 8Hz), 6.50
(1H, s), 9.63 (1H, d, J=8Hz) Example 23 7-(2-methoxyimino-3-oxo-4-
Bromobutyramide)-3-cephem-4-cal
Bonic acid (syn isomer, 10 g) was added to thiourea (2.81
g), sodium acetate (2.22g) and methanol
(50 ml) and stir at 30℃ for 5 hours.
Ru. Add diisopropyl ether to the resulting solution.
(200ml) and stir for 30 minutes. remove the precipitate
Wash with diisopropyl ether and dry.
and 7-[2-(2-aminothiazol-4-y)
)-2-methoxyiminoacetamide]-3-se
Fem-4-carboxylic acid (syn isomer, 11.2g)
get. IR spectrum (nujiol) 3700−2200, 1765, 1650, 1620 (shoulder),
1520, 1290, 1245, 1220, 1040, 985cm ^-1 NMR spectrum (D ₂ O, δppm) 3.63 (2H, m), 3.99 (3H, s), 5.16 (1H,
d, J = 5Hz), 5.81 (1H, d, J = 5
Hz), 6.28 (1H, t), 6.96 (1H, s) Example 24 7-(2-methoxyimino-3-oxo-4-
Bromobutyramide)-3-hydroxycepham
-4-carboxylic acid (syn isomer, 2.1 g), N,
N-dimethylformamide (0.8ml) and tet
Dissolve in a solution of lahydrofuran (7.6 ml). child
N,N-dimethylformamide (0.78
ml), phosphorus oxychloride (0.9ml) and tetrahydro
A solution of furan (0.7 ml) was added in one portion at -5°C,
Stir at the same temperature for 30 minutes and at 22°C for 30 minutes. obtained
Pour the solution into ice water. Remove the precipitate and add water
(50ml) and diisopropyl ether (25ml)
When washed with water and dried with phosphorous pentoxide, the 7-
Toximino-3-oxo-4-bromobutyla
mid)-3-cephem-4-carboxylic acid
1.37 g) was obtained. The mother liquor was diluted with ethyl acetate (100
ml). Wash the extract with water and add magnesium sulfate to it.
Dry with um. Concentrate the solution under reduced pressure to remove the precipitate.
When powdered with diisopropyl ether, the same
The target compound (syn isomer, 0.2 g) is obtained. Using thionyl chloride instead of phosphorus oxychloride
The target compound can also be obtained in the same manner. IR spectrum (nujiol) 3600−2200, 3240, 1780, 1700, 1690
(shoulder), 1650, 1620, 1590, 1540, 1280,
1230 (shoulder), 1210, 1050cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 3.57 (2H, d, J=4Hz), 4.05 (3H, s),
4.57 (2H, s), 5.05 (1H, d, J=5Hz),
5.78 (1H, d, d, J = 5Hz, 8Hz), 6.50
(1H, s), 9.63 (1H, d, J = 8Hz) Example 25 (1) N,N-dimethylformamide (0.42ml)
and dry ethyl acetate (1 ml).
Add phosphorous chloride (0.5 ml) under cooling and add 2-
Methoxyimino-3,3-ethylenedioxy-
Cool 4-bromobutyric acid (syn isomer, 1.2g)
Add to the bottom and stir at the same temperature. Add this to 7-ami
Nor-3-hydroxycepham-4-carboxylic acid
(1.0g), trimethylsilylacetamide (6.0
g) and dry ethyl acetate (50ml),
Add under stirring at -20℃ and stir for 1 hour at the same temperature.
Ru. Ethyl acetate (20ml) and
Add water (10ml). Separate the ethyl acetate layer
and extract the aqueous layer with ethyl acetate (20ml). vinegar
Combine the ethyl acid layer and the extract and dilute with hydrogen carbonate.
Thorium saturated aqueous solution (20ml) and water (20ml)
Extract sequentially. Add ethyl acetate (50ml) to the aqueous layer.
In addition, adjust the pH to 2.0 with 6N hydrochloric acid, and remove the ethyl acetate layer.
Separate. The aqueous layer was diluted with ethyl acetate (25ml x 2).
Extract. Combine the ethyl acetate layer and extract.
washed with a saturated aqueous solution of sodium chloride, and washed with sulfuric acid.
Dry with magnesium. Distill the solvent under reduced pressure
and powder the residue with diisopropyl ether.
do. When the precipitate is removed, 7-(2-methoxy
imino-3,3-ethylenedioxy-4-bro
Mobutyramide)-3-hydroxycepham-
4-carboxylic acid (syn isomer, 1.8 g) is obtained. IR spectrum (nujiol) 3300, 3100-2200 (broad), 1760,
1660, 1530, 1210, 1040, 950cm ^-1 NMR spectrum (DMSO−d ₆ +D ₂ O, δppm) 2.75−4.17 (3H, m), 3.83 (5H, s), 4.08
(4H, s), 4.50 (1H, d, J=6Hz),
5.17 (1H, d, J = 4Hz), 5.47 (1H, d,
d, J = 4Hz, 8Hz), 9.37 (1H, d, J
=8Hz) (2) 7-(2-methoxyimino-3,3-ethyle
dioxy-4-bromobutyramide)-3-
Hydroxycefam-4-carboxylic acid
(1 g), 70% perchloric acid (0.2 ml) and vinegar
Acid (2 ml) is treated as in Example 10(4).
