JPH0234953B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing an azetidinone compound having an oxo group, a salt thereof, or a hydrate thereof. More specifically, the present invention relates to a novel method for producing an azetidinone compound having an oxo group, a salt thereof, or a hydrate thereof, which is useful as an intermediate for synthesizing an azetidinone compound having antibacterial activity. Conventionally, methods for obtaining an azetidinone compound having an oxo group from an azetidinone compound having an amino group or a substituted amino group are known from the documents listed below, but the yields of these methods are not described. Alternatively, the reaction process is long and unsatisfactory from an industrial standpoint. (1) Patent Publication No. 102296 of 1972 (2) J.C. Sheehan:
Journal of Geoganic Chemistry, No. 42
Vol., p. 1012 (1977) As a result of intensive research, the inventors of the present invention have invented a new method for producing azetidinone compounds having an oxo group, which are useful as intermediates for synthesizing azetidinone compounds having antibacterial activity. succeeded in. The azetidinone compound having an oxo group produced by this invention is represented by the following general formula. [In the formula, A is a group

[expression] or

[Formula] (In the group, R ³ is hydrogen or alkyl, R ⁴ is hydrogen, halogen, alkyl, alkoxy, acyloxymethyl or a heterocyclic thiomethyl which may have a substituent, R ⁵ is carboxy or protected carboxy , X means -S- or -O-, respectively) The reaction formula of the production method of this invention is as follows. [In the formula, R ¹ is a trihalomethanesulfonyl group,
R ² is an acyl group, A is a group

[expression] or

[Formula] (In the group, R ³ is hydrogen or alkyl, R ⁴ is hydrogen, halogen, alkyl, alkoxy, acyloxymethyl or a heterocyclic thiomethyl which may have a substituent, R ⁵ is carboxy or protected carboxy , X means -S- or -O-, respectively] The azetidinone compound () having an oxo group and the salts in the starting materials (), (') and () of Production Methods 2 to 4 are For example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with inorganic bases such as ammonium salts, trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, and dicyclohexylamine. salt,
N,N'-dibenzylethylenediamine salt, N-
Examples include salts with organic bases such as methylglucamine salt, diethanolamine salt, triethanolamine salt, and tris(hydroxymethylamino)methane salt. Examples of salts in the starting material () of Production Method 1 include, in addition to the above-mentioned salts with bases, salts with inorganic acids such as hydrochlorides, hydrobromides, and sulfates, formates, acetates, Examples include salts with organic acids such as methanesulfonate and p-toluenesulfonate. Next, the object compound of the present invention () and manufacturing method 1
Starting materials (), (), (′) used in ~5
The definitions in and () are detailed below. Unless otherwise specified, the term "lower" includes groups containing 1 to 6 carbon atoms and the term "higher" includes groups containing 7 to 18 carbon atoms. "Trihalomethanesulfonyl group" in R ¹
Examples include trifluoromethanesulfonyl. The "acyl group" in R ² includes an aliphatic acyl group, an acyl group containing an aromatic ring, and an acyl group containing a heterocycle, and suitable examples of such acyl groups include formyl, acetyl, hexanoyl, Lower or higher alkanoyl groups such as heptanoyl and stearoyl, methoxycarbonyl,
Lower or higher alkoxycarbonyl groups such as ethoxycarbonyl, tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, lower or higher alkanesulfonyl groups such as methanesulfonyl, ethanesulfonyl, octanesulfonyl, carbamoyl groups, aliphatic acyl groups such as carbomoyl groups protected with amino-protecting groups such as mono-, di- or trihaloalkanoyl (e.g. chloroacetyl, dichloroacetyl, trichloroacetyl etc.), aroyl groups such as benzoyl, toluoyl, naphthoyl etc. alkanoyl groups such as phenyl (lower) alkanoyl such as phenyl acetyl and phenylpropionyl, aryloxycarbonyl groups such as phenoxycarbonyl and naphthyloxycarbonyl, phenoxyacetyl, phenoxypropionyl, etc. Aryloxy (lower) such as phenoxy (lower) alkanoyl
Alkanoyl groups, arylglyoxyloyl groups such as phenylglyoxyloyl and naphthylglyoxyloyl, aromatic acyl groups such as arenesulfonyl groups such as benzenesulfonyl and p-toluenesulfonyl, and heterocyclic carbonyl groups such as thenoyl and furoyl. , heterocyclic (lower) alkanoyl groups such as thienyl acetyl, furyl acetyl, heterocyclic glyoxyloyl groups such as thienylglyoxyloyl and furyl glyoxyloyl, and the above-mentioned heterocyclic carbonyl groups. , a heterocyclic (lower) alkanoyl group, and a heterocyclic glyoxyloyl group, more specifically, examples include saturated or unsaturated, monocyclic rings having at least one hetero atom such as oxygen, sulfur, or nitrogen. or a polycyclic heterocyclic group. Among these, particularly preferred heterocyclic groups include unsaturated 3- to 8-membered (preferably 5- or 6-membered) groups containing 1 to 2 sulfur atoms, such as thienyl and dihydrothienyl.
