JPH0359075B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 3-cephem compounds, which are novel intermediates of 3-cepheme compounds having antibacterial activity. More specifically, the present invention provides 3-cephem compounds, such as 7-[2-(2
-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-cephaem-4-carboxylic acid (syn isomer) or a pharmaceutically acceptable salt thereof; - To provide a method for producing a cephalic compound. The 3-cepham 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, R ⁶ is a hydroxy group, an acyloxy group, or a methylene group,
(X' represents hydrogen or halogen, and Y' represents a carbonyl group or a protected carbonyl group, respectively.) The 3-cephame compound and its salts of the present invention are produced by the following method. (In the formula, R ¹ , R ² , X' and Y' each have the same meaning as before, R ³ is a heterocyclic group that may have an appropriate substituent, and R ⁴ is an esterified carboxy group. , R ⁶ ' means a hydroxy group or methylene group, R ⁷ means an acyl group, and Y means a protected carbonyl 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 key 1 to 6 without special mention.
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 provinyl 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, isopropylene Lower alkylthio (lower) alkyl esters such as thiomethyl esters, 2-iodoethyl esters,
Halo (lower) alkyl esters such as 2,2,2,-trichloroethyl ester, acetoxymethyl ester, propionyloxymethyl ester,
Lower alkanoyloxy (lower) alkyl esters such as butyryloxymethyl ester, pareryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, mesylmethyl ester, lower alkanesulfonyl (lower) alkyl ester such as 2-mesylethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-
nitrobenzyl ester, phenethyl ester,
Trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4
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 which may have one or more suitable substituents, such as esters, phenyl esters, tolyl esters, tertiary butyl phenyl esters, xylyl esters, mesityl esters, cumenyl esters, and salicyl esters; Esters with silyl compounds such as (lower) alkylsilyl compounds, di(lower) alkylalkoxysilyl compounds, or tri(lower) alkoxylyl compounds, such as tri(lower) alkylsilyl esters such as trimethylsilyl ester, triethylsilyl ester, dimethyl methoxysilyl ester,
Examples include di(lower)alkyl alkoxysilyl esters such as dimethylethoxysilyl ester and diethylmethoxysilyl ester, and tri(lower)alkoxysilyl esters such as trimethoxysilyl ester and triethoxysilyl ester.
Among them, nitrophenyl (lower) alkyl esters such as 4-nitrobenzyl ester and 4-nitrophenethyl ester, methyl ester, 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. Suitable acyl groups include aliphatic acyl groups and acyl groups containing aromatic or heterocycles, more particularly formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,
Lower alkanoyl groups such as isovaleryl, oxalyl, succinyl, pivaloyl, preferably groups having 1 to 4 carbon atoms, more preferably groups having 1 to 2 carbon atoms, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Lower alkoxycarbonyl groups having 2 to 7 carbon atoms such as 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, Among these, groups having 2 to 6 carbon atoms are preferred, lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, arenesulfonyl groups such as benzenesulfonyl and tosyl, benzoyl, toluoyl, and naphthoyl. , phthaloyl, aroyl groups such as indancarbonyl,
Examples include ar(lower) alkanoyl groups such as phenylacetyl and phenylpropionyl, and ar(lower) alkoxycarbonyl groups such as benzyloxycarbonyl and phenyloxycarbonyl. The above acyl group may have 1 to 3 suitable substituents. Suitable substituents include chlorine, bromine, iodine or fluorine halogens, hydroxy groups, cyano groups, nitro groups, lower alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, methyl, ethyl, propyl, isopropyl, Examples include lower alkyl groups such as butyl, lower alkenyl groups such as vinyl and allyl, and aryl groups such as phenyl and tolyl. Suitable examples of such acyl groups include mono(or di- or tri)halo(lower)accanoyl groups such as chloroacetyl, dichloroacetyl, trifluoroacetyl, and the like. Examples of the heterocyclic group include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridine and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H −
triazolyl such as 1,2,3-triazolyl,
3 to 4 nitrogen atoms, such as tetrazolyl, such as 1H-tetrazolyl, 2H-tetrazolyl, etc.
8-membered (more preferably 5- or 6-membered) unsaturated monocyclic heterocyclic group, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,
Unsaturated fused heterocyclic groups containing 1 to 4 nitrogen atoms such as isoquinolyl, indazolyl, benzotriazolyl, oxazolyl, isoxazolyl, 1,
3 to 8 members containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (and preferably a 5- or 6-membered) unsaturated monocyclic heterocyclic group, thiazolyl, 1,2,4-thiazoazolyl,
3 to 3 containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazoazolyl, such as 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.