and 7-(2-methoxyimino-3-oxo-
4-bromobutyramide)-3-hydroxyse
Fuam-4-carboxylic acid (syn isomer, 0.6g)
get. IR spectrum (nujiol) 3460, 3280, 3200−2200, 1780, 1730,
1710, 1660, 1590, 1560, 1240, 1060cm ^-1 NMR spectrum (DMSO−d ₆ , δppm) 2.67−4.17 (3H, m), 4.08 (3H, s), 4.50
(1H, d, J=6Hz), 4.67 (2H, s),
5.20 (1H, d, J = 4Hz), 5.53 (1H, d,
d, J = 4Hz, 8Hz), 9.40 (1H, d, J
=8Hz) Example 26 7-amino-3-hydroxycepham-4-ka
Rubonic acid (2.18g, purity 84.8%), trimethylsilica
Lylacetamide (10.5g), 2-methoxyimide
No-3,3-dimethoxy-4-bromobutyric acid (syn
isomer, 3.24 g), N,N-dimethylformamide
(1.1ml), phosphorus oxychloride (1.36ml) and methi
Lenchloride (50ml) was added in the same manner as in Example 25(1).
Upon treatment, 7-(2-methoxyimino-3,3
-dimethoxy-4-bromobutyramide)-3-
Hydroxycefam-4-carboxylic acid (synisomer
body, 3.75 g). IR spectrum (nujiol) 3700-3100 (broad), 3100-2700 (broad)
), 2600, 1780, 1680, 1540cm ^-1 NMR spectrum (DMSO−d ₆ +D ₂ O, δppm) 2.6−4.17 (3H, m), 3.27 (6H, s), 3.77
(2H, s), 3.88 (3H, s), 4.48 (1H, d,
J = 6Hz), 5.17 (1H, d, J = 4Hz),
5.48 (1H, d, d, J = 4Hz, 8Hz), 8.87
(1H, d, J=8Hz) Example 27 7-(2-methoxyimino-3-oxo-4-
Bromobutyramide)-3-hydroxycepham
-4-carboxylic acid (syn isomer, 180 mg) and
In a solution consisting of dry tetrahydrofuran (10 ml)
Add trifluoroacetic anhydride (0.5 ml) and bring to room temperature.
Stir for 10 minutes. This is triethylamine
(0.2 ml) and stir at room temperature for 10 minutes. This solution
Add ethyl acetate to the solution and adjust the pH to 2.0 with 6N hydrochloric acid.
Ru. Solution in water and saturated aqueous sodium chloride solution
Wash sequentially and dry with magnesium sulfate. child
After concentrating it under reduced pressure, the residue was dissolved in diisopropyl ether.
When powdered with tel, 7-(2-methoxyimino
-3-oxo-4-bromobutyramide)-3-
Cepham-4-carboxylic acid (syn isomer, 171.5
mg). IR (Nujiyor) 3600−2200, 3240, 1780, 1700, 1690
(shoulder), 1650, 1620, 1590, 1540, 1280,
1230 (shoulder), 1210, 1050cm ^-1 NMR (DMSO−d ₆ ．． δppm) 3.57 (2H, d, J=4Hz), 4.57 (2H, s),
4.05 (3H, s), 5.05 (1H, d, J=5Hz),
5.78 (1H, d, d, J = 5Hz, 8Hz), 6.50
(1H, s), 9.63 (1H, d, J = 8Hz) Example 28 7-amino-3-hydroxycepham-4-ka
Rubonic acid (1.09g, purity 84.8%), trimethylsilica
Lylacetamide (5.3g), 2-methoxyimino
-3,3-diethoxy-4-bromobutyric acid
(1.8g), phosphorus oxychloride (0.68ml), N,N
-dimethylformamide (0.55ml) and methylene
chloride (25 ml) was treated in the same manner as in Example 25(1).
Then, 7-(2-methoxyimino-3,3-di
Ethoxy-4-bromobutyramide)-3-hydro
Roxicefam-4-carboxylic acid (syn isomer,
1.1g). IR (liquid film) 3600−3100, 2950, 1780−1700, 1700−
1620, 1520cm ^-1 NMR (DMSO−d ₆ , δppm) 1.08 (3H, t, J=8Hz), 1.13 (3H, t,
J = 8Hz), 3.50 (2H, q, J = 8Hz),
3.57 (2H, q, J = 8Hz), 2.90−4.20
(3H, m), 3.66 (2H, s), 3.78 (3H,
s), 4.38 (1H, d, J=6Hz), 5.08 (1H,
d, J = 8Hz), 5.38 (1H, dd, J = 4Hz,
8Hz), 8.57 (1H, d, J = 8Hz) Example 29 7-Amino-3-hydroxycepham-4-ka
Rubonic acid (10.9g, purity 84.8%), 2-methoxy
Imino-3,3-diethoxy-4-bromobutyric acid
(syn isomer, 17.9g), phosphorus oxychloride (6.8ml),
N,N-dimethylformamide (5.5ml), water
(100ml), acetone (50ml) and tetrahydro
Furan (44 ml) was treated as in Example 25(1).