member) monocyclic heterocyclic group, unsaturated 3- to 8-membered (preferably 5- to 6-membered) containing oxygen atom of furyl group
Includes monocyclic heterocyclic groups and the like. The acyl groups mentioned above may optionally carry 1 to 5 suitable substituents, which may be the same or different. Examples of substituents include lower alkyl groups such as methyl and ethyl, lower alkoxy groups such as methoxy, ethoxy, and propoxy, lower alkylthio groups such as methylthio and ethylthio, lower alkylamino groups such as methylamino, and cyclopentyl groups such as cyclopentyl and cyclohexyl. (Lower) alkyl groups, cyclo (lower) alkenyl groups such as cyclohexenyl and cyclohexadienyl, halogens such as fluoro, chloro and bromo, amino groups, cyano groups, nitro groups, carboxy groups, protected carboxy groups as described below, Examples include a sulfo group, a sulfamoyl group, an imino group, an oxo group, and an amino (lower) alkyl group such as aminomethyl and aminoethyl. Preferred examples of the acyl group in R ² defined in this way include a trihalomethanesulfonyl group and a lower alkanoyl group. "Alkyl" in R ³ and R ⁴ includes lower or higher alkyl groups, and specific examples of such groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl. , hexyl, octyl, etc., preferably a lower alkyl group,
More preferred is a C ₁ -C ₃ alkyl group. Examples of halogen in R ⁴ include chloro,
Examples include bromo and iodine. "Alkoxy" in R ⁴ includes lower or higher alkoxy groups, and specific examples of such groups include methoxy, ethoxy, propoxy,
Isopropoxy, butoxy, isobutoxy, tertiary
Examples include butoxy, benzyloxy, neopentyloxy, hexyloxy, octyloxy, etc., preferably a lower alkoxy group, and more preferably a C ₁ -C ₃ alkoxy group. The acyl moiety of "acyloxymethyl" in R ⁴ includes an aliphatic acyl group, an acyl group containing an aromatic ring, and an acyl group containing a heterocycle, and specific examples of such acyl groups include those exemplified in R ² above. Specific examples of the acyl group can be listed directly, and preferred are lower alkanoyl groups and carbamoyl groups protected with amino-protecting groups, and more preferred are C ₁ - _{C 3} alkanoyl groups and trihalo (lower) alkanoyl carbamoyl groups. . The heterocyclic moiety of "optionally substituted heterocyclic thiomethyl" in R ⁴ is, for example, a saturated or unsaturated, monocyclic or polycyclic heterocyclic ring having at least one heteroatom such as oxygen, sulfur, or nitrogen. Contains formula groups. Among these, particularly preferred heterocyclic groups include, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridine, and their N-
oxide, dihydropyridyl, pyrimidinyl,
Pyrazinyl, pyridazinyl, e.g. 4H-1,
Triazolyl such as 2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, for example 1H-tetrazolyl,
1 of tetrazolyl such as 2H-tetradolyl
unsaturated 3- to 8-membered (preferably 5- or 6-membered) monocyclic heterocyclic groups containing 1 to 4 nitrogen atoms; saturated 3- to 8-membered (preferably 5 or 6-membered) monocyclic heterocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl; 8-membered (preferably 5- or 6-membered) monocyclic heterocyclic group, unsaturated condensation containing 1 to 4 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc. Heterocyclic groups, oxazolyl, isoxazolyl, such as 1,2,4-oxadiazolyl, 1,3,4
-Unsaturated 3- to 8-membered (preferably 5- or 6-membered) monocyclic ring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxadiazolyl, 1,2,5-oxadiazolyl, etc. 1 of heterocyclic groups, morpholinyl, cydononyl, etc.
a saturated 3- to 8-membered (preferably 5- or 6-membered) monocyclic heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl, benzoxadiazolyl, etc. Unsaturated fused heterocyclic groups containing 2 oxygen atoms and 1 to 3 nitrogen atoms, thiazolyl, isothiazolyl, such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4 -Thiadiazolyl,
Unsaturated 3- to 8-membered (preferably 5- or 6-membered) monocyclic ring containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiadiazolyl such as 1,2,5-thiadiazolyl, dihydrothiazinyl, etc. Saturated 3 containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as a heterocyclic group, thiazolidinyl, etc.