8-membered (more preferably 5- or 6-membered) unsaturated monocyclic heterocyclic group, unsaturated fused heterocycle containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl, benzothiadiazolyl, etc. The above heterocyclic group has one or two suitable substituents such as lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc. Good too. Lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary
Examples include linear or branched lower alkyl groups such as butyl, pentyl, neopentyl, and hexyl, and more preferably lower alkyl 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. Halogens include chlorine, bromine, iodine and fluorine, preferably chlorine and bromine. Further, preferred examples in the above definition are 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 R ³ include 5- or 6-membered unsaturated monocyclic heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, more preferably 1, 2, 4 -thiadiazolyl, 1,3,4
- thiadiazolyl groups such as thiadiazolyl, 1,2,5-thiadiazolyl (which may also have lower alkyl groups such as methyl, ethyl, propyl), or 1 to 2 sulfur atoms and 1 to 3
An unsaturated fused heterocyclic group containing 2 nitrogen atoms, more preferably a benzothiazolyl group. Preferred examples of R ⁴ include esterified carboxy groups, more preferably lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and isopropoxycarbonyl. Preferred examples of X include halogen, more preferably bromine or chlorine. Preferred examples of X' and X'' include hydrogen or halogen, more preferably bromine or chlorine. Preferred examples of Y include lower Y' Preferred examples include carbonyl groups, lower alkylene dioxymethylene groups such as ethylenedioxymethylene and trimethylenedioxymethylene,
Examples include di(lower) alkoxymethylene groups such as dimethoxymethylene and diethoxymethylene, and lower alkoxycarbonylhydrazonomethylene groups such as methoxycarbonylhydrazonomethylene and ethoxycarbonylhydrazonomethylene. Preferred examples of R ⁶ include a hydroxy group, an acyloxy group (more preferably a lower alkanoyloxy group such as acetoxy), or a methylene group. Salts include commonly used salts, such as alkali metal salts such as sodium salts and potassium salts, metal salts such as alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, hydrochlorides, and hydrogen bromide. Salts with inorganic bases or acids, such as inorganic acid salts such as acid salts, sulfates, phosphates, carbonates, bicarbonates, and trimethylamine salts, triethylamine salts, pyridine salts, procaine salts, picoline salts, dicyclohexylamine salts, amine salts such as N,N'-dibenzylethylenediamine salts, N-methylglucamine salts, diethanolamine salts, triethanolamine salts, tris(hydroxymethylamino)methane salts, phenethylbenzylamine salts, acetate salts , organic carboxylic acids or sulfonates such as maleate, lactate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, arginine salt, aspartate, glutamate, lysine salt, serine Examples include salts with organic bases or organic acids such as basic or acidic amino acid salts, and these salts are appropriately selected depending on the type of the compound of the present invention. Next, each method of the present invention will be explained in detail. Method [A] Compound (I-a) or a salt thereof is added to the compound (I-a) or a reactive derivative thereof at the amino group or a salt thereof with the 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 formula (wherein R 1 , X' and Y have the same meanings as above) or 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 carboxyl 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, phenylazophenyl ester, phenylthioester, 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-chlorozenzotriazole, etc.),
Examples include reactive derivatives commonly used in amidation reactions. 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'-dicyclohexenecarbodiimide, 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 propyl) carbodiimide, bisimidazolide 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 (I-b) or a salt thereof is produced by subjecting compound (I-a) 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 compound (I-a) or its salt 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. It is done by doing. 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. Method [C] Compound (I-c) or a salt thereof is produced by reducing compound (I-c) or a salt thereof. This reduction includes conventional reduction methods that can be used to remove an acetoxy group or a heterocyclic thio group leaving a methylene group. Among these, preferred are acids such as hydrochloric acid, sulfuric acid, formic acid, and acetic acid, metals such as zinc, iron, and copper, metal amalgams such as zinc amalgam and aluminum amalgam, metal couples such as zinc-copper couples, and dichloromethane. Examples include reduction in combination with transition metal salts such as chromium, monochromic bromide, and monochromic acetate, and commonly used catalytic reductions such as palladium on carbon, palladium sponge, Raney nickel, platinum, platinum black, and the like. This reaction is usually carried out in a conventional solvent such as water, alcohols such as methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, or other solvents that do not adversely affect the reaction. Although the reaction temperature is not particularly limited, it is preferably carried out under cooling or slight heating. When using a combination of acid and metal as a reducing agent, it is desirable to carry out the reaction in the presence of a metal sulfate such as copper sulfate. Method [D] Compound (I-e) or a salt thereof is produced by reacting compound (I-d) or a salt thereof with compound (I-d) or a salt thereof. This reaction is preferably carried out using lower alkanols such as methanol and ethanol, tetrahydrofuran,
It is carried out in a conventional solvent such as benzene or other solvents that do not adversely affect the reaction. This reaction can be carried out in the presence of an acid such as acetic acid or propionic acid. The reaction temperature is not particularly limited, but it is preferably carried out at room temperature or under heating. Method [E] Compound (I-f) or a salt thereof is produced by oxidizing compound (I-e) or a salt thereof with ozone and then reducing the product. The reaction between compound (I-e) or a salt thereof and ozone can be carried out using a solvent that does not adversely affect this reaction, such as water, methanol, ethanol, tetrahydrofuran, methylene chloride, chloroform, diethyl ether, benzene, N,N-dimethylformamide, etc. It is usually held inside. Among these solvents, water, methanol, ethanol, tetrahydrofuran, or a mixture thereof is advantageous because it can be used subsequently in the next reaction. The reaction temperature is not particularly limited, but it is preferably carried out under cooling or at room temperature. This reaction is preferably carried out under acidic conditions using hydrochloric acid, methanesulfonic acid, or the like. The reduction carried out in the second step of the process includes any conventional reduction method capable of reducing the compound obtained above to the 3-hydroxycephalic compound, and includes an alkali metal borohydride such as sodium borohydride. , lithium aluminum hydride, and the reduction method exemplified in Method [C]. Method [F] Compound (I-h) or a salt thereof is produced by acylating compound (I-g) or a salt thereof. This reaction is carried out by treating compound (I-g) or a salt thereof with an acylating agent.
