JPS6277392A - Cephalosporin derivative, production thereof and antibacterial agent containing said derivative as active component - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is H or amino-protecting group; R<2> and R<3> are H, methyl or carboxyl; R<4> and R<5> are H or together form O; R<6> and R<7> are OH, acetoxy or protected OH; R<8> is H or catboxyl- protecting group; X is methine or N; the bond represented by wavy line is anti or syn; a and b are 0 or 1). EXAMPLE:( 6R,7R )-7-[ 2-( 2-amino-4-thiazolyl )-2-[ Z-( 3,4-bis( p-toluene- sulfonyloxy )phenyl ]oxyimino ]acetamido ]-3-[ ( 2-carboxyl-5-methyl-s-triazolo[ 1,5-a ]pyrimidin-7-yl )thiomethyl ]-8-oxo-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene-2- carboxylic acid. USE:An antibacterial agent. PREPARATION:The compound of formula II is made to react with the compound of formula III.

Description

Detailed Description of the Invention "Industrial Application Field" The present invention relates to the general formula (1) (wherein R1 represents a hydrogen atom or an amino protecting group, and R
2 and R3 represent a hydrogen atom, a methyl group, a carboxyl group or a protected carboxyl group, and R4 and R5
represents a hydrogen atom or R4 and R5 together represent an oxygen atom, R6 and R) represent a hydroxyl group, an acetoxy group, or a protected hydroxyl group, R8 represents a hydrogen atom or a carboxy protecting group, and X represents a methine group or Represents a nitrogen atom.

Bonds with wavy lines are anti-type or syn-type.
) type combination, and a and b represent integers of 0 or 1. ), cephalosporin derivatives thereof, salts thereof, compounds thereof, and hydrates of salts.

This invention relates to their production intermediates and their production methods.

The present invention further relates to a formulation for the treatment and prevention of infectious diseases, characterized by containing the cephalosporin derivative.

rConventional technology J The development of cephalosporin derivatives has been remarkable.

Products with excellent antibacterial activity against Durham-negative bacteria have been developed. However, the antibacterial activity of these cephalosporin derivatives against Durham-positive bacteria is rather weak;
Furthermore, Durham-positive bacteria (eg, methicillin-resistant Staphylococcus aureus, MR3A) that are resistant to cephalosporin antibiotics, which have been frequently used to treat Durham-positive bacterial infections, are increasing year by year.

Problems to be Solved by the Invention" In view of this background, the present inventors have developed Durham-negative bacteria, especially Pseudomonas aeruginosa, which is frequently isolated as a causative agent of refractory infections.
As a result of intensive research to develop a cephalosporin derivative that has sufficient antibacterial activity against Serratia and also has strong antibacterial activity against Durham-positive bacteria, the general formula (1) was developed.
The present invention was completed by discovering that the cephalosporin derivative represented by the following formula satisfies these conditions.

Means for Solving Problems J The present invention provides S-
Select a substituent having a triazolo (1,5-a) pyrimidine ring and also as a 7-position substituent.

This is based on the selection of a substituent having a phenacyloxyimino structure or an allylcarboxyalkyloxyimino structure.

In the cephalosporin derivative of the present invention represented by general formula (1), the aminothiazole moiety at the 7-position substituent is as shown below: (However, in formula 1, R1, R2, R3, Fl!4.R5, Ra
, R7, X, a, b and the wavy lines are the same 9 as above.
Has taste. ) It is known that there is a tautomeric relationship, and both are generally treated as the same substance. Therefore, in the present invention, both isomers are included as an aminothiazole moiety. Therefore, the compound of the present invention represented by the general formula (1) includes both of these tautomers.

Examples of salts of the compound represented by general formula (1) include the following. For example, alkali metal salts such as lithium salts and potassium salts, alkaline earth metal salts such as calcium salts, ammonium salts, salts with organic bases such as diethylamine salts, and arginine salts and lysine salts. Examples include pharmaceutically acceptable salts. The salt of the compound may be a mono-salt, a di-salt or a di-salt.

In the case of a monosalt or di-salt, it may be any salt of the carboxyl group at the 2-position of the cephem skeleton, the carboxyl group of the 1-riazolopyrimidine ring, or the carboxyl group of the substituent at the 7-position of the cephem skeleton.

Further, the compound of general formula (1') can form an acid adduct with a pharmaceutically acceptable organic acid or an inorganic acid. Examples of these salts are hydrochloride.

Mineral acid salts such as hydrobromide, sulfate, phosphate, etc.

Also included are organic acid salts such as acetate, citrate, maleate, tartrate, benzoate, ascorbate, ethanesulfonate, and toluenesulfonate. The salt of the compound may be a mono-salt or a di-salt. In the case of a monosalt, the pyrimidine ring (substituent at the 3-position of the cephem skeleton) or the pyrimidine ring may form a salt, or the aminothiazur moiety contained in the substituent at the 7-position of the cephem skeleton may form a salt.

The compound of the present invention represented by the general formula (1) has a syo or dimeric form: (wherein R1, R2, R3, R4, R5, R6, R7,
, a, and b have the same meanings as above. ) or as the ant i isomer; (wherein R1, R2, R3, R4, R5, R6, R7, X
, a, b have the same meanings as above. ) or as a mixture of these isomers. Especially s
Preference is given to the yn isomer, and also mixtures in which the syn isomer predominates.

In the compound of the present invention represented by general formula (1).

Examples of amine protecting groups include formyl, acetyl,
Chloroacetyl, t-butoxycarbonyl.

Acyl groups such as hensyloxycarbonyl, or aralkyl terminals such as hensyl, diphenylmethyl, triphenylmethyl, etc. Carboxy protecting groups include:
Protection of carboxy by esterification is mentioned, and examples of esters include alkyl esters such as methyl ester and ethyl ester, or aralkyl esters such as hensyl ester, diphenylmethyl ester, and 1-diphenylmethyl ester. Examples of hydroxy protecting groups include aralkyl groups such as benzyl, and alkoxyalkyl groups such as methoxymethyl and 1-methoxy-1-methylethyl.

Alternatively, an allylsulfonyl group such as p-1-luenesulfonyl may be mentioned. Among these protecting groups.

Considering various operations, synthesis of protected bodies, deprotection conditions, etc. as an amino protecting group, triphenylmethyl group,
Preferably, diphenylmethyl ester is used as the carboxy protecting group, and 1-nodoxy-1-methylethyl group is used as the hydroxy protecting group.

The compound of the present invention represented by general formula (1) can generally be produced as follows. Namely.

A compound represented by 18 general formula (III) (in which R8 has the same 9 tastes as above) and a compound represented by general formula (IV) in which R1, R2, R3, R4, R5, R6 ,R7,X
, a, b and the wavy line combination have the same nine meanings as above. ) can be produced by reacting with a compound represented by:

In this production method, the compound represented by the general formula (I[I) can be protected with a protecting group whose amino group can be easily removed, if desired. Further, when R8 in the compound represented by the general formula (III) is a hydrogen atom, the carboxyl group can be protected with an easily removable protecting group. Examples of easily removable protecting groups include silyl protecting groups such as trimethylsilyl for amine groups, and silyl ester protecting groups such as 1-methylsilyl ester for carboxyl groups. The carboxyl group can also be protected by forming a salt with an inorganic or organic base.

Alternatively, a compound represented by the general formula 1'), that is, an acid, and a suitable condensing agent 1, such as N,N-dicyclohexylcarbodiimide or N-ethyl-5-phenyl-isoxazolium-3'-sulfonate, are used. Then, the general formula (
It is also possible to react with a compound of formula (III) or, after converting this acid into a suitable reactive derivative, with a compound of general formula (III).

Suitable reactive derivatives include acid halides (e.g. acid chlorides), azides, acid anhydrides, active esters (N-hydroxysuccinimide ester) and active amides (
For example, imidazolide, triazolide) and the like can be mentioned.

The reaction between the compound of general formula (I[+) and the compound of general formula (TV) is generally carried out using an inert solvent 1 such as dioxane,
Tetrahydrofuran, acetonitrile.

The reaction is carried out in an organic solvent such as chloroform, methylene chloride, ethyl acetate, or dimethylformamide, and if desired, in water or a mixture of water and an organic solvent, preferably in the presence of a deoxidizing agent. As a deoxidizing agent.

Triethylamine, diethylaniline, etc. are used in IJI solvent systems, and aqueous alkalis are used in aqueous systems.

Preferably, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate, etc. are used.

These reactions can be carried out at about -30°C to room temperature, but -
Preferably it is carried out at 10°C to 10°C.

The protecting group of the cephalosporin derivative represented by the general formula (1) thus obtained can be removed if desired.

The compound represented by the general formula (III) used in this production method consists of 7-amino-cephalosporanic acid, a compound known per se, and 2-carboxy-7-norcapto-5-methyl-s-triazolo(1 , 5-a] Pyrimidine or a carboxyl group-protected derivative thereof (Patent application No. 58-24
No. 7251). This reaction can be carried out using an organic solvent such as alcohol, dimethylformamide or acetonitrile, or water as a solvent. When carried out using an organic solvent, it is preferably carried out in the presence of a Lewis acid such as a boron trifluoride/ether complex. When water is used as a solvent, it may be used in the presence of a predetermined amount of aqueous alkali (eg, sodium bicarbonate, potassium carbonate, etc.) or a buffer solution with a pl+6.0 to 7.8. This reaction takes place at approximately 40°C to 8°C.
It can be carried out in the range of 0°C, but preferably about 55°C to 65°C.
Performed at °C.

The protecting group of the compound represented by the general formula (1) thus obtained can be removed if desired.

Method B A compound represented by the general formula (V) (in the formula, R1, R8 and the bonds of wavy lines have the same meanings as above) and a compound represented by the general formula (Vl) (in the formula, R2, R3, R4, R5 ,R6,R7゜X,a
, b have the same meanings as above. ) can be produced by reacting with a compound represented by: In this production method, the compound represented by the general formula (Vl), that is, alcohol, is reacted with the compound of the general formula (■) using a suitable condensing agent 2, such as triphenylphosphine and ethyl abdicarboxylate. Alternatively, the compound represented by the general formula (■) can be converted into a suitable reactive derivative 5, such as an aralkyl halide or an aralkyl tosylate, and then reacted with the compound of the general formula (V). In view of reactivity and operability, it is preferable to convert the compound represented by formula (Vl) into an aralkyl halide and then react it with the compound represented by formula (V).