and 7-(2-methoxyimino-3,3-dietho)
(xy-4-bromobutyramide)-3-hydroxy
Cicefam-4-carboxylic acid (syn isomer, 17.1
g) is obtained. IR and NMR spectra of this compound
are IR and NM of the compound obtained in Example 28
Matching the spectra of R. Example 30 2-methoxyimino-3,3-trimethylene diode
Production of xy-4-bromobutyric acid (syn isomer) (1) Ethyl 2-methoxyimino-3-oxobutyrate
Ester (syn isomer. 10g), 1,3-Pro
Pandiol (11g), p-toluenesulfone
Acid (300mg) and dry benzene (150ml)
When treated in the same manner as in Example 1 (1), bp90-95℃/
2-methoxyimino-3,3-tri at 0.8 mmHg
Methylenedioxybutyric acid ethyl ester
4.46 g) was obtained. IR (liquid film) 3000, 2950, 2900, 2830, 1850, 1630,
1480, 14 60, 1380cm ^-1 NMR (CCl _Four , δppm) 1.26 (3H, t, J=8Hz), 1.44 (3H, s),
1.8-2.2 (2H, broad m), 3.6-4.0 (4H,
m), 3.88 (3H, s), 4.2 (2H, q, J=8
Hz) (2) Pyridinium hydrobromide perbroma
(3.32g), 2-methoxyimino-3,3
-trimethylenedioxybutyric acid ethyl ester
(syn isomer, 2.0 g) and dry tetrahydro
Furan (20 mm) was treated in the same manner as in Example 8 (2).
and 2-methoxyimino-3,3-trimethylene
dioxy-4-bromobutyric acid ethyl ester
(Syn isomer, 3.64 g) is obtained. IR (liquid film) 3400, 2950−2850, 1730, 1620, 1460,
1440, 1370, 1280−1240, 1210, 1190,
1140, 1080, 1020cm ^-1 NMR (CDCl) ₃ , δppm) 1.30 (3H, t, J=7Hz), 1.50−2.0 (2H,
m), 3.4 (2H, t, J=6Hz), 3.92 (3H,
s), 4.28 (2H, q, J=7Hz), 3.53 (2H,
s), 3.61 (2H, t, J = 6Hz) (3) 2-methoxyimino-3,3-trimethylene
Dioxy-4-bromobutyric acid ethyl ester (silica)
isomer, 3.40g), ethanol (20.4ml), water
Sodium oxide (1.32g) and water (13.6mm)
When treated in the same manner as in Example 5 (2), 2-methoxy
Shiimino-3,3-trimethylenedioxy-4
- Bromobutyric acid (syn isomer, 1.68 g) is obtained. IR (Nujiyor) 3400−2200, 1750, 1620, 1470, 1430,
1380, 1300, 1260, 1240, 1230, 1200,
1140, 1080, 1030, 1000cm ^-1 NMR (CDCl) ₃ , δppm) 1.16−1.8 (2H, broad m), 3.58 (2H,
s), 3.83-4.17 (4H, m), 4.00 (3H, s) Example 31 2-Methoxyimino-3,3-trimethylene di
Oxy-4-bromobutyric acid (syn isomer, ) carried out
When processed similarly to Examples 25(1) and 25(2), 7-(2
-methoxyimino-3-oxo-4-bromobuty
Ruamido)-3-hydroxycepham-4-cal
Bonic acid (syn isomer) is obtained. Example 32 7-(2-methoxyimino-3,3-dimethoxy
C-4-bromobutyramide)-3-hydroxy
Cepham-4-carboxylic acid (syn isomer) or
7-(2-methoxyimino-3,3-diethoxy
-4-bromobutyramide)-3-hydroxyse
Example of fuam-4-carboxylic acid (syn isomer)
When treated in the same manner as 10(4) or Example 25(2), 7-
(2-methoxyimino-3-oxo-4-bromo
butyramide)-3-hydroxycepham-4-
Carboxylic acid (syn isomer) is obtained. Example 33 (1) 7-(2-methoxyimino-3-oxo-4
-bromobutyramide)-3-hydroxycef
Am-4-carboxylic acid (syn isomer, 31.8g)
and from dry tedrahydrofuran (150 mm)
Add acetic anhydride (22.5 ml) and boron to the solution.
Stir refluoride etherate (7.5mm)
Add at room temperature for 30 minutes, then 50 minutes at the same temperature.
Stir at ℃ for 1 hour. Sodium chloride in the reaction solution
Add saturated aqueous solution (100ml) and stir for 30 minutes.
Add ethyl acetate (150ml) to this and
Separate the liquid layer and wash with saturated aqueous sodium chloride solution.
Purify. Extract the aqueous layer with ethyl acetate (100ml)
Ru. Combine the ethyl acetate layer and extract, and combine with activated carbon.
and concentrate under reduced pressure. Diisopropylene to the residue
Add ether (500 ml) and decant the solvent.
The residue was powdered with diisopropyl ether,
When removed and dried, 7-(2-methoxyimino
-3-oxo-4-bromobutyramide)-3
-acetoxycepham-4-carboxylic acid (sin
isomer, 35.3 g). IR (Nujiyor) 3250, 1710−1770, 1665, 1220cm ^-1 NMR (DMSO−d ₆ , δppm) 2.02 (3H, s), 2.68−3.45 (2H, m), 3.95
−4.15 (1H, m), 4.01 (3H, s), 4.56
(2H, s), 4.45−4.66 (1H, m), 5.19
(1H, d, J = 2.1Hz), 5.46 (1H, q, J
= 2.1Hz, 4.0Hz), 9.33 (2H, d, J = 4.0
Hz) (2) 7-(2-methoxyimino-3-oxo-4
-bromobutyramide)-3-acetoxycef
Am-4-carboxylic acid (syn isomer, 200 mg)
and dry tetrahydrofuran (2 ml).