to 8-membered (preferably 5- or 6-membered) monocyclic heterocyclic groups; Ring heterocyclic group, unsaturated fused heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as benzothiazolyl and benzothiadiazolyl, unsaturated 3 containing oxygen atom such as furyl unsaturated 3- to 8-membered (preferably 5- to 6-membered) monocyclic heterocyclic group, containing an oxygen atom and 1 to 2 sulfur atoms, such as dihydrooxathinyl;
members) monocyclic heterocyclic groups, unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms such as benzothienyl and benzodithinyl, and oxygen atoms and 1 to 2 sulfur atoms such as benzoxathinyl; and unsaturated fused heterocyclic groups containing. Such heterocyclic groups may optionally have 1 to 5 suitable substituents, which may be the same or different. Examples of substituents include lower alkyl groups such as methyl and ethyl, methoxy, ethoxy,
Lower alkoxy groups such as propoxy, methylthio,
Lower alkylthio groups such as ethylthio, lower alkylamino groups such as methylamino, cyclopentyl,
Cyclo (lower) alkyl groups such as cyclohexyl,
Cyclo (lower) alkenyl groups such as cyclohexenyl and cyclohexadienyl, hydroxy groups, halogens such as chloro and bromo, amino groups, cyano groups,
Examples include a nitro group, a carboxy group, a protected carboxy group described below, and preferably one or two sulfur atoms which may have a lower alkyl group and one
an unsaturated 5- or 6-membered monocyclic heterocyclic group containing 1 to 3 nitrogen atoms or an unsaturated 5- or 6-membered monocyclic heterocyclic group containing 1 to 4 nitrogen atoms optionally having lower alkyl; The formula group is more preferably a thiadiazolyl group or a tetrazolyl group having lower alkyl. The "protected carboxy" in R ⁵ includes a carboxy group protected with an appropriate protecting group, which is used as a carboxy protecting group at the 4- or 3-position of a normal cephalosporin or penicillin core. Protected carboxy groups include, for example, esterified carboxy groups. Suitable examples of the ester moiety of the esterified carboxy group include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester,
Tertiary butyl ester, pentyl ester, tertiary
Lower alkyl esters such as pentyl esters and hexyl esters, lower cycloalkyl (lower) alkyl esters such as 1-cyclopropylethyl esters, lower alkenyl esters such as vinyl esters and allyl esters, lower alkynyl esters such as ethynyl esters and propynyl esters. ,
Lower alkoxyalkyl esters such as methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxydiethyl ester, methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester Lower alkylthioalkyl esters, 2-iodoethyl esters, 2,2, etc.
Mono (or di or tri) halo (lower) alkyl esters such as 2-trichloroethyl ester, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, lower alkanoyloxy (lower) alkyl ester such as hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, lower alkanesulfonyl (lower) alkyl ester such as mesylmethyl ester, 2-mesylethyl ester, etc. , benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethyl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, etc. as desired. Hydroxy,
Al (lower) alkyl esters such as phenyl (lower) alkyl esters, phenyl esters, tolyl esters, tertiary
class butyl phenyl ester, xylyl ester,
It may have one or more substituents such as mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc., and is optionally substituted with halogen or lower alkoxy group. Examples include aryl esters such as substituted or unsubstituted phenyl esters, tri(lower) alkylsilyl esters such as trimethylsilyl ester, and lower alkylthioesters such as methylthioester and ethylthioester. The method for producing the object compound () of the present invention will be explained in more detail as follows. (1) Production method 1: Compound () or its salts can be produced by reacting compound (), its reactive derivative at the amino group, or its salt with a trihalomethanesulfonylating agent. The raw material compounds () used in this reaction include known and novel compounds, and the new compounds can be produced by the same methods as those for synthesizing known compounds or by conventional methods. Examples of reactive derivatives of the amino group of the compound () include silyl derivatives obtained by reacting the compound () with silyl compounds such as bis(trimethylsilyl)acetamide and trimethylsilylacetamide, isocyanates, isothiocyanates, etc.; amino groups and acetaldehyde; Isopentaldehyde, benzaldehyde, salicylaldehyde, phenyl acetaldehyde, p-nitrobenzaldehyde, m-chlorobenzaldehyde,
Schiff base or its enamine type obtained by reaction with aldehyde compounds such as p-chlorobenzaldehyde, hydroxynaphthaldehyde, furfural, and thiophenecarbaldehyde, or ketone compounds such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone, and ethyl acetoacetate. Contains tautomers. The trihalomethanesulfonylating agent used in this reaction includes, for example, trihalomethanesulfonic acid or reactive derivatives of trihalomethanesulfonic acid such as its acid halide or acid anhydride, and particularly preferred are acid chloride, acid bromide, symmetric type Examples include acid anhydrides. This reaction is preferably carried out in the presence of a base, such as, for example, an alkali metal hydride such as sodium hydride, an alkaline earth metal hydride such as calcium hydride, sodium hydroxide, potassium hydroxide, etc. Alkali metal hydroxides such as, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tertiary butoxide, etc. , trialkylamines such as triethylamine, N-alkylarylamines such as N-methylaniline and N-ethylaniline, N-methylbenzylamine,
Tertiary amines such as N-alkylaralkylamines such as N-ethylbenzylamine, N-alkylmorpholine compounds such as N-methylmorpholine,
Pyridine, lutidine, picoline, 4-(N,N-
4-(N,N) such as dimethylamino)pyridine
pyridine compounds such as -dialkylamino)pyridine, 1,5-diazabicyclo[4,3,0]-5
-Nonene, 1,5-diazabicyclo[5,4,
0]-5-undecene, diazabicyclo compounds such as 1,4-diazabicyclo[2,2,2]octane, and inorganic or organic bases such as quaternary ammonium salts such as Triton B. In this reaction, when using trihalomethanesulfonic acid or its salt, for example, N,
N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide,
N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-
Carbodiimide compounds such as N'-(3-dimethylaminopropyl)carbodiimide, ethyl polyphosphate, isopropyl polyphosphate, phosphoryl chloride, 5
In addition to phosphorus compounds such as phosphorus chloride, thionyl chloride, and oxalyl chloride, amide compounds such as dimethylformamide, diethylacetamide, and N-methylformamide are reacted with halogen compounds such as thionyl chloride, phosphoryl chloride, and phosgene. It is preferable to carry out the reaction in the presence of a condensing agent such as Ear's reagent. This reaction is usually carried out in conventional solvents or mixtures thereof that do not adversely affect the reaction, such as methylene chloride, chloroform, tetrahydrofuran, dioxane, ethyl acetate, and the like. Although the reaction temperature is not particularly limited, it is usually carried out under mild conditions such as cooling or heating. (2) Production method 2: Compound () or its salts can be produced by reacting compound () or its salts with an acylating agent. As the acylating agent used in this reaction, the above-mentioned
Included are organic carboxylic acids, organic sulfonic acids, and reaction derivatives thereof into which the acyl group described in the definition of R ² can be introduced. Suitable reactive derivatives of acylating agents include, for example, acid halides, acid anhydrides, active amides, active esters, etc., but particularly preferred are acid chlorides, acid bromides, substituted phosphoric acids (e.g., dialkyl phosphoric acids), etc. , phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.) mixed anhydrides, dialkyl phosphorous mixed anhydrides, sulfurous mixed anhydrides, thiosulfuric acid mixed anhydrides, sulfuric acid mixed anhydrides, alkyl carbonates (e.g. methyl carbonic acid, ethyl carbonate) mixed anhydrides, aliphatic carboxylic acids (e.g.