The reaction of a compound of general formula (V) with a compound of general formula (Vl) is generally carried out in an inert solvent such as dioxane, tetrahydrofuran, acetonitrile.

The reaction is carried out in an organic solvent such as chloroform, methylene chloride, ethyl acetate, or dimethylformamide, and if desired, in water or a mixture of water and an organic solvent, preferably in the presence of a deoxidizing agent. As a deoxidizing agent.

Triethylamine, diethylaniline, etc. are used in organic solvent systems, and aqueous alkalis are used in aqueous systems.

Preferably sodium hydroxide, sulfurium bicarbonate,
Potassium carbonate etc. are used.

These reactions can be carried out at about -30°C to room temperature, but -
Preferably it is carried out at 10°C to 10°C.

The protecting group of the cephalosporin derivative represented by the general formula (1) thus obtained can be removed if desired. The compound represented by the general formula (V) used in this production method can be synthesized according to the production method described in Japanese Patent Application No. 59-249193.

The compound of the present invention represented by the general formula (■) can generally be produced as follows. Namely.

Method C A compound represented by the general formula (■) (in the formula, R1 and the bond with a wavy line have the same meaning as above, and R8 represents a hydrogen atom or a carboxy protecting group), which is a known compound per se, and a compound represented by the general formula (Vl) (wherein R2, R3,
R4, R5, R6, R7°X, a, and b have the same meanings as above. ) can be produced by reacting with the compound represented by In this production method, general formula (Vl)
A compound represented by, ie, an alcohol, with a suitable condensing agent.

For example, triphenylphosphine and ethyl azodicarboxylate may be used to react with the compound of general formula (1), or the compound represented by general formula (Vl) may be reacted with a suitable reactive derivative 2 such as aralkyl halide or aralkyl halide. After converting into Toshire 1, it is also possible to react with the compound of general formula (■), but in particular, from the viewpoint of its reactivity and operability, after converting the compound represented by general formula (■) into aralkyl halide (), A method of reacting with a compound of general formula (■) is preferred.

The reaction between the compound of general formula (Vl) and the compound of general formula (■) is generally carried out in an inert solvent such as dioxane
~ Lahitorofuran, acetonitrile.

The reaction is carried out in an organic solvent such as chloroporum, methylene chloride, acetic acid, dimethylpolamide, or if desired, in water or a mixture of water and an organic solvent, preferably in the presence of a deoxidizing agent. As a deoxidizing agent.

In organic solvent systems, l-ethylamine, diethylaniline, etc. are used, and in aqueous systems, aqueous alkalis are used.

Preferably, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate, etc. are used.

These reactions can be carried out at about -30°C to room temperature;
Preferably it is carried out at -10°C to 10°C.

The method itself is a well-known compound represented by the general formula (■) (in the formula, Y represents a halogen atom, R8 represents a hydrogen atom or a carboxy protecting group, and the bond with a wavy line represents the same meaning as above). With the compound.

General formula (Vl) (in the formula R2, R3, R4, R5, R6, R7゜X, a
, b have the same meanings as above. ) in the same manner as described above, and then condensation with a thiourea derivative represented by the general formula (■) (wherein R1 has the same meaning as above). It can be manufactured by

In this production method, condensation with a thiourea derivative is carried out.

Generally, it can be carried out in a solvent such as methanol, ethanol, dioxane, tetrahydrofuran, methylene chloride, ethyl acetate, etc., preferably in the presence of a deoxidizing agent (triethylamine, diethylaniline, sodium bicarbonate, potassium carbonate, etc.). These reactions are carried out at room temperature or under elevated conditions.

Method E A compound represented by the general formula (x) (wherein R1 and R8 represent the same meanings as above) which is a known compound per se, and a compound represented by the general formula (XI) (wherein R2, R3,
R4, R5, R6, R7°X, a, and b have the same meanings as above. ) can be produced by condensing the compound represented by Book! Ii! In the second production method, methanol is generally used.

The reaction can be carried out in a solvent such as ethanol, dioxane, tetrahydrofuran, methylene monochloride, or ethyl acetate, or optionally in the presence of a molecular compound. These reactions are carried out at room temperature or under elevated conditions.

"Effect of the Invention J The compound of the present invention has a broad antibacterial spectrum against Gram-positive bacteria and Gram-negative bacteria including M. It is extremely useful as a treatment for this disease.

Next, in order to demonstrate the usefulness of the compounds of the present invention, data on antibacterial activity of one representative compound will be shown.

Test compound Compound 1: (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-[Z-(1(3,4-dihydroxybenzoyl)-1-methylethyl]oximino]acetamide )-3-[(2-carboxy-5-methyl-5-)riazolo[1,5-a)pyrimidine-7-
(6R,7R)-7-(2-(2
=amino-4-thiazolyl)-2-[Z, -(i (5
-acel-xy-4-hydroxypyridin-2-yl)
carbonyl-1-methyledyl]oximino]acetamide)-3-[(2-carboxy-5-methyl-3-1
- Riazolo l: 1. 5-a) pyrimidin-7-yl)
Thiomethylcou8-oxo-5-thia-1-azabicyclo[4.2.0]off-1-2-ene-2-carboxylic acid compound 3: (6R,7R)-7-C2-(2-amino-4 -thiazolyl)-1-[Z-[1-carboxy-2-(3,4-diacetoxyphenyl)ethyl]oxyimino]acetamif”)-3-[(2-carboxy-
5-Methyl-s-triazolo(1,5-a)pyrimidin-7-yl)thiomethylcou8-oxo-5-thia-1
-Azabicyclo[4.2,O)oct-2-ene-2-
Carboxylic acid compound 4: (6R,7R)-7-C2-(2-amino-4-thiazolyl)-1-[Z-N-carboxy-
1-(3,4-dihydroxyphenyl)ethyl]oxyimino]acetamide)-1[(2-carboxy-5-methyl-5-)riazolo(1,5-a)pyrimidine-7-
(6R,7R)-7-C2-(2-amino-4 -thiazolyl)-2-[Z-[(R)-carboxy(3,4-diacetoxyphenyl)methyl]oxyimino]acetamide)-3-[(2-carboxy-5-
Methyl-s-triazolo[1,5-a)pyrimidine-7
-yl)thiomethylcou8-oxo-5-thia-1-azabicyclo[4,2.0]oct-2-yune-2-carboxylic acid compound 6: (6R,7R) -7-(2
-(2-amino-4-thiazolyl)-2-[Z-[(S
8 -Oxo-5-thia-1-azabicyclo[4,2.0]oct-2-ene-2-carboxylic acid compound 7: (6R,7R)-7
-(2-(2-amino-4-thiazolyl)-1-[Z-
[(R)-Ruboxy(3,4-dihydroxyphenyl)methyl]oximino]acetamide)-3-[(2-
Carboxy-5-methyl-s-triazolo[1,5-a
)pyrimidin-7-yl)thiomethylcou-8-oxo-
5-thia-1-azabicyclo[4,2.0]octo-2
-ene-2-carboxylic acid compound 8: (6R,7R
) -7-C2-(2-amino-4-thiazolyl)-1
-[Z-[(S)-carboxy(3,4-dihydroxyphenyl)methyl]oxyimino]acetamide>3-[
(2-carboxy-5-methyl-5-)riazolo[1,
5-a) Pyrimidin-7-yl]thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid compound 9: (6R
,7R)-7-(2-(2-amino-4-thiazolyl)
-1-[Z-(1-carboxy-1-(3,4-diacetoxyphenyl)ethyl]oxyimino]acetamide)-3-[(2-carboxy-5-methyl-8-triazolo(1,5-a ) pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.
2.0] Oct-2-ene-2-carboxylic acid Experimental Example 1 In vitro antibacterial activity was determined by the agar plate dilution method. That is, Mueller-Hinton Bros.
A loopful of the test strain (106 bacteria/ml) cultured in 1 linton broth was placed in a Mueller-Hinton agar (M) containing each concentration of the test compound.
H-agar). After culturing at 37°C for 20 hours,
The minimum inhibitory concentration (MIC, 827ml) was determined.

The results are shown in Tables 1-a and 1-b.

Experimental Example 2 In vivo infection prevention ability was measured as follows. A group of 10 ICR4a mice were intraperitoneally infected with the test bacteria as an aqueous suspension. One hour after infection, test compounds were administered intravenously. The number of surviving animals was counted after − weeks and the dose H (EDso; mg/k
g) was calculated.

The results are shown in Table 2.

Next, Table 3 shows the LD50 of a representative example of the compound of the present invention. In addition, LD5. was determined by the Probit method.

1 Compound No.l LDso (mg/kg) i,v
, 11 1 1 >1000 1+
2 1 >1000 l+ 6 1
>1000 11 8 1 >1000 1 1 9 1 >1000 l+ 10
1 >1000 1 Compounds of the invention are 9 Gram-positive bacteria such as Staphylococcus aureus, Streptococcus, or eg Escherichia coli.

It is useful in the treatment of infections caused by infections caused by Gram-negative bacteria such as Klebsiella pneumoniae, M. 1 Morgan, M. marcescens, Citrobacterium enterobacter, and Flavobacter.

The cephalosporin derivatives provided by the present invention are:
They can be used as pharmaceutical compositions, for example in the form of preparations containing them together with suitable pharmaceutically acceptable carrier substances such as lactose, carboxymethylcellulose, etc. Examples of formulations can be solid (eg, tablets, capsules, etc.) or liquid (eg, injections, etc.) form. In addition, the preparation can be sterilized, and auxiliary agents commonly used in pharmaceuticals, such as sodium bicarbonate, citric acid, propylene glycol, twin 8
0 (Tween80) and the like.

Further, the compound is in the form of a lyophilizate or dry powder,
It is also preferable to dissolve it in a conventional solubilizing agent 1, such as water or physiological saline, before use. The compound can be used by oral or parenteral administration, depending on the patient's age,
1 per adult, although it varies depending on the condition, type of disease, and medical condition.
A daily dose of from about 0.01 g to about 1 g can be used, preferably from about 0.1 g to about 5 g. Also.

Parenteral administration of the compounds provided by the invention is particularly preferred.

Examples of the present invention are shown below, but the present invention is not limited to the following examples.

Margin below List of representative examples of compounds OTs represents p-1-luenesulfonyloxy group.