Add acetic anhydride (0.2 ml) and sodium acetate to the solution.
(0.12g) and N,N-dimethylformamide
Add (2 drops) and stir at 28°C for 1 hour. child
Add 6N hydrochloric acid (0.2ml) to the mixture and evaporate the solvent under reduced pressure.
do. Add water to the residue, remove the precipitate, and wash with water.
When dried, 7-(2-methoxyimino-
3-oxo-4-bromobutyramide)-3-
Cepham-4-carboxylic acid (syn isomer) and
and 7-(2-methoxyimino-3-oxo-4
-chlorobutyramide)-3-cepham-4-
Mixture of carboxylic acids (syn isomer) (0.09g)
get. 7-(2-methoxyimino-3-oxo-4-
Bromobutyramide)-3-cepham-4-cal
Bonic acid (syn isomer) IR (Nudiyol) 3600−2200, 3240, 1780, 1700, 1690
(shoulder), 1650, 1620, 1590, 1540, 1280,
1230 (shoulder), 1210, 1050cm ^-1 NMR (DMSO−d ₆ , δppm) 3.57 (2H, d, J=4Hz), 4.57 (2H, s),
4.05 (3H, s), 5.05 (1H, d, J=5Hz),
5.78 (1H, dd, J=5Hz, 8Hz), 6.50
(1H, s), 9.63 (1H, d, J = 8Hz) Example 34 Ethyl orthoformate (14.0g) and borontri
Fluoride diethyl etherate (0.45g)
, ethyl 2-methoxyimino-3-oxobutyrate
Ester (syn isomer, 10g) and ethanol
(20ml) and stirred at 70℃ for 4 hours.
do. Add to this a saturated aqueous solution of sodium bicarbonate.
(20ml) and diisopropyl ether (30ml)
Add. After separating the organic layer, the aqueous layer was separated by diisopropylene.
Extract with lopylether (30 ml). organic layer and
Combine the extracts with water and saturated sodium chloride.
Wash sequentially with aqueous solution (30 ml), then remove magnesium sulfate.
Dry with. When this was dried under reduced pressure, 2-methoxy
Shiimino-3,3-diethoxybutyric acid methyl ester
(syn isomer, 13.9 g). IR (liquid film): 2980, 2940.2900, 2830, 1750,
1640，1490，1440，1400，1380，1300，
1250, 1170, 1130, 1100, 1080, 1060−
1030cm ^-1 NMR (CDCl) ₃ , δ): 1.17 (6H, t, J=7
Hz), 1.60 (3H, s), 3.90 (3H, s), 3.55
(4H, q, J = 7Hz), 3.83 (3H, s) Example 35 Anhydrous sodium carbonate (8.89g) was
Shiimino-3,3-diethoxybutyric acid methyl ester
(syn isomer, 10 g) and chloroform (40 g)
ml). This includes sulfuric acid chloride.
(6.94 g) was added dropwise over 50 minutes at -6 to 02°C.
Stir for 10 minutes at the same temperature. Remove solvent from reaction solution
After distilling off, add ethanol (10ml) to the residue.
Stir for 30 minutes. Add water (25ml) to this and
Extract twice with sopropyl ether (20 ml). Lottery
Pour the eluate into water (10ml) and saturated sodium chloride solution.
After sequentially washing with liquid, dry with magnesium sulfate.
Ru. When this is dried under reduced pressure, 2-methoxyimino
-3,3-diethoxy-4-chlorobutyric acid ethyl ester
Stell (syn isomer, 11.23 g) is obtained. IR (liquid film): 2980, 2940, 2900, 2830, 1750,
1705, 1630, 1600, 1490, 1440, 1400,
1375, 1320, 1280, 1260, 1210, 1150,
1130, 1110, 1070−1030cm ^-1 NMRCDCl ₃ , δ): 3.82 (2H, s), 1.18
(6H, t, J=7Hz), 3.94 (3H, s),
3.11 (4H, q, J = 7Hz), 3.87 (3H, s) Example 36 2-Methoxyimino-3,3-diethoxybutyric acid
Example 35 Ethyl ester (syn isomer, 10g)
When treated in the same way, 2-methoxyimino-
3,3-diethoxy-4-chlorobutyric acid ethyl ester
ter (syn isomer, 21.6 g) is obtained. IR (liquid film): 2995, 2950, 2830, 2810, 1750,
1630, 1470, 1465, 1400, 1380, 1310,
1285, 1260, 1210, 1160, 1130, 1110,
1060, 1040cm ^-1 NMR (CDCl) ₃ , δ): 1.18 (6H, t, J=6
Hz), 1.29 (3H, t, J=6Hz), 3.56 (4H,
q, J=6Hz), 3.75 (2H, s), 3.88 (3H,
s), 4.27 (2H, q, J = 6Hz) Example 37 Sodium hydroxide (4.3g) and water (20ml)
A solution consisting of 2-methoxyimino-3,3-
Diethoxy-4-chlorobutyric acid ethyl ester
isomer, 10g) and ethanol (30g)
Add to the solution and stir at 50°C for 3 hours. reaction solution
Adjust the pH to 7.5 with 20% sulfuric acid and distill off the ethanol.
do. Add diethyl ether (100ml) to this and cool on ice.