Acid mixed anhydrides such as pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid) mixed anhydride, aromatic carboxylic acid (e.g. benzoic acid) mixed anhydride, symmetrical acid anhydrides, etc. . Such reactive derivatives are appropriately selected depending on the type of compound () actually used. This reaction is carried out in substantially the same manner as Production Method 1, and therefore the reaction mode (e.g. base, condensing agent, etc.), reaction conditions (e.g. reaction solvent, reaction temperature, etc.) are the same as Production Method 1. The explanation given can be used as is. (3) Production method 3: Compound (') or its salts are compound ()
Alternatively, it can be produced by reacting a reactive derivative at the amino group or a salt thereof with an acylating agent. This reaction is carried out in substantially the same manner as Production Method 2, and therefore, the specific examples of the acylating agent can be the same as those described in Production Method 2, and the reaction mode (e.g., base, condensing agent, etc.) can be cited as is. etc.), reaction conditions (for example, reaction solvent, reaction temperature, etc.), etc., the explanation given in Production Method 1 can be used as is. (4) Manufacturing method: 4 Compound () or its salts are compound (')
Alternatively, it can be produced by reacting a salt thereof with a trihalomethanesulfonylating agent. This reaction is carried out in substantially the same manner as Production Method 1, and therefore the trihalomethanesulfonylating agent, reaction mode (e.g., base, condensing agent, etc.), reaction conditions (e.g., reaction solvent, reaction temperature, etc.), etc. Law 1
The explanation given in can be used as is. (5) Production method 5: The compound () or its salt or its hydrate is produced by reacting the compound () or its salt with a base and then subjecting it to hydrolysis. In this reaction, as shown in the reaction formula below, compound () or a salt thereof is reacted with a base to form compound () via carbanion compound ('), and then the compound is subjected to hydrolysis. By doing so, the target compound () is obtained. As the base used in this reaction, the specific examples of the organic bases exemplified in the above production method can be mentioned as they are, and preferably tertiary amines such as trialkylamines and diazabicyclo compounds are mentioned. In addition, the hydrolysis in this reaction is a normal C
Hydrolysis that can convert =N- groups into C=O groups is applied, and examples of such hydrolysis include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, formic acid,
Examples include hydrolysis in the presence of acids such as organic acids such as acetic acid, propionic acid, benzenesulfonic acid, toluenesulfonic acid, and the like. This reaction is usually carried out in a solvent that does not have an adverse effect on the reaction, and examples of such a solvent include the specific examples of the solvents mentioned in Production Method 1 above. Although the reaction temperature is not particularly limited, it is usually carried out under mild conditions such as cooling or heating. In this reaction, the azetidinone compound having an oxo group represented by the formula () is expressed by the following formula (')
Although these compounds are sometimes isolated in the form of hydrates, such compounds are also included in the target compounds. In the production method of this invention, the above production methods 1 to 4
The target compounds (), () and (') can also be subjected to the next production method as they are without isolation. The azetidinone compound having an oxo group, its salt, or its hydrate produced by the present invention can be converted into a substance useful as an antibacterial agent, for example, by the method described in the following literature. (1) JC Sheehan et al., Journal of Organic Chemistry Vol. 38, p. 3227 (1973) (2) J.C. Sheehan et al., Journal of Organic Chemistry Vol. 42, p. 1012 (1977) (3) Patent Publication No. 5788 of 1972 Next, this invention will be explained in detail with reference to Examples. Example 1 (1) A solution of 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester (3.96 g) in methylene chloride (60 ml) - 60
After cooling to ℃, triethylamine (3.35 ml) and trifluoromethanesulfonic anhydride (4.71 ml) were added, and the mixture was heated at the same temperature for 1 hour at −50 to −30° C.