Representative examples of compounds 7 List of five representative examples of compounds Example 1 (6R,7R)-7-C2-(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4- diacetoxyphenyl)methyl]oximino]acetamido)-3-[(2-carboxy-5-methyl-5-triazolo[1,5-a)pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia- 1-Azabicyclo [4.
2.0] Production process of oct-2-ene-2-carboxylic acid 1 Production of 3.4-diacetoxyphenylacetic acid 3.4-dihydroxyphenylacetic acid 38.8g'c Acetic anhydride 60ml
A small amount of concentrated sulfuric acid was added dropwise while cooling with water. After stirring this solution for 1 hour at room temperature.

The mixture was poured into 600 ml of water, heated and dissolved at 70°C, and filtered while hot. The filtrate was cooled and the precipitated crystals were collected by filtration to obtain 51.1 g of the title compound.

NMR spectrum (CDCl2; ppm) 9.9
(IH, bs) 7.1 (3H, s) 3, 6 (211, s) 2. 3 (6') l, s) Step 2 Production process of 2-bromo-(3,4-diacetoxyphenyl)acetic acid 51.1 g of the compound obtained in l was suspended in carbon tetrachloride, and 60 ml of thionyl chloride was added. and heated to 70°C. After 1 hour, it was cooled to room temperature, and 42.3 g of N-bromosuccinimide and 105 ml of carbon tetrachloride were added. A trace amount of hydrobromic acid was added and the mixture was heated for 1 hour and then concentrated. The residue was dissolved in carbon tetrachloride, insoluble matter was filtered off, and the filtrate was concentrated. The residue was dissolved in 400 ml of acetone, and saturated sodium bicarbonate solution was added dropwise under water cooling to adjust the pH to 4.0, followed by extraction with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 61.4 g of the above title compound.
I got it.

NMR spectrum (CD(13; ppm) 9.0
(IH, bs) 7.5-7.1 (3H, m) 5, 3 (IIl, s) 2, 3 (6H, s) Step 3 2-bromo-(3,4-diacetoxyphenyl) diphenyl acetate Methyl ester manufacturing process 61.4 g of the compound obtained in 2 was dissolved in 500 ml of acetone, and diphenyldiazomethane was added. After confirming that the starting materials had disappeared, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 48.4 g of the title compound.

TR spectrum (KB r ; cm-1) 1772.
1?56.1752,1505゜1371.1259,
1212, 1113° NMR spectrum (CDC13;
ppm) 7.4 to 7.1 (13H, m) 6.9 (IH, s) 5.4 (IH, s) 2.3 (6H, s) Step 4 2-N-phthaloyloxy-(3 , 4-Diacetoxyphenyl) Preparation of acetic acid diphenylmethyl ester 15.9 g of N-hydroxyphthalimide was suspended in 300 ml of acetonitrile, cooled with water, and triethylamine 13.
6ml was added. Under stirring, compound 4 obtained in step 3
A solution of 8.4 g dissolved in 200 ml of acetonitrile was added dropwise and stirred for 1.5 hours under water cooling. The reaction solution was concentrated, diluted with ethyl acetate, washed once with water, IN citric acid, and saturated brine, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by silica gel column chromatography to obtain 15.3 g of the above title compound.

TR spectrum (KB r ; cm-1) 1772.
1735, 1506.1371゜1260.1209,
1186.1114°0O NMR spectrum (CDCl2; ppm) 7.7
(4H,s) 8.0-7.1 (13H,m) 6, 9 (IH,s) 6, 0 (III, s) 2, 3 (6H,s) Step 5 2-Aminooxy-(3 ,4-diacetoxyphenyl)
Production process of acetic acid diphenyl methyl ester 15.3 g of the compound obtained in step 4 was dissolved in 200 ml of notylene chloride, cooled to -60°C, and 1.34 ml of methylhydrazine was slowly added.

After dropping, the temperature was gradually raised to 0°C and stirred for 2 hours.

Further, 0.07 ml of methylhydrazine was added and after stirring for 30 minutes, insoluble matter was filtered off and the filtrate was concentrated.

The residue was purified by silica gel column chromatography to obtain 8.7 g of the above title compound.

TR spectrum (KBr; cm-1) 1772.1?52.1506, 1371°1256.
1210, 1180, 1113° NMR spectrum (C
D(13; pI)m)7, 7-7. 0 (13
H, m) 6, 9 (IH, s) 5. 2 (IH,s) 2, 27 (3H,s) 2, 26 (3H,s) Step 6 2-(2-triphenylmethylamino-4-thiazolyl)-1-[Z-diphenylmethyloxycarbonyl(3
, 4-diacetoxyphenyl)methyl]oxyiminoacetic acid. 7.62 g of (2-triphenylmethylaminothiazol=4-yl) glyoxylic acid was dissolved in 400 ml of methanol, and the compound obtained in step 5 was dissolved under stirring at room temperature. 8.
A solution of 7 g in 150 ml of methanol was added dropwise. After 1.5 hours, the two reaction solutions were concentrated to obtain 16.0 g of the title compound as a crude product.

IR spectrum (KB r ; cm-1) 1772.
1256,1209.11B0゜754.701 NMR spectrum (DMSO-d6; ppm)
8, 9 (11-1,s) 7, 3-7. 2 (28TI, m)6, 9 (
Ill, s) 6, 8 (IH, s) 5, 9 (11-1, s) 2, 3 (61-(, s) Step 7 (6R,7R)-7-(2-(21liphenylmethyl amino-4-thiazolyl)-2-[Z-[diphenylmethyloxycarbonyl(3,(1 diacetoxyphenyl)
Methyl]oximino]acetamiF-]-3-[(2-
diphenylmethyloxycarbonyl-5-methyl-s-
triazolo[1,5-a)pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[
4,2.0] Production process of oct-2-ene-2-carboxylic acid diphenylmethyl ester 5.6 g of the compound obtained in 6 and (6R27R)-
7-Amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-3-triazolo(1,5-a)pyrimidin-7-yl)thiomethyl]-8-oxo-5-
Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester 5.0 g
was dissolved in 170 ml of methylene chloride, 1.4 g of dicyclohexylcarbodiimide was added under water cooling, and P was heated at room temperature for 5 hours.
I worshiped i1. After filtering out insoluble materials and concentrating the filtrate.

Ethyl acetate was added to the residue, and the insoluble matter was filtered. The filtrate was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was concentrated and purified by silica gel column chromatography to obtain 0.73 g of a low polar compound and 1.39 g of a high polar compound of the title compound.

Low polarity IR spectrum (KB r ; cm-1) 17B0,
1742, 1737, 1507° 1249.1205.
1182,70ONMR spectrum (DMSO-d6
; ppm) 9, 7 (I H, d, J
= 8 Hz) 8.9 (11 (, bs) 7, 5 ~ 7. 1 (50H', m) 6, 9
(IH,s) 6, 82 (LH,s) 6, 78-(lI-1,5) 5- 9 (IH,s) 5, 8 (IH,dd, J-4,8Hz
)5, 2 (IH, d, J=4Hz)4, 3
(2H, bs) 3, 6 (2H, ABq) 2, 6 (3H, s) 2, 2 (6H, s) Highly polar substance IR spectrum (KB r ; cm-1) 1780.
1?42,1596,1507゜1450.1372,
1205.1182°0O NMR spectrum (DMSO-d6; ppm)9
．． 7 (IH, d, J=9Hz) 8.9 (IH, s) 7, 4-7. 2 (501(, m>7.0
(IH, s) 6, 82 (IH, s) 6, 76 (IH, s) 5, 9 (LH, s) 5, 9 (IH, dd, J=4.9Hz) 5
, 2 (IH,, d, J=4Hz)4,
3 (2H, bs) 3, 7 (2H, ABq) 2, 6 (3H, s) 2, 25 (3H, s) 2, 20 (3H, s) Step 8 (6R, 7R) -7-(2 -(2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-diacetoxyphenyl)methyl]oxyimino]acetamide)-3-[(2-carboxy-5-methyl -5-1-
RiazoloC1,5-a)pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4
．． 2.0] Production process of oct-2-ene-2-carboxylic acid 0.73 g of the compound (low polarity) obtained in step 7 was dissolved in 3 ml of dichloroethane and cooled on ice.

After adding 0.4 ml of anisole and 0.8 ml of alifluoroacetic acid to this mixture, the mixture was stirred at room temperature for 3 hours. Further, 0.6 ml of trifluoroacetic acid was added, stirred for 30 minutes, 5 ml of dichloroethane was added, the supernatant was removed by decantation, and the residue was washed with dichloroethane.

Crystallization from ether gave 0.37 g of the above title compound.

IR spectrum (KB r ; cm-1) 1773.
1735, 1684, 1637゜1598.1509,
1373, 1206° NMR spectrum (DMSO-d
s; ppm) 9, 6 (I H, d
, J = 8 I-1z) 7.6~7
．． 2 (4H, m) 6.8 <IH, s) 5.8 (LH, dd, J=4.8Hz) 5.6
(LH, s) 5, 2 (IH, d, J=4Hz) 4, 4
(2H, bs) 3, 72 (LH, d, J=22Hz) 3,
48 (IH, d, J-2211z) 2, 6
(3H,s) 2, 2 (6H,s) [α] Next -2,9'(cm1.0.methanol;
Acetone-1;1) Example 2 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-(, Z-[(R)-carboxy(3,4-
diacetoxyphenyl)methyl]oximino]acetamido)-3-[(2-carboxy-5-methyl-3-triazolo(1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia- 1-azabicyclo[4
, 2,0] Production of oct-2-ene-2-carboxylic acid Compound obtained in step 7 of Example 1 (high polar body>
1.3 g was dissolved in 6 ml of dichloroethane and cooled with water. After adding 0.8 ml of anisole and 1.6 ml of trifluoroacetic acid to this solution, the mixture was stirred at room temperature for 4 hours. Add 6 ml of dichloroethane to the reaction solution, remove the supernatant by decant,
The residue was washed with dichloroethane and crystallized with ether to obtain 0.78 g of the above title compound.

rR spectrum (KB r ; cm-1) 1773.
1735, 1683, 1636゜1598.1509,
1373, 1205° NMR spectrum (DMSO-d
s ; ppm) 9, 7 (114, d,
J = 9 Hz) 7.4-7.2 (4H, m) 6.8 (IH, s) 5.8 (IH, dd, J = 4.9Hz) 5.6 (
IH, s) 5.2 (IH, d, J=4Hz> 4.5 (2H, bs) 3.79 (IH, d, J=17Hz>3, 60
(IT(, d, J = 17 T-1z)2
, 6 (3H,s) 2. 3 (Cil-L s) [α)'J-17.4° (cm1.0. Methanol:
Acetone = 11) Example 3 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-[Z-[(R)-carboxy(3,4-dihydroxyphenyl)methyl]oximino ] acetamido)-3-[(2-carboxy-5-methyl-5-)riazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.
2,0] Preparation of oct-2-ene-2-carboxylic acid 0.5 g of the compound obtained in Example 2 was suspended in 20 ml of water, and sodium hydrogen carbonate was slowly added to adjust the pH to 7.6-8.
．． 0 and stirred at room temperature. After 6 hours, the two reaction solutions were adsorbed onto Diaion HP 10, eluted with water, and fractions containing the target compound were collected and lyophilized to yield 0.2 g of the title compound.
I got it.