Examples of acylating agents include alkanesulfonic acids such as methanesulfonic acid, organic sulfonic acids such as arenesulfonic acids such as p-toluenesulfonic acid, organic carboxylic acids such as haloalkanoic acids such as trifluoroacetic acid, acetic anhydride, and trifluoroacetic acid. Organic carboxylic acid anhydrides such as fluoroacetic anhydride, combinations of acids and acid anhydrides such as formic acid and acetic anhydride, organic sulfonic acid halides such as mesyl chloride and tosyl chloride, organic carboxylic acid halides such as acetyl chloride, and oxychlorides. Examples include acid halides such as inorganic acid halides such as phosphorus and thionyl chloride. This reaction is desirably carried out under anhydrous conditions and is usually carried out in a conventional solvent such as tetrahydrofuran, 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. The 3-cepham compound of the present invention can be prepared, for example, by the method shown in the Examples, and has antibacterial activity.
(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer). In order to clarify the usefulness of the above-mentioned 3-cephem 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 following agar plate multiple dilution method. One platinum loop of the test strain, cultured overnight in trypticase soy broth and diluted 100 times,
Heart infusion agar (HI agar) containing each concentration of compound was inoculated and incubated at 37°C.
After 20 hours of 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 suspended in 5% mucin to prepare suspensions of viable bacteria for each test. 0.5 ml of this suspension was intraperitoneally inoculated into mice. Solutions of test compounds were injected subcutaneously into mice at various doses 1 hour after the above inoculation. After 4 days, ED ₅₀ values were calculated from the number of surviving mice at each dose. (2) Test results

【table】

[Table] 3. Acute toxicity test (1) Test method Ten 6-week-old ICL-SD male rats and 10 female rats were used as one group. Test compounds were dissolved in distilled water and injected subcutaneously and intravenously to rats. Seven days after injection, the number of dead rats was calculated using the Richfield-Filcoxon method.
_LD50 values were calculated. (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 sibutyric 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. Aqueous layer with 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 (DMCO−d ₆ , δppm) 1.55 (3H, s) 3.85 (3H, s) 3.97 (4h, s) Example 2 2-Methoxyimino-3,3-ethylenedioxy
Production of sibutyric 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, 4) 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). 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 a 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) solution
water with sodium hydroxide (3.3g) dissolved in
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 ice cooling 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, 1020
cm ^-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-promobutyric 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
(100 ml) 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, quantitative yield) 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%). 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 Methoxyimino-3,3-ethylenedioxybutylene
Production of 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) Hz 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 with 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 the extract, and add sodium chloride.
Washed with thorium saturated aqueous solution and magnesium sulfate
Dry in a vacuum and filter. When the liquid is concentrated, 2
-methoxyimino-3,3-ethylenedioxy
Butyric acid ethyl ester (syn isomer, quantitative)
obtain. 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 is the same as that of Example 1. , 2, 3, 4
or 2-methoxyimino-
3,3-ethylenedioxybutyric acid (syn isomer),
2-methoxyimino-3,3-ethylenedioxy
C-4-chlorobutyric acid (syn isomer), or 2
-methoxyimino-3,3-ethenedioxy
-4-bromobutyric acid (syn isomer)
can. 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, 31.85g) and
Sulfuryl chloride in a solution of loloform (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 , δppm) 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
imino-3,3-ethylenedioxy-4-chloro
roacetic 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, 955
cm ^-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-Hydoxyimino-3, 3-ethylenedio
xy-4-chlorobutyric acid ethyl ester (syn-4-chlorobutyric acid ethyl ester)
(0.5 g) and dry acetone (5 ml).
Add potassium carbonate (0.29g) to the solution and
Add chilled sulfuric acid (0.265g) dropwise at room temperature while stirring.
Ru. The mixture is stirred at room temperature for 7 hours and filtered.
When the liquid is concentrated, 2-methoxyimino-3,
Ethyl 3-ethylenedioxy-4-chlorobutyrate
The 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 4(2)
Similarly, 2-methoxyimino-3,3-ethyl
Tyledioxy-4-chlorobutyric acid (synisomer
body). 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 , δppm) 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) 2methoxyimino-3,3 -dimethoxybutyric acid
Ethyl ester (syn isomer, 1.0g) and
Pip into a solution of dry tetrahydrofuran (10 ml).
lysinylhydropromide verbromide
(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, 1356, 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-bromoacid ethyl ester (1.06g) and
Add 2N sodium hydroxide to a solution of
Thorium methanol solution (6.5ml) was cooled on ice.
Add and stir at room temperature for 3 hours. 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 the pH to 1.6 with 6N hydrochloric acid. Separate the organic layer and add water
Extract the layer with diethyl ether (30ml). Yes
Combine the extract with water and sodium chloride.
magnesium sulfate.
Dry with. The solution is concentrated under reduced pressure to form an oil.
2-methoxyimino-3,3-dimethoxy-
4-bromoacid (syn isomer, 0.4 g) is obtained. 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-
Production of 4-bromocarboxylic acid (syn variant) (1) Ethyl 2-methoxyimino-3-oxocarboxylate
Ester (syn isomer, 0.5g), orthoformate
Chill (1.71g), Amberlyst 15 (trade name,
200 mg) and dry ethanol (2 ml).