Stir for 30 minutes at °C, then for 30 minutes at -30 to -10 °C. The reaction mixture was poured into a cold aqueous sodium chloride solution and extracted with a mixed solvent of diethyl ether (250 ml) and ethyl acetate (50 ml). The extract is washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent is distilled off. When the resulting crystalline solid is washed with a mixed solvent of diisopropyl ether and hexane, 7-[N,N-
Bis(trifluoromethanesulfonyl)amino]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cepheme-4-
Carboxylic acid benzhydryl ester (5.40g)
get. mp125-127℃ (decomposition) IR (Nujiol): 1800, 1720, 1240cm ^-1 MNR δ ppm (CDCl ₃ ): 3.84 (2H, ABq,
J = 14Hz), 4.60 (2H, ABq, J = 13Hz),
5.14 (1H, d, J = 5Hz), 5.90 (1H, d, J
=5Hz), 7.07 (1H, s), 7.3-7.7 (10H,
m) (2) A solution of 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester (5.00 g) in methylene chloride (100 ml) at -65
After cooling to ℃, triethylamine (1.55 ml) and trifluoromethanesulfonic anhydride (1.87 ml) were added, and the mixture was stirred at the same temperature for 30 minutes.
The reaction solution is washed successively with an aqueous sodium chloride solution containing 1N hydrochloric acid and an aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent is distilled off. The resulting oil was crystallized from a mixed solvent of ethyl acetate and diethyl ether to give 7-(N
-trifluoromethanesulfonylamino)-3
-(1-Methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester (4.90 g) was obtained. mp100-105℃ IR (nujiol): 1780, 1720, 1240 cm ^-1 NMR δppm (CDCl ₃ ): 3.73 (2H, broad s), 3.80 (3H, s), 4.33 (2H, ABq, J=
13Hz), 5.00 (1H, d, J=5Hz), 5.40 (1H,
d, J=5Hz), 6.93 (1H, s), 7.2-7.6
(10H, m) The compound obtained above (1.00g) was dissolved in methylene chloride (20ml) and cooled to -60°C. Add triethylamine (0.32 g) and trifluoromethanesulfonic anhydride (0.90 g) to this solution,
Stir at the same temperature for 1 hour, then at -50 to -30°C for 1 hour. The reaction solution was poured into an aqueous sodium chloride solution and extracted with ethyl acetate. The extract is washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent is distilled off. The resulting oily residue is crystallized with diisopropyl ether to give 7-[N,N-bis(trifluoromethanesulfonyl)amino]-3
-(1-Methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester (0.85 g) was obtained. IR (Nudiyol): 1800, 1720, 1240cm ^-1 (3) 7-[N,N-bis(trifluoromethanesulfonyl)amino]-3-(1-methyl-1H
-tetrazol-5-ylthiomethyl)-3-
A solution of cefem-4-carboxylic acid benzhydryl ester (1.27 g) in methylene chloride (15 ml) was cooled to -60°C, and then triethylamine (0.408
ml) and stir at the same temperature for 1.5 hours. After pouring into a mixture of benzene and 0.1N hydrochloric acid, separate the organic solvent layer. After washing with an aqueous sodium chloride solution and drying with magnesium sulfate, the solvent is distilled off. The resulting oil was subjected to column chromatography using silica gel and eluted with a mixture of benzene and acetone (volume ratio 100:2 to 100:8). Fractions containing the target product were collected and concentrated to dryness under reduced pressure to form an oily 7-oxo-3-(1
-Methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester (0.58 g) was obtained. IR (CHCl ₃ ): 1820, 1780, 1720 cm ^-1 NMR δppm (CDCl ₃ ): 3.76 (2H, broad s), 3.80 (3H, s), 4.34 (2H, ABq, J
= 14Hz), 5.28 (1H, s), 7.00 (1H, s),
7.1-7.5 (10H, m) Example 2 (1) 7-Aminocephalosporanic acid benzhydryl ester (1.71g) in methylene chloride (20ml)
After cooling the solution to -65°C, triethylamine (1.06 g) and trifluoromethanesulfonic anhydride (2.80 g) are added. Stirring is carried out while the reaction temperature is gradually raised to 0° C. over a period of 2 hours. After cooling this solution to -60°C, add trifluoromethanesulfonic acid (0.57g) and triethylamine (0.21g), and stir while gradually increasing the reaction temperature to -10°C over 1 hour and 40 minutes. . After pouring the reaction solution into a mixture of ethyl acetate and water, the organic solvent layer is separated. This solution was washed successively with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off, yielding 7-[N,N-bis(trifluoromethanesulfonyl)amino]cephalosporanic acid benzhydryl ester (2.49 g). get. IR (CH ₂ Cl ₂ ): 1810, 1750, 1220, 1160 ^{cm -1} (2) 7-aminocephalosporanic acid benzhydryl ester (1.0 g) in methylene chloride (15 ml)
After cooling the solution to -60°C, triethylamine (0.277 g) and trifluoromethanesulfonic anhydride (0.708 g) were added in a nitrogen stream, and the mixture was stirred at the same temperature for 10 minutes. After pouring the reaction solution into a mixture of ethyl acetate and dilute hydrochloric acid, the organic solvent layer is separated. This solution was washed with 1N hydrochloric acid and then with an aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent was distilled off. The resulting residue was subjected to column chromatography using silica gel (16 g) and eluted with a mixed solvent of methylene chloride and ethyl acetate (volume ratio 15:1). Fractions containing the target product were collected and the solvent was distilled off to obtain 7-(N-trifluoromethanesulfonylamino)cephalosporanic acid benzhydryl ester (1.03 g).