IR spectrum (KB r ; cm-1) 1763,
1601. 1516. 1474°1404, 1
358. 1314 NMR spectrum (D20; ppm) 7, 2 (LH,s) 7, 0-6. 9 (4H, m)5, 6
(1tI, d, J = 5 Hz)
5, 4 (LH, s) 5, 0 (IH, d, J=5Hz) 4, 4
．． (2H, ABq) 3, 4 (2H, ABq) 2, 6 (3tl, s) (α)W +21.8° (cm1.0.water) Example 4 (6R,7R)-7-(2- (2-amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-dihydroxyphenyl)methyl]oximino]acetamide)-3-[(・2-carboxy-5-methyl-s -triazoloC1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4
．． 2,0] Production of oct-2-ene-2-carboxylic acid Compound obtained in Step 8 of Example 1 0. 27 g was suspended in 11 ml of water, the pH was adjusted to 8.0 by slowly adding sodium hydrogen carbonate, and the mixture was stirred at room temperature. After 6 hours, the 9 reaction mixtures were adsorbed onto Diaion HPIO and eluted with water, and the fractions containing the target compound were lyophilized to give 0.1% of the above title compound.
4g was obtained.

]R spectrum (KB r ; cm-]) 1763.
1599. L514,1474°1404.1360.
1314 NMR spectrum (D20; pp pm) 7.2 (
IH, s) 7.0 ~ 6.8 (4H, m) 5.7 (IH, d, J = 5Hz) 5.4 (IH, s) 5, 0 (11-1, d, J = 51- 1
z ) 4.3 (2H, ABq) 3, 4 (2H, ABq) 2, 6 (3H, s) [α] Kan +27.4° (c-1,0, water) Example
5 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-[Z-(3,4-bis-(p-)luenesulfonyloxy)phenyl]oximino]acetamide)-3 -[(2-carboxy-5-methyl-5-)riazolo(1,5-a)pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicycloC4,2
．． 0] Production process of oct-2-ene-2-carboxylic acid
1 Production of 4-methoxycatechol 60 g of 2-hydroxy-4-methoxyacetophenone was dissolved in 390 ml of dioxane and 314 ml of water.
Cooled to ℃. Add 35% hydrogen peroxide solution to this solution 34.
After dropping 8 ml, while blowing nitrogen gas,
% sodium hydroxide aqueous solution was added dropwise over 30 minutes,
Stirred for 1.5 hours.

The reaction solution was adjusted to pH 7 with IN hydrochloric acid, extracted with ether, dried over anhydrous magnesium sulfate, and concentrated to obtain 50 g of the title compound.

IR spectrum (KB r ; cm-1) 1610.
1527, 1521, 1251゜115B, 11.1B
, 1040.957°800.732 NMR spectrum (CD(13; pp pm)6.
8-6.3 (3H, m) 6.0 (IH, s) 5.6 (IH, s) 3.7 (3H, s) Step 2 3.4-bis-(p-toluenesulfonyloxy)anisole Manufacturing process 40 g of the compound obtained in 1 was dissolved in 570 ml of acetone, 316 g of potassium carbonate was added little by little, and the mixture was cooled with water. While stirring, a solution of 109 g of p-toluenesulfonyl chloride dissolved in 50 Qml of acetone was added dropwise over 1 hour. After the addition was completed, the insoluble matter was filtered and the filtrate was concentrated. Add 700ml of ether to the residue, add water twice,
It was washed twice with an aqueous IN sodium hydroxide solution and once with a saturated saline solution, and dried over anhydrous sodium sulfate. After concentrating the filtrate,
Crystallization from ether and hexane yields the above title compound 100.
．． 7g was obtained.

IR spectrum (KB r ; cm゛l) 1504
．． 1376.1205, 1192.1170.849,
780,709°663.555 NMR spectrum (CD(13; ppm) 7.7~
6.7 (11H, m) 3, 8 (3H, s) 2.4 (6H, s) Step 3 Obtained in Step 2 for producing 3.4-bis-(pt-luenesulfonyloxy)phenol 100.0g of compound to 304m of acetic acid
1, suspended in 304 ml of hydrobromic acid and 30 ml of hydroiodic acid.
．． After adding 4 ml, the mixture was refluxed.

After 12 hours, cool to room temperature and add ethyl acetate 1.51 and water I
The ethyl acetate layer was washed three times with water and dried over anhydrous sodium sulfate. After concentration.

The residue was purified by silica gel column chromatography to obtain 48 g of the above title compound.

IR spectrum (KB r ; cm-1) 1609.
158B, 1495.13B0゜1365.1196,
1178,849°717.532 NMR spectrum (DMSO-d6; ppm) 10.
0 (IH,s) 7.7-7.3 (8H,m) 6,' 9-6.6 (3H,m,) 2.4 (6H,s) Step 4 3.4-bis-(p -Preparation of -toluenesulfonyloxy)phenoxyamine After washing 1.15 g of sodium hydride (oil-based) with hexane, dry dimethylformamide was added, the atmosphere was replaced with nitrogen, and the mixture was cooled on ice. Compound 18 obtained in step 3 is added to this suspension.
．． After 8 g of dry dimethylbormamide solution was added dropwise over 10 minutes, the mixture was stirred at room temperature for 30 minutes. Add 2 to this solution,
A solution of 4.3 g of 4-dinitrophenoxyamine in dry dimethylformamide was added dropwise over 2 hours. After the dropwise addition was completed, after stirring at room temperature for 2 hours, 1.66% of trifluoroacetic acid was added.
ml was added dropwise and poured into ice-cooled saturated saline solution 11. After extraction with 21 ether, 0. It was washed twice with 500 ml of 5N sodium hydroxide solution, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration,
The residue was purified by silica gel column chromatography to obtain 5.3 g of the above title compound.

IR spectrum (KB r ; cm-1) 1610.
1600, 1489.1375゜1195.1179,
1157,1092°967.85O NMR Subek(・ru(DMSO-ds; ppm>7.8
~6.9 (IITI, m) 2, 4. (6tl, s) Step 5 Production of 2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(3,4-bis-(p-toluenesulfonyloxy)phenyl]oxyimino]#-acid 1.0 g of (2-triphenylmethylaminodizur-4-yl)glyoxylic acid was added to 3 Q ml of methanol and dissolved by heating. To this solution was added 1.3 g of the compound obtained in step 4 in methanol. 3Qm19 suspension was added and stirred for 1 hour.The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain 0.98 g of the above title compound.
I got it.

IR spectrum (KB r ; cm-1) 1598.
1491, 1380, 1195゜1180.1168,
1080,850°705.551 NMR spectrum (DMSO-d6; pI)m)
8.9 (IH,s) 7.7-7.0 (27H,m) 2, 4 [(ilLs) Step 6 (6R,7R)-7-C2-(2-triphenylmethylamino-4- Thiazolyl) -2-[Z-C3,4-bis-(p-1-luenesulfonyloxy)phenyl]oximino]acetamide]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo(
1,5-a)pyrimidin-7-yl)thiomethyl]-8
-oxo-5-thia 1-azabicyclo[4,2,0J
Production process of oct-2-ene-2-carboxylic acid diphenylmethyl ester 0.94 g of the compound obtained in step 5 and (6R17R)
-7-Amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo(1,5-a)
pyrimidin-7-yl)thiomethyl]-8-oxo-5
-thia-1-azabicyclo[4,2,0]octo-2-
En-2-carboxylic acid diphenylmethyl ester 0.6
5 g was dissolved in 30 ml of dry methylene chloride and cooled on ice. To this /8 liquid, dicyclohekilyl force l-'0.2
3 g was added and left at room temperature overnight. Insoluble matter was filtered off, and the filtrate was concentrated. Ethyl acetate was added to the residue, insoluble materials were collected by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 1.04 g of the above title compound.

IR spectrum (KB r ; cm-1) 1792.
1740, 1600, 1507° 1492.1377.
1196,1180°1169.70O NMR spectrum (DMSO-d6; p prn
) 9.9 (IH, d, J=8Hz) 9.0 (IH, s) 7.6~7.0 (501(, m) 5, 7 (IH, dd, J=5.
ENIz) 5.3 (III, d, J=5Hz) 4.3 (2H, bs) 3.7 (2H, ABq) 2.6 (3H, s) 2.4 (3H, s) 2, 3 ( 3H,s) Step 7 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-[Z-(3,4-bis-(p-toluenesulfonyloxy)phenyl]oxyimino) acetamido)-3-[(2-carboxy-5-methyl-5-)riazolo(1,5-a)pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2
．． 0] Production process of oct-2-ene-2-carboxylic acid
0.98 g of the compound obtained in step 6 was dissolved in 3.5 g of dichloroethane.
In ml? 8 fat j l, cooled on ice. To this solution were added 0.46 ml of anisole and 0.92 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into 60 ml of ether, the supernatant was removed by decantation, the crystals were washed with methylene chloride and acetone, and two were collected by filtration to obtain 0.35 g of the above-mentioned title compound.