When treated in the same manner as in Example 8 (1), 2-methoxyi
Mino-3,3-diethoxylic 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, 104
cm ^-1 NMR spectrum (CCl _Four , δ8ppm) 1.13 (6H, t, J = 7Hz) 1.28 (3H, t, J = 7Hz) 1.50 (3H, s) 3.50 (4H, t, J = 7Hz) 3.85 (3H, s) 4.18 (2H, q , J=7Hz) (2) 2-methoxyimino-3,3-diethoxy alcohol
Acid ethyl ester (syn isomer, 10.0g), pi
Lysinium hydrobromide perbromide
(15.5g) and tetrahydrofuran (100ml)
When treated in the same manner as in Example 8(2), 2-meth
xiimino-3,3-diethoxy-4-bromo
Alcoholic 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-bromoacid ethyl ester (syn isomer,
10.0g), sodium hydroxide (3.68g) dissolved in water
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-bromoacid
(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) in small portions 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) 5.20 (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
Hydrochloric acid (3.8g), ethyl acetate (80ml)
Add 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) with stirring.
(1.5 g) and stir for 30 minutes under ice cooling.
Add 2-methoxyimino-3,3-ethyl to this solution.
Tylendioxyacid (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:
Extract twice with the mixed solvent (200 ml) of 1). Up
The insoluble matter is ethyl acetate:methanol (4:
1) Soak in mixed solvent (200ml) for 30 minutes
Stir and strain. Combine the liquid and the above extract.
washed with saturated aqueous sodium chloride solution and sulfurized.
Dry over magnesium chloride and concentrate under reduced pressure.
Add diisopropyl ether to the residue and refrigerate.
Leave it in the refrigerator. Decant the solvent and remove the residue.
When powdered in n-hexane, 7-(2-
Methoxyimino-3,3-ethylenedioxib
tylamido)-3-(benzothiazol-2-y)
ruthiomethyl)-3-cephem-4-carvone
The 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, 1000cm ^-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) 7.27-7.62 (2H, m) 7.76-8.17 (2H, m) 9.37 (1H, d, J=8Hz) (3) Method A 7 -(2-methoxyimino-3,3-ethyle
dioxybutyramide)-3-(benzothiazo
(2-ylthiomethyl)-3-cephem-
4-carboxylic acid (syn isomer, 2g) and
Solution of N,N-dimethylformamide (10ml)
, formic acid (10ml), tetrahydrofuran (40ml)
and water (10ml). Add sublime to this mixture.
Add lead powder (1.4 g) at 0 to 2°C with stirring,
Stir at the same temperature for 1.5 hours. After reaction mixing,
Wash the residue with tetrahydrofuran. liquid
Combine the washing liquid and concentrate under reduced pressure. residue
Diluted with water (50ml) and ethyl acetate (150ml).
Extract. Wash the extract with water and dilute with sodium hydrogen carbonate.
Extract with an aqueous solution. Ethyl acetate (50%
ml) and adjust the pH to 2 with 6N hydrochloric acid. organic
Separate the layers and extract the aqueous layer with ethyl acetate (50ml)
do. Combine the ethyl acetate layer and extract and add water and
and saturated aqueous sodium chloride solution, and
Dry over magnesium chloride and concentrate under reduced pressure.
Add n-hexane to the oily residue and store in the refrigerator.
Leave it overnight to turn it into a powder. remove the precipitate
and 7-(2-methoxyimino-3,3-ethyl
dioxybutyramide)-3-methylenethe
fam-4-carboxylic acid (mine isomer) and
7-(2-methoxyimino-3,3-ethylene
dioxybutyramide)-3-methyl-3-se
Fem-4-carboxylic acid (syn isomer) (5:
A mixture of 1) (0.5 g) 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) Method B 7-(2-methoxyimino-3,3-ethylene
dioxybutyramide)-3-(benzothiazo
(2-ylthiomethyl)-3-cephem-
4-carboxylic acid (syn isomer, 500 mg), tetra
Solution of hydrofuran (6 ml) and water (2 ml)
Add acetic acid (1 ml) to the solution. Add zinc powder to this solution.
(500 mg) and copper sulfate pentahydrate (50 mg) at room temperature.
and stirred at the same temperature for 2 hours. The resulting solution
The liquid is treated in the same manner as in Method A of Example 10(3) above.
and 7-(2-methoxyimino-3,3-ethyl
dioxybutyramide)-3-methylenethe
fam-4-carboxylic acid (syn isomer) and
7-(2-methoxynomi-3,3-ethylenedi
Oxybutyramide)-3-methyl-3-cef
Em-4-carboxylic acid (syn isomer) (5:1)
A mixture of (120 mg) is obtained. (4) The mixture obtained in Example 10(3) (346 mg) and
70% perchloric acid in a solution of acetone (5 ml)
Add liquid (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 acetic acid
Combine the ethyl extracts, water and sodium chloride
Wash with a saturated aqueous solution of magnesium, then with magnesium sulfate.
Dry and concentrate under reduced pressure. Diisoprop the residue
Powderize with lopyl ether and remove the precipitate.
and 7-(2-methoximino-3-oxobuty)
Ruamide)-3-methylenecephaam-4-cal
Bonic acid (syn isomer) and 7-(2-methoxy)
siimino-3-oxobutyramide)-3-methane
Chil-3-cephem-4-carboxylic acid
A mixture (290 mg) of (5:1) is obtained. 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
zonoptilamide)-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) 5.30 (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 that, excess ozone is removed through nitrogen gas.