get. IR (CH ₂ Cl ₂ ): 3300, 1790, 1730, 1210 cm ^-1 NMR δppm (DMSO-d ₆ ): 1.95 (3H, s),
3.64 (2H, m), 4.74 (2H, ABq, J=13Hz),
5.15 (1H, d, J = 4.5Hz), 5.67 (1H, d,
J=4.5Hz), 6.89 (1H, s), 7.2-7.5 (10H,
m) The compound thus obtained (1.40 g) was dissolved in methylene chloride (20 ml), and after cooling to -60°C, triethylamine (0.264 g) and trifluoromethanesulfonic anhydride (0.669 g) were added,
The mixture was stirred while gradually raising the reaction temperature to -20°C over 1 hour and 20 minutes, and left in the refrigerator overnight. The reaction solution is concentrated to about one third, and the concentrated solution is poured into ethyl acetate. This solution is washed successively with 1N hydrochloric acid, an aqueous sodium bicarbonate solution, water, and an aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off, and the resulting residue (1.38 g) was subjected to column chromatography using silica gel (25 g) and eluted with methylene chloride. When fractions containing the target product are collected and the solvent is distilled off, 7-[N,N-
Bis(trifluoromethanesulfonyl)amino]
Cephalosporanic acid benzhydryl ester (0.64 g) is obtained. IR (CH ₂ Cl ₂ ): 1810, 1750, 1220, 1160 cm ^-1 NMR δppm (CDCL ₃ ): 2.03 (3H, s), 3.50
(2H, ABq, J = 16Hz), 5.00 (1H, d, J
= 4Hz), 5.10 (2H, ABq, J = 14Hz), 5.80
(1H, d, J=4Hz), 6.93 (1H, s), 7.33
(10H,s) (3) A solution of 7-[N,N-bis(trifluoromethanesulfonyl)amino]cephalosporanic acid benzhydryl ester (2.49 g) in methylene chloride (20 ml) was cooled to -60°C, and then triethylamine (0.394 Add g) all at once. at the same temperature
After stirring for 40 minutes triethylamine (0.073g)
was added at -50°C, and the reaction temperature was raised to -35°C over 30 minutes while stirring. The reaction solution is poured into a mixture of ethyl acetate and dilute hydrochloric acid, and the organic solvent layer is separated. This solution is washed with dilute hydrochloric acid and then with saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The resulting residue (2.22 g) was subjected to column chromatography using silgel (22 g) and eluted with methylene chloride and then with a mixed solvent of methylene chloride and ethyl acetate (volume ratio 10:1). Fractions containing the desired product were collected and the solvent was distilled off to obtain oily 7-oxocephalosporanic acid benzhydryl ester (1.40 g). IR (CH ₂ Cl ₂ ): 1830, 1790, 1740 cm ^-1 NMR δppm (CDCl ₃ ): 2.00 (3H, s), 3.50
(2H, ABq, J=18Hz), 4.93 (2H, ABq,
J=14Hz), 5.27 (1H, s), 7.00 (1H, s),
7.33 (10H, s) Example 3 (1) Add p-toluenesulfonate of 6-aminopenicillanic acid benzyl ester (478 mg) to a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The ethyl acetate layer is separated and the remaining aqueous solution is extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was distilled off, and the resulting residue (320 mg) was dissolved in methylene chloride (6 ml), followed by triethylamine (242 mg) and trifluoromethanesulfonic anhydride (795 mg).
was added at -60°C, the reaction temperature was raised to 0°C over about 2 and a half hours with stirring, and then further raised to 0°C.
Continue stirring for 30 minutes. Ethyl acetate was added to the reaction solution, washed successively with a dilute aqueous sodium hydrogen carbonate solution, 1-dihydrochloric acid and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off to give 6-[N,N-bis(trifluoromethanesulfonyl). Amino]penicillanic acid benzyl ester (467 mg) is obtained. IR (nujiol): 1800, 1735, 1725 cm ^-1 NMR δppm (acetone-d ₆ ): 1.50 (3H,
s), 1.73 (3H, s), 4.52 (1H, s), 5.25
(2H, s), 5.45 (1H, d, J=3.5Hz), 6.26
(1H, d, J = 3.5Hz), 7.38 (5H, s) (2) Dissolve 6-[N,N-bis(trifluoromethanesulfonyl)amino]penicillanic acid benzyl ester (467 mg) in methylene chloride (6 ml). Cool to -60℃. Add triethylamine (71 mg) to this solution and stir for 30 minutes, then add triethylamine (22 mg) and stir for 10 minutes. After adding the reaction solution to a mixture of ethyl acetate and 1N hydrochloric acid, the organic solvent layer is separated. This solution is washed with a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The residue (423 mg) obtained by distilling off the solvent was subjected to column chromatography using silica gel (4.5 g) and eluted with a mixed solvent of methylene chloride and ethyl acetate (volume ratio 9:1). Fractions containing the target product were collected and the solvent was distilled off to obtain oily benzyl 6-oxopenicillanic acid ester (239 mg). IR (CH ₂ Cl ₂ ): 1830, 1780, 1735 cm ^-1 NMR δppm (CDCl ₃ ): 1.48 (3H, s), 1.55
(3H, s), 4.82 (1H, s), 5.24 (2H, s),
5.79 (1H, s), 7.36 (5H, s), Example 4 A solution of 7-aminocephalosporanic acid benzhydryl ester (1.71 g) in methylene chloride (20 ml) was cooled to -60°C, and then triethylamine (1.29
ml) and trifluoromethanesulfonic anhydride (1.52 ml), and the reaction temperature was gradually raised to -8°C over 2.5 hours while stirring. The reaction solution was cooled to -60℃, and triethylamine (0.62ml) was added.