IR spectrum (KB r ; cm-1) 1784.
1685.1676.1637゜1598.1509,
14.91,1375°1195,118O NMR spectrum (DMSO-ds; ppm)9,9
(LH, d, J-811z) 7, 6 ~
7. 0 (13H, m)5, 9 (IH
, dd, J-5, 8Hz) 5, 3 (I H
, d, J = 5 Hz) 4, 4 (2H
, bs) 3, 7 (2H,ABq) 2, 6 (3H,s) 2, 4 1 (31-1,s) 2, 38 (3tl, s) Example 6 (6R,7R)-7-[ 2-(2-amino-4-thiazolyl)-2-[Z-(1-(3,4-dihydroxybenzoyl)-1-methylethyl]oxyimino]acetamide)-3-[(2-carboxy-5-methyl -5-)liazolo(1,5-a]pyrimidin-7-yl)thiomethylcou8-oxo-5-thia-1-azabicyclo[4.
2,0] Production process of oct-2-ene-2-carboxylic acid 1 (6R,7R)-7-C2-(2-triphenylmethylamino-4-thiazolyl)-1-[Z-(1-( 3,4
-diacetoxybenzoyl)-1~Methylconityl]oxyimino]acekumi(.]-3-[(2-diphenylmethyloxycarbonyl-5-methy-ru-s-triazolo[1,5-a] pyrimidine-7 -yl)thiomethylcou8-oxo-5-thia-1-azabicyclo[4
．． 2,0] Manufacture of oct-2-ene-2-carboxylic acid diphenylmethyl ester Compound 1-(2
-1-rifle methylamino-4-thiaduryl)-2
-[Z-1-(3,4-diacetoxybenzoyl)-1
-Methyl ethyl]oxyiminoacetic acid (5.1 g) was dried in methylene chloride (5 Qml). I understand, <6R,
7R)-7-Amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo(1,'
5-a) 5.0 g of pyrimidin-7-yl)thiomethylcou8-oxo-5-thia-1-azabicycloC4,2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester were added. 50 ml of dry tetrahydrofuran was added to this solution, and 1.5 g of dicyclohexylcarboxylic acid F' was added while cooling with water, followed by stirring at room temperature for 3 hours. Insoluble matter was filtered off, and the filtrate was concentrated. Ethyl acetate was added to the residue, insoluble materials were collected by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain the above title compound 3.8.
5g was obtained.

IR spectrum (KB r ; cm-1) 1781,
．． 1735, 1686, 1596° 1508.1372
, 1242.701 NMR Spec 1 Hell (DMSO-d
s ; ppm) 9, 7 (1tl, d
, J = 9 Hz)8.9 (IH,S) 8.3~7.2 (40H,m) 6, 9 (If-1,5) 6-7 (IH,s) 5.9 (1) -1, dd, J=5.9Hz)5,
3 (IH, d, J = 5 Hz)
4, 4 (211, bs) 3, 7 (211, AB q) 2, 6
(-3H,s) 2, 3 (6H,s) 1, 5 (6H,s) Step 2 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-[Z- (1-(3,4-diacetoxybenzoyl)-1-methylethyl]oxyimino]acekumi F)-3-[(2-carboxy-5-methyl-5-triaduro(1,5-a)pyrimidine-7- yl)thiomethylcou8-oxo-5-thia-1-azabicyclo[4,
2,0] Production process of oct-2-ene-2-carboxylic acid 3.8 g of the compound obtained in 1 was added to 28 m of dichloroethane.
Thaw 1/8 and cool on ice. Anisole 1°95m1. ) Add 3.8 ml of refluoroacetic acid.

Stirred at room temperature for 3.5 hours. The supernatant was removed by decantation, washed twice with dichloroethane, and solidified with ether to obtain 1.8 g of the above title compound.

IR spectrum (KB r ; cm-1) 1774.
1685.1636, 1598°1509.1373,
1203.1112 NMR spectrum (DMSO-d6
; p prn) 9, 7 (I It,
d, J = 91-1z) 8.1-7.3
(4H, m) 6.7 (IH, S) 5.9 (LH, dd, J=5.91(z)5,
2 (1]-1, d, J = 51-1 z
)4.4 (2H,bs) 3.7 (211,ABq) 2, 6 (311,S) 2.3 (6H,s) 1.5 (6H,s) Step 3 (6R,7R) -7 -(2-(2-amino-4-thiazolyl)-2-[Z-(1-(3,4-dihydroxybenzoyl)-1-methylethyl]oxyimino]acetamide: l-3-[(2-carboxin- 5-methyl-5-
triazolo(1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[
4.2,0] Production process of oct-2-ene-2-carboxylic acid 0.6 g of the compound obtained in step 2 was suspended in 20 ml of water, and sodium hydrogen carbonate was added to the mixture to pH 8.

Adjusted to 0. After stirring at 30° C. for 5 hours, the reaction solution 6 was adsorbed onto Diaion 11 P 10 and eluted with methanol/water. The fraction containing the target product was freeze-dried to obtain 0.34 g of the above-mentioned title compound.

IR spectrum (KBr; cm-1) 1772.1598, 1513.140G.

1363.1189.1163 NMR spectrum (DMSO-d6; ppm
) 9.6 (IH, d, J=9Hz) 7.7~G, 6 (4H, m) 6.6 (IH, s) 5, 8 (11-(, dd, J=5.
9Hz) 5.1 (IH, d, J=5Hz) 4, 6 (2H, A Bq) 3, 7 (
:NI, ABq) 2, 6 (3H,S) 1, 5 (6H,s) Example 7 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-2-[Z- [1-(5-7setoxy]-4-hydroxypyridin-2-yl)carbonyl-1-methylethyl]oximino]acetamide)-3-[(,2-carboxy-5-methyl-5-triazolo(1, 5-a)
pyrimidin-7-yl)thiomethyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0]octo-2
-Production process of -ene-2-carboxylic acid 1 2-(2-)lifelemethylamino-4-thiazolyl)-2-Z-(1-(5-acetoxy-4-hydroxypyridin-2-yl)carbonyl- 1-methylethyl]
Manufacture of oximinoacetic acid The compound 2-(2-[rifer methylamino-
0.083 g of 4-thiazolyl)-2-Z-C1 [4.5-diacetoxypyridin-2-yl)carbonyl-1-methylethyl]oxyiminoacetic acid and 0.83 m of pyridine.
1 and add anhydrous vinegar [0.41 ml to 8 ml at room temperature.
Stir for hours. After adding ethyl acetate, the mixture was washed with IN hydrochloric acid and saturated brine, and then dried over anhydrous magnesium sulfate. The residue was concentrated, washed with hexane, and crystallized with isopropyl ether to obtain 0.058 g of the title compound.

NMR spectrum (CDC13; ppm) 8, 5
(11-i, !() 8.1 (IH, s) 7.3 (16H, s) 6.7 (IH, s) 2.3 (3H, S) 1.6 (6H, S) Step 2 <6R,7R) -7-[1-(S”)rifer methylamino-4-thiaduryl)-2-[Z-(1-(5
-acetoxy-4-hydroquinpyridin-2-yl)carbonyl-1-methylethyl]oxyimino]acetamide)-3-[(2-diphenylmethyloxycarbonyl-5-methyl-5-triazolo [1,5-a) Production process of pyrimidin-7-yl)thiomethyl]-8-oxo-5-der-]-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester Compound 0 obtained in 1 .058g and (6R,7R)-
7-amino-1-[(2-diphenylmethyloxycarbonyl-5-methyl-5-1~riazolo(1,5=a)
pyrimidin-7-yl)thiomethyl]-8-oxo-5
-thia-1-azabicycloC4,2.0]octo-2-
En-2-carboxylic acid diphenylmethyl ester 0.0
7 g of dry methylene chloride and 0.7 ml of dry tetra
Fran Q, 7m! It was dissolved in a mixed solution of and cooled on ice.

Nitrogen-substituted dicyclohexylcarbodiimide 0°019
g was added. After stirring at room temperature for 4 hours, 4 insoluble materials were collected by filtration, and 1v of the filtrate was concentrated. The residue was purified by silica gel chromatography to obtain 0.024 g of the above-mentioned title compound.

NMR spectrum (CD(13;I')pm)8
．． 6 (IH,s) 8.0 (1+(,s) 7, 5~6.6 (411-1,m)6.0 (
III, dd, J=4.8l-1z)5.1 (II
I, d, J=4Hz) 4.3 (2H, bs) 3.6 (2H, bs) 2.5 (3H, s) 2, 3 (3FI, s) 1, 6 (6H, s) Step 3 (6R,7R)-7-(2-(2-amino-4-thiazuryl)-2-[Z-(1-(5-acetoxy-4-hydroxypyridin-2-yl)carbonyl-1-methylethyl] Oximino]acetamide)-3-[(2-carboxy-5-methyl-3-triazolo (1,5-a)
pyrimidin-7-yl)thousomethyl]-8-oxo-5-thia-1-azabicycloC4,2.0]octo-
Production process of 2-ene-2-carboxylic acid 0.024 g of the compound obtained in 2 was mixed with 0.28 m of dichloroethane! Anisole 0.01 was dissolved in water and cooled with water.
2m1. 0.024 ml of I~lifluoroacetic acid was added, and the mixture was stirred at room temperature for 3.5 hours.

The supernatant was removed by decantation, and ether was added to the residue for crystallization to obtain 0.01 g of the above title compound.

TR spectrum (KB r ; cm-1) 1781.
1'? 74.1676.1671°+637.1196
．． 1143 NMR spectrum (DMSO-ds;I')J)m
)9, 6 (I H, d, J = 8 Hz
)8, 0 (IT-L s) 7.4 (21(,s) 6, 8 (IH,s) 5.9 (III, dd, J=4.8Hz) 5.3
(II-T, d, J=411z) 4, 4 (2H
, bs) 3, 7 <21-1. ABq) 2, 6 (
3H,s) 2,3←3H,s) 1,6 (6H,s) Example 8 (6R,7R)-7-(2-(2-amino-4-thiazolyl)-i [Z-[1 -carboxy-2-(3,4-
diacetoxyphenyl)ethyl]oximino]acetamide)-3-[(2-calhoki]-5-methyl-5-triazolo[1,5-a)pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia -1-Azabicyclo [4
．． , 2,0]'A of oct-2-ene-2-carboxylic acid
M step 1 Production of 3.4-diacetoxyphenylpropionic acid 20 [3.4-dihydroxyphenylpropionic acid] was added to 30 ml of acetic anhydride! P! The mixture became cloudy, and a small amount of concentrated sulfuric acid was added while cooling with water. After stirring for 3.5 hours at room temperature.

The reaction solution was poured into water and heated to 70°C, then cooled to room temperature and extracted with ethyl acetate. 2 times with water, 1 time with saturated saline
After washing twice, it was dried with anhydrous sodium sulfate. After concentration, the residue was crystallized from Hegisan to obtain the above title compound 22.
I got g.