,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). Adjust the compound to PH2.0 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 as in 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) 4.30 (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.
Added drobromide verbromide (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, 52.2 mg). IR spectrum (nujiol) 3600−220, 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) 4.70 (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
Othiurea (8.4 mg) was added to a solution of
Stir at room temperature for 1 hour, then at 50°C for 30 minutes.
Ru. Ethanol is distilled off from the reaction mixture under reduced pressure.
Then, 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)
Subjected to column chromatography using
Wash with water (5 ml) and remove with 20% aqueous isopropyl alcohol.
Elute with alcohol. Eluent 1N sodium hydride
Adjust the pH to 6.5 with an aqueous solution of aluminum under ice cooling and reduce the pressure.
Concentrate below. When the residue is freeze-dried, 7
-[2-(2-aminothiazol-4-yl)-
2-methoxyiminoacetamide]-3-ceph
Em-4-carboxylic acid sodium salt (synisomer
body, 15 mg). 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 = 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-ethylenedioxyacid (mine isomer)
2.3 g) and stirred on ice for 1 hour.
7-amino-3-(5-methyl-1,3,4-
thiazazol-2-ylthiomethyl)-3-
Cefem-4-carboxylic acid (3,44g), tri
Ethylamine (4.9ml) and dry methylene chloride
Stir the above solution into a solution of loride (70ml)
It takes 30 minutes to drop to -20 to -30℃.
Stir for 1.5 hours. Add hydrogen carbonate to the resulting solution
Add aqueous sodium solution, separate the aqueous layer, and add acetic acid.
Wash with ethyl. Ethyl acetate in aqueous solution: meth
Add a mixed solvent of alcohol (4:1) and cool on ice.
Adjust the pH to 2.5 with 20% sulfuric acid and filter. Liquid?
Separate the ethyl acetate layer, and add the aqueous layer to ethyl acetate.
(50ml) twice. ethyl acetate layer and
Combine the extracts and saturated with water and sodium chloride.
Wash sequentially with aqueous solution and dry with magnesium sulfate
and concentrate under reduced pressure. Diisopropylene residue
Powder it with pill ether and remove the precipitate.
and yellow powdered 7-(2-methoxyimino-
3,3-ethylenedioxybutyramide)-3
-(5-methyl-1,3,4-thiazole-2
-ylthiomethyl)-3-cephem-4-cal
Bonic 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-Methoxyimino-3,3-ethylene
dioxybutyramide)-3-(5-methyl-
1,3,4-thiazazol-2-ylthiome
Chyl)-3-cefem-4-carboxylic acid (syn)
isomer, 500 mg), tetrahydrofuran (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 tetrahydrofuran (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 (DMOS-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) (3) The mixture obtained in (2) above was mixed with 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 , 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 = 9Hz) Example 12 (1) Method A 7-amino-3-(5-methyl-1,3,4
-thiadiazol-2-ylthiomethyl)-3
-Cefem-4-carboxylic acid (3.44g), acetate
(60ml) and a solution of 6N hydrochloric acid (25ml),
Add zinc powder (3.44g) with stirring and leave at room temperature for 1 hour.
Stir for a while. Strain the resulting mixture and wash with water
Combine the solution and washing solution, add ethyl acetate (30
ml) twice. Aqueous solution of 4N sodium hydride
When the pH is adjusted to 7.5 with an aqueous solution of 7-amino
No-3-methylenecefam-4-carboxylic acid
and 7-amino-3-methy-3-cephem-4
- Obtaining a solution containing carboxylic acid. On the other hand, N, N
-dimethylformamide (0.92g) and dry
Thionyl chloride in a solution of ethyl acetate (16ml)
(1.52g) was added under ice-cooling and heated to 0 to 5℃ for 30 minutes.
Stir for a minute. In this suspension, 2-methoxy
Imino-3,3-ethylenedioxyacid
isomer, 2.3 g). Add this solution to the above
Add 4N sodium hydroxide to the solution under ice cooling.
Maintain the same temperature with an aqueous solution at PH7.0 to PH7.5.
Stir for 2 hours at 30°C. From the resulting solution under reduced pressure
The solvent was distilled off, and the residue was diluted with ethyl acetate (100ml).
Add. Adjust the solution to PH2.0 with 6N hydrochloric acid and add
Separate the machine layer. The aqueous layer was diluted with ethyl acetate (50ml).
Extract twice and wash sequentially with water and sodium chloride.
Clean, dry over magnesium sulfate, and remove under reduced pressure.
Concentrate. Dilute the residue with diisopropyl ether.
After powdering and removing the precipitate, 7-(2-methane)
Toxiimino-3,3-ethylenedioxybutylene
Ruamide)-3-methylenecephaam-4-cal
Bonic acid (syn isomer) and 7-(2-methoxy)
Shiimino-3,3-ethylenedioxybutyla
(mido)-3-methyl-3-cephem-4-cal
A mixture (1.59 g) of bonic acids (syn isomer) was obtained.
Ru. 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
-Cefem-4-carboxylic acid (3.44g) and
p-Toluenesulfonic acid in a solution of water (60 ml)
Add monohydrate (11.4g). In this solution,
Add lead powder (3.4 g) and let the mixture stand at room temperature for 1 hour.
Stir. Strain the resulting mixture and add water (10
ml). Combine the solution and washing solution and add acetic acid ethyl chloride.