After adding to the bottom, adjust the pH to 2.5 with 20% sulfuric acid. Ji
Separate the ethyl ether layer and remove the aqueous layer with diethyl ether.
Extract with tel (50ml). Combine the organic layer and extract, add sodium chloride
After washing with saturated aqueous solution, dry with magnesium sulfate.
dry This solution was dried under reduced pressure to form a residue (8.71
g) is obtained. When this is powdered with n-hexane,
2-Methoxyimino-3,3-diethoxy-4-
Chlorobutyric acid (syn isomer, 6.47 g) is obtained. IR (Nujiyor): 3240, 2970-2850, 1750,
1640, 1600, 1470, 1460, 1410, 1380,
1300, 1280, 1195, 1130, 1115, 1110,
1070−1010cm ^-1 NMR (CDCl) ₃ , δ): 1.19 (6H, t, J=7
Hz), 3.63 (4H, q, J = 4Hz), 3.83 (2H,
s). 3.98 (3H, s), 10.10 (1H, broad
s) Example 38 2-methoxyimino-3,3-diethoxy-4
-chlorobutyric acid methyl ester (syn isomer, 4.83
When g) is treated in the same manner as in Example 37, 2-methoxy
Shiimino-3,3-diethoxy-4-chlorobutyric acid
(Syn isomer, 3.83 g) is obtained. IR (Nujiyor): 3240, 2970-2850, 1750,
1640, 1600, 1470, 1460, 1410, 1380,
1280, 1195, 1130, 1115, 1110, 1070−
1010cm ^-1 NMR (CDCl) ₃ , δ): 1.19 (6H, t, J=7
Hz), 3.63 (4H, q, J = 7Hz), 3.83 (2H,
s), 3.98 (3H, s), 10.10 (1H, broad
s) Example 39 Phosphorus oxychloride (1.24 ml) was dissolved in N,N-dimethyl
Formamide (1.01ml) and dry tetrahydro
Added to a solution consisting of furan (2 ml) at -20°C,
Stir for 30 minutes at the same temperature. 2-methoxy
Mino-3,3-diethoxy-4-bromobutyric acid
isomer, 3.3 g) at -20°C, -20 - -10
Stir at ℃ for 1 hour. This reaction solution was mixed with dihydrogen phosphate.
Potassium (3.63g), sodium phosphate and water
(1000ml) at pH 6.1 under ice-cooling.
Stir for 2 hours. Remove the precipitate, wash it with water, and dry it.
, 2-methoxyimino-3,3-diethoxy
-4-Bromobutyric acid chloride (syn isomer, 3.0g)
get. mp33−35℃ IR (nujiol): 1780, 1620, 1400, 1290,
1245, 1210, 1200 (shoulder), 1140cm ^-1 NMR (CDCl) ₃ , δ): 1.2 (6H, t, J=7
Hz), 3.6 (4H, q, J = 7Hz). 3.70 (2H,
s), 4.0 (3H, s) Example 40 2-methoxyimino-3,3-diethoxy-4
- Chlorobutyric acid (syn isomer, 2.54 g) Example 39
The resulting reaction solution was treated in the same manner as n-hexane.
(200ml). Extract with water and salt
Wash sequentially with saturated sodium aqueous solution and soak in sulfuric acid mag- netic solution.
When dried with Si, 2-methoxyimino-3,
3-diethoxy-4-chlorobutyric acid chloride (syn
isomer, 2.58 g). IR (liquid film): 2990, 2950, 2910, 1800, 1620,
1490, 1470, 1460, 1445, 1405, 1300,
1220, 1200, 1140, 1120, 1100, 1060cm ^-1 NMR (CDCl) _Four , δ): 1.18 (6H, t, J=7
Hz), 3.57 (2H, q, J=7Hz), 3.68 (2H,
s), 3.98 (3H, s) Example 41 Methanol (40 ml) was dissolved in 7-amino-3-hydro
Xicefam-4-carboxylic acid (2g), carbonated water
From sodium (0.57g) and water (13.4g)
Add to the solution under ice cooling. 2-methoxy
imino-3,3-diethoxy-4-chlorobutyric acid
loride (syn isomer, 1.34g) and dry tetra
A solution consisting of hydrofuran (2 ml) from pH 6.5
After adding the drops while adjusting the temperature to 7.8, cool on ice for 3 o'clock.
Stir for a while. After adjusting the reaction mixture to PH7.5,
The solvent is removed under reduced pressure. Adjust the residual liquid to pH 7.5 under ice cooling.
After adjusting, add diisopropyl ether (10ml) to
Add to that. Separate the aqueous layer and add to it ethyl acetate.
(20ml) and adjust the pH to 2.0 with 20% sulfuric acid.
Separate the ethyl acetate layer and dilute the aqueous solution with ethyl acetate (10
ml) twice. Ethyl acetate layer and extract
were combined and washed with saturated aqueous sodium chloride solution.