IR spectrum (KB r ; cm-1) 1776.
1716, 1698, 1508゜1376.1260.
1202,1180°1113.899 NMR spectrum 1-(CDC13; ppm) 9.2
(11-1, bs) 7.1-7.0' (3H, m) 3.0-2.6 (4H, m) 2.3 (6H, s) Step 2 2-bromo-1 (3, 4-Diacetoxyphenyl) propionic acid diphenylmethyl ester production/process 22 g of the compound obtained in step 1 was mixed with 15 m of carbon tetrachloride.
1, and added 24.2 ml of dionyl chloride to 60-7
Heated at 0°C for 1 hour. The reaction solution was cooled to room temperature and N-
Bromosuccinimide 17.7g, carbon tetrachloride 713m
Add a small amount of 1,47% hydrogen bromide and heat at 70°C for 15 minutes.
After heating at 90°C for 40 minutes, it was concentrated. Carbon tetrachloride was added to the residue, the insoluble matter was filtered off, the filtrate was concentrated, and acetone 16
0ml/8 solved. While cooling with water, add sodium bicarbonate to pH4.

0, and further adjusted to PI (2,0) with IN hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After concentration, the residue was diluted with 2QQml.
Dissolve it in acetone and add diphenylcyadmethane until the purple color no longer disappears.

The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 6.0 g of the above title compound.

IR spectrum (KB r ; cm-1) 1773.
1741, 1506.137].

1260.1212.1183, 1113° NMR spectrum (CD(13; ppm) 7, 3-6.
8 (14H, m)4, 5 (IH,t,
J=8tlz) 3, 6-3. 2 (2H, m) 2, 3 (6H, s) Step 3 2-phthaloyloxy-3-(3,4-diacetoxyphenyl)propionic acid diphenylmethyl ester manufacturing step 6.0 g of the compound obtained in Step 2 was dissolved in 20ml of dimethylformamide, and 1.9ml of hydroxyphthalimide was dissolved in 20ml of dimethylformamide.
2 [was added. 1.62 g of potassium carbonate was added at room temperature and stirred for 1.5 hours. The reaction solution was poured into water-cooled IN citric acid, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue after concentration was purified by silica gel column chromatography to obtain 36 g of the above title compound.

IR spectrum (KB r ; cm-1) 1771.
1736, 1372, 1260°1213.1187.
1115.70ONMR Subek] Le (CDCl2
;ppm) 7, 7 (/IN, s) 7, 3-6. 9 (1411,s)5, 2 (
JH, t, J=7Hz) 3, 3 (2H, d,
J = 7Hz) 2, 3 (6H, s) Step 4 Production step of 2-aminooxy-3-(3,4-diacetoxyphenyl)propionic acid diphenylmethyl ester 3.6 g of the compound obtained in step 3 was dried and chlorinated. Dissolve in 5Qml of methylene and cool at -70°C for 7 days.

0.33 ml of methylhydrazine was added dropwise. 10 minutes later,
The mixture was cooled with water and stirred for 30 minutes. Insoluble materials were collected by filtration, the filtrate was concentrated, and purified by silica gel column chromatography to obtain 1.68 g of the title compound.

NMR spectrum (CD(13; ppm) 7.3
~6.9 (I 4H, m) 4.5 ~ 4.4 (III, m) 3, 1 ~ 2. 9 (2H, m) 2. 3 (611,S) Step 5 2-(2-1-diphenylmethylamino-4-thiazolyl)-2-Z-(1-Schiff]-nylmethyloxycarbonyl-2-(3,4-diacetoxyphenyl) ethyl〕
1.35 g of MM (2-triphenylmethylaminethiazur-4-yl)glyoxyl M of oxyiminoacetic acid was heated/dissolved in 70 ml of methanol. Step 4 at room temperature
1.68 g of the compound obtained in 30 ml of methanol
After the solution was added dropwise, it was stirred for 1.5 hours. After concentration.

3.0 g of the above title compound was obtained as a crude product.

■R spectrum (KB r ; cm-1) 1768.
1764,1752.12]4°1185.701 NMR spectrum (DMSO-d6; ppm)8.
8 (LH, s) 7.3~7.1 (29H, m) 6, 8 (11-1, S) 4, 9 (Ill, t, J=711z) 3,
2 <2tl, d, J=7Hz)2, 2
(6H,s) Step 6 (6R,7R)-7 C2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-[1-diphenylmethyloxycarbonyl-2-(3,4-di acetoxyphenyl)ethyl]oxyimino]acetamide>3-
[(2-diphenylmethyloxycarbonyl-5-methyl-s-triaduro(1,5-a)pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct Production process of -2-ene-2-carboxylic acid diphenylmethyl ester 3.0 g of the compound obtained in step 5 and (6R97R)-7-amino-3-[
(2-diphenylmethyloxycarbonyl-5-methyl-5-)riazolo(1,5-a)pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0] Oct-2-ene-2-carboxylic acid diphenylmethyl ester 2,63 g'C:<
'b It was dissolved in 100 ml of dry methylene chloride, and 0.72 g of dicyclohexylcarbodiimide was added while cooling with water.

After stirring at room temperature for 3 hours, 0.07 g of dicyclohexylcarbodiimide was added, and the mixture was further stirred for 2 hours. After filtration,
The filtrate was concentrated, ethyl acetate was added to the residue, and the insoluble matter was filtered off. The filtrate was washed once with saturated brine and dried over anhydrous sulfuric acid. The residue after concentration was purified by silica gel column chromatography to obtain 3.0 g of the above title compound.

IR spectrum (KB r ; cm-1) 1791.
1774, 1741.1507゜1207.1183.
70O NMR spectrum (DMSO-d6; ppm)
9, 6 (11(, d, J = 8 Hy
, )8.8 (IH, S) 7.5+-6,7 (53H, m) 5, 9 (IH, dd, J=5.8
Hz) 5, 2 (111, d, J = 5
Hz)5, 0 (III, t, J=7
Hz) 4, 3 (2N, bs) 3, 7 (2I(, AB(1) 3.2 (2H, d, J=7Hz) 2, 5 (3H, s) 2, 2 (6H, S) Process 7 (6R,7R)-7-C2-(2-amino-4-thiazolyl)-2-[Z-[1-carboxy-2-(3,4-
diacetoxyphenyl)ethyl]oxyimino]acetamide)-3-[(2-carboxy-5-methyl-5-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia- 1-Azabicyclo [4
．． , 2゜0] Production process of oct-2-ene-2-carboxylic acid 3.0 g of the compound obtained in step 6 was dissolved in dichloroethane 5
ml. After straining 2 liters of anisole, add 4 ml of ice-cooled trifluoro vinegar.

Stirred at room temperature for 2 hours. Add 25m of dichloroethane to the reaction solution.
1 was added thereto, the supernatant was decanted, and the residue was crystallized with chlorine to give 1.07 g of the above-mentioned title compound.

IR spectrum (KB r ; cm-1) 1772.
1735. lG31b +637°1597.150
9.1259.1205°NMR spectrum (DMSO
d6; p pm) 9.6 and 9. 5 (II
-1,m) 7.4 (II(,s) 7, 2 (31-1,s) 6.84 and 6.81 (IH,S) 5.8 (
IH, m) 5, 2 (IH, d', J -4HZ
)4, 8 (11-1, m) 4.4 (2H, bs) 3.7 (21+, ABq) 3.2 (2H, m) 2.6 (31(,s) 2, 2 (61- 1,s) Fruitful example 9 (GR,7R)-7-C2-(2-amino-4-thiazolyl) -2-[Z-[l-carboxy-2-(3,4
-DihiIroxyphenyl)ethyl]oximino]acekumi1'') -3-[(2-carboxy-5-medyluse-1-diazoo[1,5-a]pyrimidin-7-yl)thiomethylcou8=oxo5 -Production of thia-1-azabicycloC4,,2゜0]oct-2-ene-2-carboxylic acid 0.5 g of the compound obtained in Step 7 of Example 8 was suspended in 20 ml of water, and Sodium hydrogen carbonate was added thereto to adjust the pH to 8.0 to 8.5. After 1 hour, the mixture was heated to 30° C. and stirred for a further 5 hours.

The reaction solution was adsorbed on Diamond Ion HPIO and eluted with 2 water.
The fraction containing the target compound was lyophilized to yield 0.17% of the above title compound.
I got g.

IR spectrum (KB r ; cm-1) 1765,
1597. I 516. 1474°1408.
1356.1314 NMR spectrum (D20; ppm) 7.4 and 7.2 (IH,s) 7, 0 (IH,S) 6,8-6. 6 (3H, s) 5, '7 (III, m) 5, 2 (I H, m) 5, 0 (IH, m) 4, 5 (2H, ABq) 3, 7 (2H, ABq) 3, 0 (2H,m) 2, 6 (31L s) Example 10 (6R,7R)-7[Z(2-amino-4-thiazolyl)-2-[Z-(1-carboxy-1-(3, 4-Diacetoxyphenyl)ethyl]oxyimino]acetamide]-3-[(2-calphoxy]-5-methyl-9-triazolo(1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo -5-thia-1-azabicycloC4,
, 2,0] Production process of oct-2-ene-2-carboxylic acid 1 Production of 3.4-dimethoxyphenylacetic acid methyl ester 3. Melt 500 g of 4-dino-1-xyphenylacetic acid M in 200 ml of tetrahydrofuran and cool on ice. An ethereal solution of diazomethane was added to the solution until the yellow color no longer disappeared. After stirring for 30 minutes at room temperature, excess diazomethane was decomposed with acetic acid, extracted with 300 ml of ether, and diluted with 300 ml of IN hydrochloric acid.
ml, 300ml of saturated sodium bicarbonate aqueous solution
After washing twice with 300ml of saturated saline, anhydrous sulfuric acid solution
- Dry with a lium. After concentration, chloroform 300m
1 was added, dried over anhydrous magnesium sulfate, and after 30 minutes, concentrated to obtain 53 g of the above title compound.