Wash with chill (90ml), 4N sodium hydroxide
Adjust the pH to 7.0 with an aqueous solution. In this aqueous solution, a
Add setone (40ml) and mix the mixture with Example 12(1)
2-methoxyimino obtained in the same manner as method A
-3,3-ethylenedioxyacid (synisomer)
reacts with an activated acid solution of the body). obtained
Add ethyl acetate (100ml) to the reaction mixture,
Adjust the pH to 2.0 with 6N hydrochloric acid. Separate the ethyl acetate layer.
Separate and extract the aqueous layer twice with ethyl acetate (50ml).
Ru. Combine the ethyl acetate layer and extract and chloride
Wash with saturated aqueous sodium solution and soak with magnesium sulfate.
and concentrate under reduced pressure. oily residue
When things are washed with diisopropyl ether, 7
-(2-methoxyimino-3,3-ethylenedi
Oxybutyramide)-3-methylenecefam
-4-carboxylic acid (syn isomer) and 7-
(2-methoxyimino-3,3-ethyledioxy
Sibutyramide)-3-methyl-3-cephem
- Obtain a mixture of 4-carboxylic acids (syn isomer)
Ru. 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) (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) 4.30 (3H, s) 5.1 (1H, s) 5.28 (2H, s) 5.32 (1H, d, J=5Hz) 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 used 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, 105cm ^-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-elendioxybutyric acid
15.1 g) was treated in the same manner as in Example 10(2).
Then, 7-(2-meth) at mp145-152℃ (decomposition)
xiimino-3,3,ethylenedioxybutyl
amide)-3-(1,3,4-thiazoazole-
2-ylthiomethyl)-3-cephem-4-ka
Rubonic 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 = 5 Hz, 8 Hz) 9.38 (1H, d, J = 8 Hz) 9.58 (1H, s) (2) The compound obtained in (1) above was used in Examples 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
-thiazol-2-ylthiomethyl)-3-se
Fem-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 ml 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
Add to a solution of saturated hydrogen solution (160 ml) and refrigerate.
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, 1.89g), N,
N-dimethylformamide (1.42ml), nitrogen chloride
onyl (1.32 ml) and dry ethyl acetate (10
ml) under cooling in Vilsmeier reagent prepared from
Add and stir at pH 7.0 to 7.5 for 30 minutes to activate.
Make a solution of the acid. Add this solution to the above solution.
Add to A under ice cooling and stir for 1 hour at pH 7.0 to 7.5.
Stir. Acetone is distilled off under reduced pressure and remains
Wash the solution with ethyl acetate (50ml) and separate the aqueous layer.
take. Add ethyl acetate (100ml) to the aqueous layer,
Saturate sodium chloride and adjust the pH to 2.0 with 6N hydrochloric acid.
Arrange. Separate the ethyl acetate layer and dilute it with sodium chloride.
Wash with a saturated aqueous solution of magnesium and dry with magnesium sulfate.
dry Concentrate the solution under reduced pressure and dilute the residue.
Powder with propyl ether. remove the precipitate
and when dried, 7-(2-methoxyimino-
3,3-ethylenedioxybutyramide)-3
-Hydroxycefam-4-carboxylic acid (sin
isomer, 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-ethylene
dioxybutyramide)-3-hydroxycetate
Fuam-4-carboxylic acid (syn isomer, 50mg)
and in a solution of tetrahydrofuran (5 ml),
Trifluoroacetic anhydride (0.1ml) and trielua
Add Min (0.2 ml) and stir at room temperature for 10 minutes.
Add sodium bicarbonate aqueous solution to the resulting solution.
(2 ml) and heat for 2 minutes. acetic acid in solution
Add ethyl and water, acidify with 6N hydrochloric acid,
Separate the ethyl acetate layer. The aqueous layer was diluted with ethyl acetate.
Extract. Combine the ethyl acetate and aqueous layers,
Wash sequentially with water and sodium chloride solution.
and dry with magnesium sulfate. Vacuum the solution
Concentrate and powder the residue with diethyl ether.
7-(2-methoxyimino-3,3
-ethylenedioxybutyramide)-3-cef
Em-4-carboxylic acid (syn isomer, 30mg)
obtain. IR spectrum (nujiol) 3300, 1790, 1730, 1700, 1650, 1550, 1470
cm ^-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)
(1.09 g) 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 , ppm) 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, d, 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 place it in a water tank.
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 , ppm) 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 drain the water tank into 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 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=3
Hz), 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.
When the precipitate is removed and dried next to pentoxide,
7-(2-methoxyimino-3-oxo-4-bu
lomobutyramide)-3-cephem-4-carbo
phosphoric acid (syn isomer, 0.82 g). 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 (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 20 7-amino-3-methylenecephaam-4-cal
Bonic acid (107g) was added to methanol (6.4) and methanol.
Dissolve in a solution of tansulfonic acid (57.7g). child
until the starting compound is no longer detected in the solution of
Pass ozone at -70 to -75℃. The resulting mixture
After passing nitrogen gas through the mixture, sodium methoxane
(3.5 g) at -65°C. Separately, hydroxide
Solution of sodium (14.4g) and water (3.2)
Add sodium borohydride (56.7g) to
After stirring for 20 minutes at room temperature, cool. In this solution,
Add the above oxidizing solution over a period of 3 minutes, -4 to 0
Stir for 20 min at °C. Adjust the solution to PH4.0 with 6N hydrochloric acid.