Then, dry with magnesium sulfate. Reduce this solution
When concentrated under pressure, 7-(2-methoxyimino-3,
3-diethoxy-4-chlorobutyramide)-3
-Hydroxycepham-4-carboxylic acid
2.97 g) was obtained. NMR (DMSO−d ₆ , δ): 1.12 (6H, t, J=
8Hz), 2.6-3.2 (3H, m), 3.51 (4H, q,
J=8Hz), 3.80 (3H, s), 4.35 (1H, d,
J = 6Hz), 5.08 (1H, d, J = 5Hz),
5.39 (1H, dd, J=5Hz, 9Hz), 8.61
(1H, d, J=9Hz) Example 42 2-methoxyimino-3,3-diethoxy-4
- Bromobutyric acid chloride (syn isomer, 400.5g)
and 7-amino-3-hydroxycepham-4
-Carboxylic acid (230g) treated as in Example 41
Then, 7-(2-methoxyimino-3,3-di
Ethoxy-4-bromobutyramide)-3-hydro
Roxicefam-4-carboxylic acid (syn isomer,
621g). IR (liquid film): 3600-3100 (broad), 2950,
1780−1700, 1520, 1380, 1040 (broad)
cm ^-1 NMR (DMSO−d ₆ , δ): 1.12 (6H, t, J=7
Hz), 3.57 (4H, q, J=7Hz), 2.62−
3.93 (3H, m), 3.77 (2H, s), 3.90 (3H,
s), 4.42 (1H, d, J=6Hz), 5.13 (1H,
d, J=4Hz), 5.45(1H, dd, J=4Hz,
8Hz), 8.60 (1H, d, J = 8Hz) Example 43 Acetic anhydride (27.3ml) was mixed with 7-(2-methoxyimide)
No-3,3-diethoxy-4-bromobutyrami
)-3-hydroxycepham-4-carboxylic acid
(syn isomer, 30 g) and dry tetrahydrof
Add at room temperature to a solution consisting of run (300 ml) for 28
Stir for 30 min at °C. Sodium acetate
(4.0g) and potassium acetate (4.7g) were added.
Afterwards, the solution is stirred at 28-30°C for 3 hours. reaction
Add the solution to ethyl acetate (300ml) and sodium chloride.
In addition to a solution consisting of saturated aqueous solution (300 ml), 20
Adjust the pH to 2.0 with % sulfuric acid. Separate the organic layer and add water
The layers are extracted twice with ethyl acetate (100ml). organic
Combine the layers and extract and add saturated sodium chloride water.
After cleaning with solution, dry with magnesium sulfate.
Ru. This solution is treated with activated carbon and dried under reduced pressure.
Ru. Adding n-hexane to this and decanting it produces an oily
7-(2-methoxyimino-3,3-dieto)
xy-4-bromobutyramide)-3-cepham
-4-carboxylic acid (syn isomer, 35.1 g) was obtained.
Ru. IR (liquid film): 35000-2200 (broad), 3000,
2950, 2900, 1800, 1650 (broad),
1540, 1380, 1300, 1130, 1050cm ^-1 NMR (DMSO-d ₆ , δ): 1.17 (6H, t, J=
7Hz), 3.47-3.70 (2H, broad m),
3.57 (4H, q, J=7Hz), 3.73 (2H, s)
3.93 (3H, s), 5.07 (1H, d, J=4Hz),
6.78 (1H, dd, J=4Hz, 8Hz), 6.47
(1H, t, J = 4Hz), 8.80 (1H, d, J
=8Hz) Example 44 7-(2-methoxyimino-3,3-diethoxy
C-4-chlorobutyramide)-3-hydroxy
Cepham-4-carboxylic acid (syn isomer, 2.0g)
When treated in the same manner as in Example 43, 7-(2-meth
xiimino-3,3-diethoxy-4-chlorobu
tylamido)-3-cephem-4-carboxylic acid
(Syn isomer, 1.87 g) is obtained. NMR (DMSO-d ₆ , δ): 1.13 (3H, t, J=
7Hz), 3.6 (4H, q, J=7Hz), 3.33−
3.83 (2H, broad m), 3.87 (3H, s),
3.92 (2H, s), 5.08 (1H, d, J=5Hz),
5.8 (1H, dd, J = 5Hz, 8Hz), 6.5 (1H,
t, J = 5Hz), , 8.93 (1H, d, J = 8
Hz) Example 45 7-(2-methoxyimino-3,3-diethoxy
C-4-bromobutyramide)-3-hydroxy
Cepham-4-carboxylic acid (syn isomer, 5g),
Acetic anhydride (4.55ml), sodium acetate (1.45g)
Example: and methyl isobutyl ketone (50ml)
When treated in the same manner as 43, 7-(2-methoxyimide
No-3,3-diethoxy-4-bromobutyrami
)-3-cephem-4-carboxylic acid (synisomer
body, 3.36g) IR (liquid film): 3500-2200 (broad), 3000,
2950, 2900, 1800−1650 (broad),
1540, 1380, 1300, 1130, 1050cm ^-1 NMR (DMSO-d ₆ , δ): 1.17 (6H, t, J=
7Hz) 3.47-3.70 (2H, broad m), 3.57
(4H, q, J=7Hz), 3.73 (2H, s),
3.93 (3H, s), 5.07 (1H, d, J=4Hz),
6.78 (1H, dd, J=4Hz, 8Hz), 6.47
(1H, t, J = 7Hz), 8.80 (1H, d, J
= 8 Hz) Example 46 70% perchloric acid (3.4 ml) was diluted with 7-(2-methoxyi
Mino-3,3-diethoxy-4-bromobutyla
(mido)-3-hydroxycepham-4-carvone
Acid (syn isomer, 5.0g) and acetone (40ml)
Add to the solution consisting of under ice cooling and stir at the same temperature for 1 hour.