After adding, stir for an additional 50 minutes. During this stirring, the reaction temperature is gradually raised to -30°C. The reaction solution is poured into a mixture of ethyl acetate and water, and the organic solvent layer is separated. This solution is washed with 1N hydrochloric acid and then with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. Residue obtained by distilling off the solvent (2.34 g)
The product was subjected to column chromatography using silica gel (25 g) and eluted with methylene chloride and then with a mixed solvent of methylene chloride and acetone (volume ratio 19:1). Fractions containing the desired product were collected and concentrated to dryness under reduced pressure to obtain crude 7-oxocephalosporanic acid benzhydryl ester (0.86 g). IR (CH ₂ Cl ₂ ): 1830, 1790, 1740 cm ^-1 Example 5 7-amino-3-methoxy-3-cephem-4
-Reacting carboxylic acid 4-nitrobenzyl ester with trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid in the same manner as in Examples 1 to 4 to obtain 7-oxo-3-methoxy-3-cepheme-
4-Carboxylic acid 4-nitrobenzyl ester (1
hydrate). mp115-120℃ (decomposition) IR (Nujiol): 1770, 1750cm ^-1 NMR δppm (DMSO―d ₆ ): 3.56 (2H, ABq,
J=16Hz), 3.77 (3H, s), 4.75 (1H, s),
5.33 (2H, s), 7.78 (2H, d, J=9Hz),
8.33 (2H, d, J = 9Hz) Example 6 7-amino-3-chloro3-cephem-4-
Carboxylic acid 4-nitrobenzyl ester is reacted with trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid in the same manner as in Examples 1 to 4,
7-oxo-3-chloro-3-cefem-4-carboxylic acid 4-nitrobenzyl ester (monohydrate) is obtained. mp105-106℃ (decomposition) IR (Nujiol): 1760, 1735cm ^-1 NMR δppm (DMSO―d ₆ ): 3.83 (2H, ABq,
J=17Hz), 4.97 (1H, s), 5.50 (2H, s),
7.75 (2H, d, J = 9Hz), 8.30 (2H, d, J =
9Hz) Example 7 7-amino-3-cefem-4-carboxylic acid 4
-Nitrobenzyl ester is reacted with trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid in the same manner as in Examples 1 to 4 to obtain 7-oxo-
3-Cefem-4-carboxylic acid 4-nitrobenzyl ester is obtained. mp141-142℃ (decomposition) IR (CH ₂ Cl ₂ ): 1830, 1790, 1730, 1520 cm ^-1 NMR δppm (CDCl ₃ ): 3.60 (2H, m), 5.29
(1H, s), 5.40 (2H, s), 6.69 (1H, dd, J
=5Hz, 6Hz), 7.60, 8.19 (4H, ABq, J=
8Hz) Example 8 7-amino-2-methyl-3-cephem-4-
Carboxylic acid 2,2,2-trichloroethyl ester is reacted with trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid in the same manner as in Examples 1 to 4 to obtain 7-oxo-2-methyl-3-cephem-4-carboxylic acid. 2,2,2-trichloroethyl ester is obtained. mp98℃ IR (CH ₂ Cl ₂ ): 1820, 1780, 1730 cm ^-1 NMR δppm (CDCl ₃ ): 1.52 (3H, d, J=
7Hz), 3.75 (1H, dq, J = 6Hz, 7Hz),
4.93 (2H, s), 5.25 (1H, s), 6.79 (1H,
d, J = 6 Hz) Example 9 7-amino-1-oxadethia-3-cephem-4-carboxylic acid benzyl ester was reacted with trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid in the same manner as in Examples 1 to 4, 7-
Oxo-1-Oxadethia-3-Cefem-4-
A carboxylic acid benzyl ester is obtained. IR (CH ₂ Cl ₂ ): 1820, 1780, 1720 cm ^-1 NMR δppm (CDCl ₃ ): 4.66 (2H, m), 5.26
(1H, s), 5.33 (2H, s), 6.45 (1H, m),
7.37 (5H, s) Example 10 7-amino-3-[N-(2,2,2-trichloroacetol)carbamoyloxymethyl]-3
-Cefem-4-carboxylic acid benzhydryl ester was reacted with trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid in the same manner as in Examples 1 to 4 to obtain 7-oxo-3-[N-(2,2,
2-Trichloroacetyl)carbamoyloxymethyl]-3-cephem-4-carboxylic acid benzhydryl ester is obtained. IR (CH ₂ Cl ₂ ): 3380, 1825 (shoulder), 1805, 1790,
1750 (shoulder), 1730 cm ^-1 NMR δppm (CDCl ₃ ): 3.60 (2H, ABq, J
= 20Hz), 5.15 (2H, ABq, J = 14Hz), 5.33
(1H, s), 7.10 (1H, s), 7.44 (10H, s),
8.73 (1H, Broad s) Example 11 7-amino-3-methyl-3-cephem-4-
Carboxylic acid 2,2,2-trichloroethyl ester is reacted with trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid in the same manner as in Examples 1 to 4 to obtain 7-oxo-3-methyl-3-cephem-4-carboxylic acid. 2,2,2-trichloroethyl ester is obtained. IR (CH ₂ Cl ₂ ): 1820, 1780, 1740 cm ^-1 NMR δppm (CDCl ₃ ): 2.37 (3H, s), 3.50
(2H, ABq, J=18Hz), 4.93 (2H, ABq,
J = 11Hz), 5.38 (1H, s) Example 12 7-amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-
7-
Oxo-3-(1,3,4-thiadiazole-2