Adjust and leave at 5℃ overnight. Take the precipitate and meth
After washing with alcohol and drying, 7-amino-3-
Hydroxycefam-4-carboxylic acid (70.8g)
get. 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-methylformamide
(438 mg), 7-amino-3-cephem-4-ka
Rubonic acid (1g), trimethylsilylacetamide
(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
phosphoric acid (syn isomer, 2.25 g) 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) 35.1 (1H, d, J=4Hz), 5.8 (1H,
d, d, J = 4Hz, 8Hz), 6.52 (1H, t, J
= 4 Hz), 9.47 (1H, d, J = 8 Hz) Example 22 7-(2-methoxyimino-3-oxo-4-
Bromobutyramide)-3-hydroxycepham
-4-Carboxylic acid (syn isomer, 10g) was dried.
Add to tetradrofuran (100 ml) at 30°C. child
Add acetic anhydride (10 ml) to the solution and stir at the same temperature for 3 minutes.
Stir for a minute. Add sodium acetate (3g) to the solution
Add and stir at 30°C for 4 hours. 6N to the reaction mixture
Add hydrochloric acid (10ml) dropwise under ice-cooling and evaporate at below 30°C.
is distilled off under reduced pressure. Add water to the residue and mix
Stir at 2 to 25°C for 30 minutes. remove the precipitate
After washing with water and drying, 7-(2-methoxyi
Mino-3-oxo-4-bromobutyramide)-
3-Cefem-4-carboxylic acid (syn isomer, 7
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), 4.57 (H, 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
(50ml) 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-(aminothiazol-4-yl)-
2-methoxyiminoacetamide]-3-cefe
Mu-4-carboxylic acid (syn isomer, 11.2 g) was obtained.
Ru. 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=5Hz), 6.28
(1H, t), 6.96 (1H, s) Example 24 7-(2-methoishiimino-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 butyrate (50 ml) in a solution of
Add under stirring at -20℃ and stir at the same temperature for 1 hour.
Ru. Ethyl butyrate (20ml) and
Add water (10ml). Separate the ethyl butyrate layer
Then extract the aqueous layer with ethyl butyrate (20ml). Dairy
Combine the ethyl acid layer and the extract, and add the carbon-hydrogen solution.
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-ethylene
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-methylformamide
(1.1ml), phosphorus oxychloride (1.36ml) and methylene
chloride (50ml) was treated in the same manner as in Example 25(1).
When analyzed, 7-(2-methoxyimino-3,3-
dimethoxy-4-bromobutyramide)-3-hyde
Droxycefam-4-carboxylic acid (synisomer
body, 3.75 g). IR spectrum (nujiol) 3700-3100 (broad), 3100-2700 (blow)
), 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=6
Hz), 5.17 (1H, d, J=4Hz), 5.48 (1H, d,
d, J=4Hz, 8Hz, 8.87 (1H, d, J=8
Hz) Example 27 7-(2-methoxyimino-3-oxo-4-
Bromobutyramide)-3-hydroxycepham
-4-carboxylic acid (syn isomer, 180ml) 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-
Cefem-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
Ex-4-bromobutyramide)-3-hydro
Xicefam-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 = 8
Hz) 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
The spectrum matches that of R. Example 30 2-methoxyimino-3,3-trimethylenedi
Production of oxy-4-bromobutyric acid (syn isomer) (1) Ethyl 2-methoxyimino-3-oxobutyrate
Ester (syn isomer, 10g), 1,3-pro
Pandiol (11g), p-toluenesulfone
Acid (300ml) 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, 1460, 1460, 1380cm ^-1 NMR (DCl _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 (20ml) was treated 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 (13.6ml)
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-trimethylenedi
Example of oxy-4-bromobutyric acid (syn isomer)
25(1) and 25(2), 7-(2-
Methoxyimino-3-oxo-4-bromobutyl
Amido)-3-hydroxycepham-4-carbo
phosphoric 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-oiso-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 tetrahydrofuran (150ml)
Add acetic anhydride (22.5 ml) and poronto to the solution.
Stir refluoride etherate (7.5ml)
Add at room temperature for 30 minutes, then 50 minutes at the same temperature.
Stir for 1 hour at °C. 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, 4.0
Hz), 9.33 (2H, d, J = 4.0Hz) (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-
Cefem-4-carboxylic acid (syn isomer) and
and 7-(2-methoxyimino-3-oxo-4
-chlorobutyramide)-3-cephem-4-
Mixture of carboxylic acids (syn isomer) (0.09g)
get. 7-(2-methoxyimino-3-oxo-4-
Bromobutyramide)-3-cephem-4-ka
Rubonic acid (syn isomer) IR (Nudiyol) 3600−2200, 3240, 1780, 1700, 1690 (shoulder),
165, 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
Stell (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). 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 , δppm): 1.17 (6H, t, J=7
Hz), 1.60 (3H, s), 3.90 (3H, s), 3.55 (4H,
q, J = 7 Hz), 3.83 (3H, s) Example 35 Anhydrous sodium carbonate (8.89 g) was
Shiimino-3,3-diethoxybutyric acid methyl ester
(syn isomer, 10 g) and chloroform (40 g)
ml). This includes sulfuric acid chloride.