Stir. Collect the precipitate and add twice with acetone (5 ml).
After washing and drying, 7-(2-methoxyimino
-3-oxo-4-bromobutyramide)-3-
Hydroxycefam-4-carboxylic acid (synisomer
body, 1.85 g). IR (Nujiyor): 3460, 3280, 3200−2200,
1780, 1730, 1710, 1660, 1590, 1560,
1240, 1060cm ^-1 NMR (DMSO-d ₆ , δ): 2.67−4.17 (3H, m),
4.08 (3H, s), 4.50 (1H, d, J=6Hz),
4.67 (2H, s), 5.20 (1H, d, J=4Hz),
5.53 (1H, dd, J=4Hz, 8Hz), 9.40
(1H, d, J = 8Hz) Combine the mother liquor and washing solution, and add water (16ml) to this.
Add. PH this with a saturated aqueous sodium carbonate solution.
After adjusting to 2.0, acetone is distilled off. residual liquid
Add saturated aqueous sodium chloride solution (16 ml) to
Leave it in the refrigerator overnight. Remove the precipitate and add water and
Wash with saturated aqueous sodium chloride solution and dry.
When dried, the compound obtained above and 7-(2-methane)
Toxiimino-3-oxo-4-chlorobutyla
(mido)-3-hydroxycepham-4-carvone
A mixture with acid (syn isomer, 1.35 g) is obtained. IR (Nujiyor): 3450, 3250, 3050, 1765,
1710, 1650, 1590, 1550, 1460, 1400,
1380, 1230, 1060cm ^-1 NMR (DMSO-d ₆ , δ): 2.3−3.6 (2H, m),
3.6-4.0 (1H, broads), 4,05 (3H,
s), 4.33 (1H, d, J=6Hz), 4.83 (2H,
s), 5.17 (1H, d, J=4Hz), 5.50 (1H,
dd, J = 4Hz, 8Hz), 9.33 (1H, d, J
= 8 Hz) Example 47 70% perchloric acid (0.54 ml) was mixed with 7-(2-methoxy
imino-3,3-diethoxy-4-bromobutyl
Amido)-3-cephem-4-carboxylic acid (synamide)-3-cephem-4-carboxylic acid
isomer, 1g) and methyl isobutyl ketone
(4 ml) under ice-cooling and at the same temperature.
Stir for 20 minutes. Add water (4 ml) to the reaction solution,
Stir for 5 minutes. Collect the precipitate, wash it with water, and convert it into pentachloride.
When dried over phosphorus, 7-(2-methoxyimino-3
-oxo-4-bromobutyramide)-3-cef
Em-4-carboxylic acid (syn isomer, 502 mg)
obtain. IR (Nujiyor): 3600-2200, 3240, 1780,
1700, 1690 (shoulder) 1650, 1620, 1590, 1540,
1280, 1230 (shoulder), 1210, 1050cm ^-1 NMR (DMSO−d ₆ , δ): 3.57 (2H, d, J=
4Hz), 4.57 (2H, s), 4.05 (3H, s)
5.05 (1H, d, J=5Hz), 5.78 (1H, dd,
J = 5Hz, 8Hz), 6.50 (1H, t, J = 4
Hz), 9.63 (1H, d, J = 8Hz) Example 48 6N hydrochloric acid (2 ml) was dissolved in 7-(2-methoxyimino-
3,3-diethoxy-4-bromobutyramide)
-3-Hydroxycepham-4-carboxylic acid
isomer, 500 ml) and methylene chloride (5 ml)
Add to the solution consisting of under ice cooling and stir at room temperature for 70 minutes.
Stir. Take the precipitate and dissolve it in saturated sodium chloride water.
Wash sequentially with solution (5 ml) and methylene chloride (1 ml).