-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester is obtained. IR (CHCl ₃ ): 1825, 1780, 1720, 1665 cm ^-1 Example 13 7-Aminocephalosporanic acid was reacted with trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid in the same manner as in Examples 1 to 4, and 7- Oxocephalosporanic acid is obtained. IR (Nujiyor): 3450-3150, 1835, 1780,
1735, 1710 (shoulder), 1640 cm ^-1 Example 14 After cooling a solution of 6-[N,N-bis(trifluoromethanesulfonyl)amino]penicillanic acid benzyl ester (0.80 g) in tetrahydrofuran (8 ml) to -60°C Add 1,5-diazabicyclo[5,4,0]undecene-5 (0.298g),
Stir at the same temperature for 30 minutes. Add p-toluenesulfonic acid (monohydrate) (0.32g) to this reaction solution, and -
Stir for 10 minutes at 52°C. The reaction solution was poured into a mixture of ethyl acetate and water, and the organic solvent layer was separated, washed with dilute hydrochloric acid, then with an aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off, and carbon tetrachloride was added to the resulting oil (0.67 g) to remove the precipitated solid. After concentrating the liquid, it was subjected to column chromatography using silica gel (6.5 g), and methylene chloride and ethyl acetate (volume ratio 6:
Elute with the mixed solvent of 1). Fractions containing the target product were collected and concentrated to dryness under reduced pressure, resulting in a yellow oily 6-
Oxopenicillanic acid benzyl ester (280mg)
get. IR (CH ₂ Cl ₂ ): 1830, 1780, 1735 cm ^-1 Example 15 (1) A solution of 7-(N-trifluoromethanesulfonylamino)cephalosporanic acid benzhydryl ester (290 mg) in methylene chloride (6 ml) was heated to -60°C. Triethylamine (199
mg), then acetic acid chloride (150 mg) was added to −40
Stir at ℃ for 2 hours. After adding ethyl acetate and ice water to the reaction solution, the organic solvent layer is separated. This solution is washed with water and then with an aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent is distilled off. The resulting residue (510 mg) was dissolved in silica gel (3.5
g) and eluted with methylene chloride. Fractions containing the target product are collected and the solvent is distilled off, resulting in 7-(N-acetyl-
N-trifluoromethanesulfonylamino)cephalosporanic acid benzhydryl ester (334 mg) is obtained. IR (CH ₂ Cl ₂ ): 1800, 1740, 1215 cm ^-1 NMR δppm (CDCl ₃ ): 2.02 (3H, s), 2.58
(3H, s), 3.36 (2H, ABq, J=16Hz),
4.99 (1H, d, 4.5Hz), 5.06 (2H, ABq, J
= 13Hz), 5.45 (1H, d, J = 4.5Hz), 6.92
(1H, s), 7.3 (10H, s)

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a trihalomethanesulfonyl group,
R ² is an acyl group, A is a group [Formula] or [Formula] (In the group, R ³ is hydrogen or alkyl, and R ⁴ is hydrogen, halogen, alkyl, alkoxy, acyloxymethyl, or may have a substituent. Heterocyclic thiomethyl, R ⁵ is carboxy or protected carboxy, X means -S- or -O-, respectively] ] and then subjected to hydrolysis to form the general formula (In the formula, A has the same meaning as above) A method for producing an azetidinone compound having an oxo group, a salt thereof, or a hydrate thereof, characterized by obtaining an azetidinone compound having an oxo group, a salt thereof, or a hydrate thereof . 2 General formula [In the formula, A is a group [Formula] or [Formula] (In the group, R ³ is hydrogen or alkyl, R ⁴ is hydrogen, halogen, alkyl, alkoxy, acyloxymethyl, or a heterocycle that may have a substituent) thiomethyl, R ⁵ means carboxy or protected carboxy, X means -S- or -O-, respectively)] or a reactive derivative at the amino group, or a salt thereof is reacted with a trihalomethanesulfonylating agent and then an acylating agent, or is reacted with an acylating agent and then a trihalomethanesulfonylating agent to obtain the general formula (In the formula, R ¹ is a trihalomethanesulfonyl group,
R ² means an acyl group, A has the same meaning as above) An azetidinone compound having a di-substituted amino group or a salt thereof represented by the following is treated with a base, then subjected to hydrolysis, and the general formula (In the formula, A has the same meaning as above) A method for producing an azetidinone compound having an oxo group, a salt thereof, or a hydrate thereof, characterized by obtaining an azetidinone compound having an oxo group, a salt thereof, or a hydrate thereof .