(6.94g) was added dropwise over 50 minutes at -6 to -2℃.
and stir at the same temperature for 10 minutes. Remove the solvent from the reaction solution.
After evaporation under reduced pressure, ethanol (10 ml) was added to the residue.
and stir for 30 minutes. Add water (25ml) to this,
Extract twice with diisopropyl ether (20 ml)
Ru. The extract was diluted with water (10 ml) and saturated with sodium chloride.
After sequentially washing with aqueous solution, wash with magnesium sulfate.
dry. When this is dried under reduced pressure, 2-methoxy
imino-3,3-diethoxy-4-chlorobutyric acid
The thyl ester (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 NMR (CDCl) 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 manner as 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 = 6Hz),
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=7Hz),
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=7Hz),
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 (1.10ml) and dry tetrahydro
Added to a solution consisting of furan (2 ml) at -20°C,
Stir for 3 minutes at the same temperature. 2-methoxy
Mino-3,3-diethoxy-4-bromobutyric acid
isomer, 3.3 g) at -20°C, -20-
Stir at -10°C for 1 hour. This reaction solution was mixed with phosphoric acid 2
Potassium hydrogen (3.63g), sodium phosphate and
Add to the solution consisting of water (1000ml) and adjust the pH under ice-cooling.
Stir at 6.1 for 2 hours. Remove the precipitate, wash with water,
When dried, 2-methoxyimino-3,3-diene
Toxy-4-bromobutyric acid chloride (syn isomer,
3.0g). mp33−35℃ IR (nujiol): 1780, 1620, 1400, 1290,
1245, 1210, 1200 (shoulder), 1140cm ^-1 NMR (CDCl) ₃ , δ): 1.2 (6H, t, J=7Hz),
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
Process in the same way as . The resulting reaction solution was diluted with 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 (CCl _Four , δ): 1.18 (6H, t, J = 7Hz),
3.57 (2H, q, J=7Hz), 3.68 (2H, s),
3.98 (3H, s) Example 41 Methanol (40 ml) was added to 7-amino-3-hydro
Roxycefam-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).
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 = 9
Hz) 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
−100, 1520, 1380, 1040 (broad) cm ^-1 NMR (DMSO−d ₆ , δ): 1.12 (6H, t, J=
7Hz), 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 diluted with 7-(2-methoxyi
Mino-3,3-diethoxy-4-bromobutyla
(mido)-3-hydroxycepham-4-carvone
acid (syn isomer, 30g) and dry tetrahydro
Added to a solution consisting of furan (300 ml) at room temperature,
Stir for 30 minutes at 28°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 dilute with 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-cephem
-4-carboxylic acid (syn isomer, 35.1 g) was obtained.
Ru. 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, q, J=4Hz), 6.78
(1H, dd, J = 4Hz, 8Hz), 6.47 (1H, t,
J = 4 Hz), 8.80 (1H, d, J = 8 Hz) 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 = 8Hz) 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, 3.36 g). 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 = 8Hz) Example 46 70% perchloric acid (3.4ml) was added to 7-(2-methoxy
imino-3,3-diethoxy-4-bromobutyl
Amido)-3-hydroxycepham-4-carbo
acid (syn isomer, 5.0 g) and acetone (40
ml) under ice-cooling, and at the same temperature
Stir for an hour. Collect the precipitate and add acetone (5 ml)
After washing twice and drying, 7-(2-methoxy
imino-3-oxo-4-bromobutyramide)
-3-Hydroxycepham-4-carboxylic acid
isomer, 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, broad s), 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=4
Hz, 8Hz), 9.33 (1H, d, J = 8Hz) Example 47 70% perchloric acid (0.54ml) was added to 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=4Hz), 9.63 (1H,
d, J = 8 Hz) Example 48 6N hydrochloric acid (2 ml) was diluted with 7-(2-methoxyimino-
3,3-diethoxy-4-bromobutyramide)
-3-Hydroxycepham-4-carboxylic acid
isomer, 500 mg) and methylene chloride (5 ml)
under ice-cooling and stirred 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, 8Hz), 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=5
Hz, 8Hz), 6.50 (1H, t, J=4Hz), 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=4
Hz, 8Hz), 6.53 (1H, t, J=5Hz), 9.43
(1H, dJ=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 treated in the same manner as 48, 7-(2-methoxyimide
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=4
Hz, 8Hz), 6.53 (1H, t, J=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, R ⁶ is a hydroxy group, an acyloxy group, or a methylene group,
(X' means hydrogen or halogen, Y' means carbonyl group or protected carbonyl group, respectively) or their salts. 2 General formula (In the formula, R ² means a carboxy group or a protected carboxy group, and R ⁶ ' means a hydroxy group or a methylene group, respectively.) (In the formula, R ¹ is a lower alkyl group, X' is hydrogen or halogen, and Y is a protected carbonyl group.) or a reactive derivative thereof in the carboxyl group or a salt thereof is reacted. , general formula (In the formula, R ¹ , R ² , R ⁶ ', X' and Y have the same meanings as above.) A method for producing a 3-cephame compound, which is characterized by obtaining a compound represented by the following formula 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, X' is hydrogen or a halogen, and Y' is a carbonyl group or a protected carbonyl group) or By reacting the salts with an acylating agent, the general formula (In the formula, R ⁷ means an acyl group, and R ¹ , R ² , X' and Y' have the same meanings as above) Production of a 3-cepham compound characterized by obtaining a compound or a salt thereof Law.