After cleaning and drying over phosphorus pentachloride, the 7-(2-methane)
Toximino-3-oxo-4-bromobutyla
(mido)-3-hydroxycepham-4-carvone
Acid (syn isomer, 517 mg) (purity 57.8%) is obtained. IR (Nujiyor): 3460, 3280, 3200−2200,
1780, 1730, 1710, 1660, 1590, 1560,
1240, 1060cm ^-1 NMR (DMSO−d ₆ , δ): 2.67−4.17 (3H,
m), 4.08 (3H, s), 4.50 (1H, d, J=
6Hz), 4.67 (2H, s), 5.20 (1H, d, J
= 4Hz), 5.53 (1H, dd, J = 4Hz, 8
Hz), 9.40 (1H, d, J = 8Hz) Example 49 7-(2-methoxyimino-3,3-diethoxy
c-4-bromobutyramide)-3-cephem-
Example of 4-carboxylic acid (syn isomer, 500 mg)
When treated in the same manner as 48, 7-(2-methoxyimide
Nor-3-oxo-4-bromobutyramide)-3
-Cefem-4-carboxylic acid (syn isomer, 250
mg) (purity 85.7%). IR (Nujiyor): 3600-2200, 3240, 1780,
1700, 1690 (shoulder), 1650, 1620, 1590,
1540, 1280, 1230 (shoulder) 1210, 1050cm ^-1 NMR (DMSO−d ₆ , δ): 3.57 (2H, d, J=
4Hz), 4.57 (2H, s), 4.05 (3H, s),
5.05 (1H, d, J=5Hz), 5.78 (1H, dd,
J = 5Hz, 8Hz), 6.50 (1H, t, J = 4
Hz), 9.63 (1H, d, J = 8Hz) Example 50 70% perchloric acid (0.75ml), 7-(2-methoxyi
Mino-3,3-diethoxy-4-chlorobutyla
mid)-3-cephem-4-carboxylic acid
(1.82 g) and methyl isobutyl ketone
(7.3 ml) was treated in the same manner as in Example 47, resulting in 7-
(2-methoxyimino-3-oxo-4-chloro
butyramide)-3-cephem-4-carboxylic acid
(Syn isomer, 0.98 g) is obtained. IR (Nujiyor): 3250, 3050, 1780, 1710,
1650, 1620, 1590, 1550, 1280, 1230,
1060cm ^-1 NMR (DMSO−d ₆ , δ): 3.60 (2H, d, J=
5Hz), 4.07 (3H, s), 4.83 (2H, s),
5.10 (1H, d, J=4Hz), 5.83 (1H, dd,
J = 4Hz, 8Hz), 6.53 (1H, t, J = 5
Hz), 9.43 (1H, d, J = 8Hz) Example 51 6N hydrochloric acid (2.4ml), 7-(2-methoxyimino-
3,3-diethoxy-4-chlorobutyramide)
-3-cefem-4-carboxylic acid (syn isomer,
Example: 301.5 mg) and methylene chloride (3 ml)
When 48 is treated in the same way, 7-(2-methoxyimino)
Nor-3-oxo-4-chlorobutyramide)-3
-Cefem-4-carboxylic acid (syn isomer,
110.4 mg). IR (Nujiyor): 3250, 3050, 1780, 1710,
1650, 1620, 1590, 1550, 1280, 1230,
1060cm ^-1 NMR (DMSO−d ₆ , δ): 3.60 (2H, d, J=
5Hz), 4.07 (3H, s), 4.83 (2H, s),
5.10 (1H, d, J=4Hz), 5.83 (1H, dd,
J = 4Hz, 8Hz), 6.53 (1H, t, J = 5
Hz), 9.43 (1H, d, J = 8Hz) 7-(2-methoxyimino-3 obtained above
-oxo-4-chlorobutyramide)-3-cef
Example 10 Em-4-carboxylic acid (syn isomer)
- When treated in the same manner as (10), 7-[2-(2-amino
Thiazol-4-yl)-2-methoxyiminoa
Cetamide]-3-cephem-4-carboxylic acid
(syn isomer) is obtained. Example 52 2-methoxyimino-3-oxo-4-bromo
Ethyl ester of butyric acid (syn isomer) and ethyl ester
Treated in the same manner as in Example 3-(1) using glycol.
Then, 2-methoxyimino-3,3-ethylene
Ethyl ester of dioxy-4-bromobutyric acid (silica)
isomer). bp118-120℃/0.95mmHg IR (liquid film): 3000, 2960, 1745, 1630, 1300,
1265, 1040cm ^-1 NMR (DMSO−d ₆ , δ): 1.33 (3H, t, J=
6Hz), 3.78 (2H, s), 3.93 (3H, s),
4.17 (4H, s), 4.35 (2H, q, J = 6Hz)

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a lower alkyl group, R ² is a carboxy group or a protected carboxy group, X″ is hydrogen or a halogen, Y′ is a carbonyl group or a protected carbonyl group, and Y′ is a carbonyl group. In the case of , X″ is hydrogen) or its salts. 2 General formula (In the formula, R ² means a carboxy group or a protected carboxy group) (In the formula, R ¹ is a lower alkyl group, X' is hydrogen or halogen, and Y is a protected carbonyl group.) A compound represented by the formula or a reactive derivative of its carboxy group is reacted to form a compound of the general formula (In the formula, R ¹ , R ² , X' and Y have the same meanings as before.) A method for producing a 3-cephem compound, which is characterized by obtaining a compound or a salt thereof. 3 General formula (In the formula, R ¹ is a lower alkyl group, R ² is a carboxy group or a protected carboxy group, and Y is a protected carbonyl group.) Following the elimination reaction of
general formula (In the formula, R ¹ and R ² have the same meanings as above.) A method for producing a 3-cephem compound, which is characterized by obtaining a compound or a salt thereof. 4 General formula (In the formula, R ¹ is a lower alkyl group, R ² is a carboxy group or a protected carboxy group, X' is hydrogen or a halogen, and Y is a protected carbonyl group) or a salt thereof,
Following the dehydration reaction, the general formula (In the formula, R ¹ , R ² , X' and Y have the same meanings as before.) A method for producing a 3-cephem compound, which is characterized by obtaining a compound or a salt thereof. 5 General formula (In the formula, R ¹ is a lower alkyl group and R ² is a carboxy group or a protected carboxy group.) A compound represented by the formula or a salt thereof is subjected to a dehydration reaction, and then (In the formula, R ¹ and R ² have the same meanings as above.) A method for producing a 3-cephem compound, which is characterized by obtaining a compound or a salt thereof.