NMR spectrum (CD(13; ppm)6.
8 (3H,s) 3.87 (3H,s) 3.86 (3H,s) 3, 7 (311,S) 3, 6 (211,s) Step 2 α-Methyl-3,4-dimethoxyphenyl Preparation of methyl acetate 24.1 ml of diisopropylamine was dissolved in 200 ml of tetrahydrofuran, cooled to -70°C,
n-) Chillithium (1,55 mol) l'af night 11
1 ml was added, the temperature was raised to -20°C, and the mixture was stirred for 30 minutes. Compound 36 obtained in step 1 was cooled again to -70°C.
．． A solution of 1 g dissolved in 30 ml of tetrahydrofuran was added. After 30 minutes, add 24.4g of Tenka methyl and add 170g of
After stirring at °C for 3 hours, the temperature was raised to -20 °C and the reaction solution was
Pour into 300ml of hydrochloric acid.

Extracted with 500 rnl of ether. IN hydrochloric acid 200m
l, saturated aqueous sodium bicarbonate solution 2! 00 m,
1 twice and 200 ml of saturated saline, and then dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography to obtain the above title compound 27.
．． 9g was obtained.

NMR spectrum (CDCl2;11)I)m)6
．． 8 (3H, s) 3.88 (3+1.s) 3, 85 (311, s) 3, 66 (IH, q, J = 711z) 3,
65 (311,s) 1, 5 (3H,d, J = 71-1z) Step 3 Production step of α-methyl-3,4-dihydroxyphenylacetic acid Compound 27.5 [+ 47% The mixture was dissolved in 137.5 ml of hydrobromic acid, and 68.8 ml of acetic anhydride was added dropwise under one stream of nitrogen. Heat the reaction solution to 130°C and
Stir for hours. b''The residue after condensation of AA was dissolved in 1.21 ml of ethyl acetate, washed five times with 500 ml of saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain the title compound 22.

NMR spectrum (DMS○-d6; ppm)12.
2 (LH, bs) 8.8 (2H, bs) 6.8 to 6.4 (3)1. m> 3, 4 (I H, q, J = 7 Hz
)1, 3 (3H, d, J = 7 Hz
) Step 4 Production of α-methyl-3,4-diacetoxyphenylacetic acid 22 g of the compound obtained in step 3 was added to 9 Q ml of acetic anhydride, and 2 ml of concentrated sulfuric acid was added under water cooling.

After stirring at room temperature for 30 minutes, pour into water 1.21 and add 60 to 65
Warmed to ℃. Extracted twice with 500 ml of ethyl acetate and washed 5 times with 100 ml of saturated brine.

It was dried with anhydrous sodium sulfate. After concentration, 32 g of the above title compound was obtained.

NMR spectrum (CDC13; p pm) 8.3
(IH, s) 7.2 (3H, s) 3.7 (IH, q, J=7'1iZ) 2.3 (6
H,S) 1.5 (31T, d, J=7+-+Z) Step 5 Production of α-bromo-α-methyl-3,4-diacetoxyphenylacetic acid diphenylmethyl ester Compound obtained in Step 4 10. 0g of carbon tetrachloride 5' = 10 ml
in addition to 12 ml of thionyl chloride. A trace amount of dimethylformamide was added and heated at 70"C for 30 minutes. After necrosis,
The residue was poured into 20 ml of carbon tetrachloride, 5 ml of thionyl chloride, 7.22 g of N-phyrosuccinimide, and 1 ml of hydrobromic acid Q were added, followed by stirring at 585°C for 1.5 hours. Insoluble materials were collected by filtration, and the filtrate was concentrated. The residue was dissolved in 60 ml of acetone, and saturated aqueous sodium hydrogen carbonate solution was added.

After adjusting to PI-15 at 10°C or lower, the pH was adjusted to 1 with IN hydrochloric acid. Extract with 400ml of ethyl acetate,
It was washed four times with 100 ml of saturated brine and dried over anhydrous sodium sulfate. After washing with concentrated lamination, 60 ml of acetone was added to the residue, 7 g of diphenylcyazmethane was added, and the mixture was left overnight.

After concentration, the residue was purified by silica gel column chromatography to obtain 4.1 g of the above title compound.

NMI2 spectrum (CD(13; ppm)7
．． 4-7.0 (13H, m) 6, 9 (IH, s) 2. 28 [(ill, S) 2, 27 (311, s> Step 6 α-Methyl-α-=phthaloyloxy]-3,4-diacetoxyphenylacetic acid diphenyl methyl ester Production step 5 Compound 4゜1 g was dissolved in 13 ml of dry dimethylformamide, and 1.3 g of N-hydroxyfuclimide was added while cooling with water.

Anhydrous potassium carbonate was added over 10 minutes. After stirring at room temperature for 1.5 hours, 100 ml of IN citric acid was added. ethyl acetate 100
The mixture was extracted by pouring the mixture into ml and washed with 10Qml of saturated brine three times, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by silica gel column chromatography to obtain 1.3 g of the above title compound.

IR spectrum (KB r ; cm-1) 1773.
1741, 1736, 1372゜1263.1208,
1191,1170°1119,702 NMR spectrum (CD(13;r) pm
)7, 8 (4H, m) 7, 4-7. 2 (131i m>6, 9
(III, S> 2, 28 (311,s) 2, 27 (3H,s) 1, 9 (3I], S) Step 7 α-aminooxy-α-methyl-3,4-diacetoxyphenylacetate diphenyl Methyl ester manufacturing process 1.3 g of the compound obtained in step 6 was dissolved in dry methylene chloride 2Q m I and cooled to -70'C.

Under a nitrogen stream, 0.2 g of methylhylazine was added and stirred for 10 minutes, and then stirred for 40 minutes under water cooling. Insoluble materials were collected by filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain 0.61 g of the above-mentioned title compound.

NMR Spectrum (CD(13; I) rim)
7, 3-7. 0 (13I-1,s)6, 9
(IH, s) 2, 28 (3H, s) 2, 26 (3)1. s) 1, 9 (3H,s) Step 8 2-(2-triphenylmethylamino-4-thiazolyl)-1-Z-(1-diphenylmethyloxycarbonyl-1-(3,4-diacetoxyphenyl) Preparation of (2-triphenylmethylaminethiazol-4-yl)glyoxyl MO, 49 g was dissolved in 25 ml of methanol while heating, and 0.61 g of the compound obtained in step 7 was added to 10 ml of methanol at room temperature. and stirred for 1.5 hours. After concentration, the residue was purified by silica gel column chromatography to obtain 0.8 g of the above title compound.
I got it.

IR spectrum (KB r ; cm-1) 1773.
1751.1?43.1262゜1209.1168,
1115.701 NMR spectrum (DMSOd6
; pp pm) 8, 8 (IT(, s) 7, 3~7. 1 (28H, m) 6, 8 (
,LH,s) 6, 7 (IH,s) 2, 3 (611,s) 1, 9 (3H,s) Step 9 (6R,7R) -7-(1-(2-1-liphenylmethyl) amino-4-thiazolyl)-1-[Z-[1-diphenylmethyloxycarbonyl-1-(3,4-diacetoxyphenyl)ethyl]oximino]rocetamide)
-3-[(2-diphenylmethyloxycarbonyl-5
-Methyl-5-)riazolo(1,5-a)pyrimidine-
7-yl)thiomethyl]-8-oxo-5-thia-1-
Production process of azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester 0.8 g of the compound obtained in step 8, (6R.

7R1-7-Amino-3-[(2-diphenylnotyloxycarbonyl-5-methyl-5-1 Riaduro (I,
5-a) Pyrimidin-7-yl)thiomethyl]-8-
Oxo-5-thia-1-azabinclo[4.2.0]off-1-2-ene-2-carboxylic acid diphenylmethyl ester 0.7 [was dissolved in 30 ml of dry methylene chloride,
Dicyclohexyl force lupo diimide F0.19cr under water cooling
was added and left at room temperature overnight. Insoluble materials were removed, the liquid was concentrated, and the residue was purified by silica gel column chromatography to remove the title compound 0.6.7.

IR spectrum (KT3 r; cm-1) 179
1.1774.174.1,173G.

1507.120'7.1171.70ONMR spectrum (DMS○-da; ppm) 9.9 and 9, 7
(I H, d, J = 8 Hz)8,
9 (III, s) 7.5~G, 8 (53H, m) 5.9~5.7 (IH, m) 5, 2 (11-1, d, J = 51 (z
)4.3 (2N, bs) 3, 7 (21+, △Bq) 2, 6 (31+, S) 2, 23 (3H, s) 2, 19 <3t1. s) 1,9 (3H,s) Step 10 (6R,7R)-7-[Z-(2-amino-4-thiazolyl)-2-[Z-N-calhoki]-1(3,4-di acetoxyphenyl)ethyl]oxyimino]acetamide]-3-[(2-carboxy-5-methyl-5-l-riazolo(1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia -Production process of 1-azabicyclo[4゜2゜0]oct-2-ene-2-carboxylic acid 0.6 g of the compound obtained in step 9 was added to 1 m of dichloroethane.
0.5 ml of anisole was added. Add 1 ml of 1-lifluoroacetic acid while cooling with water.

After stirring at room temperature for 2 hours, cool on ice again and add 1 ml of trifluoroacetic acid.
ml was added and left overnight at room temperature. Add 20 ml of dichloroethane to the reaction solution and decant.

The residue was crystallized with ether to obtain 0.31 g of the above title compound.
I got it.

rR spectrum (KB r ; cm-1) 1772.
1735, 1683.1636°1597.1509.
1263.1232°1203.1172 NMR spectrum (DMS〇-da; ppm) 9.8~
9.7 (IH, m) 7, 4-7. 0 (4H, m) 6.78 and 6, 74 (1) I, s) 5.8-5.7
(LH, m)5, 3-5. 2 (11-1, m)4.4 (2
H, bs) 3.7-3゜6 (2H, rn) 2, 6 (311, s) 2.2 (6H, S) 1.8 (3+1.bs) Example 11 (6R, 7R)-7 -C2-(2-amino-4-thiazolyl)-2-[Z-(1-calhoki]-1- (3,4
-dihydroxyphenyl)ethyl]oxyimino]acekumi I”)-3-[(2-carboxy-5-methyl-S
-triazolo[1,5-a]biwamidin-7-yl)thiomethyl]-8=oxo-5-thia-1-azabicyclo[4.2゜0]oct-2-ene-2-carboxylic acid r
A-Building Example Step 10 Compound obtained in step 10 0゜2
8 g was suspended in 11 ml of water. Sodium hydrogen carbonate was added to the mixture to adjust Pl (8.5) and dissolved. The mixture was purged with nitrogen, protected from light, and stirred at room temperature for 5.5 hours.

Purified with Diaion HP 10. Elute with water.

The fraction containing the target compound was lyophilized to obtain the above-mentioned title compound 0, C.
194g was obtained.

IR spectrum (KB r ; cm-1) 1772.
1596.1509, 1404゜1395.1389,
1355.1311NMJ Spec) Le (J] 20;
ppm) 7.2-6.8 (5!1.m) 5.8-5.7 (IJl, m) 5, 2-5. 1 (IH, m) 4. 5 (2+(,Al3q) 3, 5 (211,Al3q) 2, 6 (311,s) 1, 8 (3H,s) (1 other person)・゛

Claims (46)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents a hydrogen atom or an amino protecting group,
R^2 and R^3 represent a hydrogen atom, a methyl group, a carboxyl group, or a protected carboxyl group, and R^4 and R^5 represent a hydrogen atom, or R^4 and R^5 together represent an oxygen atom. , R^6 and R^7 represent a hydroxyl group, an acetoxy group, or a protected hydroxyl group, and R^8
represents a hydrogen atom or a carboxy protecting group, X represents a methine group or a nitrogen atom, and the wavy line bond represents an anti (ant
i) type or syn type bond, and a and b represent an integer of 0 or 1. ), salts thereof, hydrates thereof, and hydrates of salts. (2) The cephalosporin derivative and salt thereof according to claim 1, wherein R^6 and R^7 are p-toluenesulfonyloxy groups, X is a methine group, and a and b are 0. , its hydrates and salt hydrates. (3) R^2 and R^3 are methyl groups, R^4 and R^5 together are oxygen atoms, R^6 and R^7 are hydroxyl groups, and X is methine group. 2. A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of a salt according to claim 1, wherein a and b are 1. (4) R^2 and R^3 are methyl groups, R^4 and R^5 together are oxygen atoms, R^6 is a hydroxyl group, and R^7 is an acetoxy group, A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of a salt according to claim 1, wherein X is a nitrogen atom, and a and b are 1. (5) R^2, R^4 and R^5 are hydrogen atoms,
R^3 is a carboxyl group, R^6 and R^7 are an acetoxy group, X is a methine group, and a and b
The cephalosporin derivative according to claim 1, wherein 1 is 1, a salt thereof, a hydrate thereof, and a hydrate of the salt. (6) R^2, R^4 and R^5 are hydrogen atoms,
The cephalosporin derivative according to claim 1, wherein R^3 is a carboxyl group, R^6 and R^7 are hydroxyl groups, X is a methine group, and a and b are 1; Salts, their hydrates and hydrates of salts. (7) R^2 is a hydrogen atom, R^3 is a carboxyl group, and the carbon atom to which R^3 is bonded is in the R configuration,
The cephalosporin derivative, its salt, and its hydrate according to claim 1, wherein R^6 and R^7 are acetoxy groups, X is a methine group, a is 1, and b is 0. and salt hydrates. (8) R^2 is a hydrogen atom, R^3 is a carboxyl group, and the carbon atom to which R^3 is bonded is in the S configuration,
The cephalosporin derivative, its salt, and its hydrate according to claim 1, wherein R^6 and R^7 are acetoxy groups, X is a methine group, a is 1, and b is 0. and salt hydrates. (9) R^2 is a hydrogen atom, R^3 is a carboxyl group, R^6 and R^7 are an acetoxy group,
A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of a salt according to claim 1, wherein X is a methine group, a is 1, and b is 0. (10) R^2 is a hydrogen atom, R^3 is a carboxyl group, the carbon atom to which R^3 is bonded is in the R configuration, R^6 and R^7 are hydroxyl groups, and X is methine A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of a salt according to claim 1, wherein a is 1 and b is 0. (11) R^2 is a hydrogen atom, R^3 is a carboxyl group, the carbon atom to which R^3 is bonded is in the S configuration, R^6 and R^7 are hydroxyl groups, and X is methine A cephalosporin derivative, a salt thereof, a hydrate thereof, and a hydrate of a salt according to claim 1, wherein a is 1 and b is 0. (12) A patent in which R^2 is a hydrogen atom, R^3 is a carboxyl group, R^6 and R^7 are hydroxyl groups, X is a methine group, a is 1, and b is 0 A cephalosporin derivative according to claim 1, a salt thereof, a hydrate thereof, and a hydrate of the salt. (13) R^2 is a methyl group, R^3 is a carboxyl group, R^6 and R^7 are acetoxy groups, X is a methine group, a is 1, and b is 0. A cephalosporin derivative according to claim 1, a salt thereof,
its hydrates and hydrates of its salts. (14) A patent in which R^2 is a methyl group, R^3 is a carboxyl group, R^6 and R^7 are hydroxyl groups, X is a methine group, a is 1, and b is 0 A cephalosporin derivative according to claim 1, a salt thereof, a hydrate thereof, and a hydrate of the salt. (15) Cephalosporin derivatives, salts thereof, hydrates thereof, and hydrates of salts according to claims 2 to 14, wherein the bond indicated by the wavy line is a syn-type bond. (16) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 represents a hydrogen atom or an amino protecting group,
R^2 and R^3 represent a hydrogen atom, a methyl group, a carboxyl group, or a protected carboxyl group, and R^4 and R^5 represent a hydrogen atom, or R^4 and R^5 together represent an oxygen atom. , R^6 and R^7 represent a hydroxyl group, an acetoxy group, or a protected hydroxyl group, and R^8
represents a hydrogen atom or a carboxy protecting group, X represents a methine group or a nitrogen atom, and the wavy line bond represents an anti (ant
i) type or syn type bond, and a and b represent an integer of 0 or 1. ) is an intermediate compound in the synthesis of cephalosporin derivatives. (17) R^6 and R^7 are p-toluenesulfonyloxy groups, X is a methine group, and a and b are 0
The compound according to claim 16, which is (18) R^2 and R^3 are methyl groups, and R^4
and R^5 are together an oxygen atom, R^6 and R^7 are a hydroxyl group, X is a methine group, and a and b are 1, the compound according to claim 16 . (19) R^2 and R^3 are methyl groups, and R^4
and R^5 are together an oxygen atom, R^6 is a hydroxyl group, R^7 is an acetoxy group, X is a nitrogen atom, and a and b are 1. 1
Compound according to item 6. (20) R^2, R^4 and R^5 are hydrogen atoms, R^3 is a protected carboxyl group, R^6 and R^7 are acetoxy groups, and X is a methine group. 17. The compound according to claim 16, wherein a and b are 1. (21) R^2, R^4, and R^5 are hydrogen atoms, R^3 is a protected carboxyl group, R^6 and R^7 are hydroxyl groups, and X is a methine group. , a and b are 1. (22) R^2 is a hydrogen atom, R^3 is a protected carboxyl group, and the carbon atom to which R^3 is bonded is R
17. The compound according to claim 16, wherein R^6 and R^7 are acetoxy groups, X is a methine group, a is 1, and b is 0. (23) R^2 is a hydrogen atom, R^3 is a protected carboxyl group, and the carbon atom to which R^3 is bonded is S
17. The compound according to claim 16, wherein R^6 and R^7 are acetoxy groups, X is a methine group, a is 1, and b is 0. (24) R^2 is a hydrogen atom, R^3 is a protected carboxyl group, R^6 and R^7 are acetoxy groups, X is a methine group, a is 1, and b is 17. The compound according to claim 16, which has a molecular weight of 0. (25) R^2 is a hydrogen atom, R^3 is a protected carboxyl group, and the carbon atom to which R^3 is bonded is R
17. The compound according to claim 16, wherein R^6 and R^7 are hydroxyl groups, X is methine group, a is 1, and b is 0. (26) R^2 is a hydrogen atom, R^3 is a protected carboxyl group, and the carbon atom to which R^3 is bonded is S
17. The compound according to claim 16, wherein R^6 and R^7 are hydroxyl groups, X is methine group, a is 1, and b is 0. (27) R^2 is a hydrogen atom, R^3 is a protected carboxyl group, R^6 and R^7 are hydroxyl groups, X is a methine group, a is 1, b is 0 The compound according to claim 16, which is (28) R^2 is a methyl group, R^3 is a protected carboxy group, R^6 and R^7 are acetoxy groups, X is a methine group, a is 1, and b is 17. The compound according to claim 16, which has a molecular weight of 0. (29) R^2 is a methyl group, R^3 is a protected carboxy group, R^6 and R^7 are hydroxyl groups, X is a methine group, a is 1, b is 0 The compound according to claim 16, which is (30) The wavy bond is anti(an) to the thiazole ring.
ti) Claims 17 to 2 which are combinations of the form
Compound according to item 9. (31) General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (In the formula, R^8 represents a hydrogen atom or a carboxy protecting group.) Reaction in the compound or its amino group General formula (IV) ▲ Numerical formula, chemical formula, table, etc. ▼ (IV) (In the formula, R^1 represents a hydrogen atom or an amino protecting group,
R^2 and R^3 represent a hydrogen atom, a methyl group, a carboxyl group, or a protected carboxyl group, and R^4 and R^5 represent a hydrogen atom, or R^4 and R^5 together represent an oxygen atom. , R^6 and R^7 represent a hydroxyl group, acetoxy group, or a protected hydroxyl group, X represents a methine group or a nitrogen atom, and the wavy bond is an anti(a
represents a nti)-type or syn-type bond, and a and b represent an integer of 0 or 1. ) or a reactive derivative at the carboxyl group or a salt thereof, and optionally removing the amino-, hydroxy- and/or carboxy-protecting group. Formula ( I
) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1, R^2, R^3, R^4, R^5, R
^6, R^7, R^8, X, a, b, and the bond of the wavy line have the same meanings as above. ) A method for producing a cephalosporin derivative represented by (32) General formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R^1 represents a hydrogen atom or an amino protecting group,
R^8 represents a hydrogen atom or a carboxy protecting group, and the wavy bond represents an anti-type or syn-type bond. ) or their salts include the general formula (VI) ▲Mathematical formula, chemical formula, table, etc.▼(VI) (In the formula, R^2 and R^3 are hydrogen atoms, methyl groups, carboxyl groups or represents a protected carboxy group, R
^4 and R^5 are hydrogen atoms or R^4 and R^5
together represent an oxygen atom, R^6 and R^7 represent a hydroxyl group, an acetoxy group or a protected hydroxyl group, X represents a methine group or a nitrogen atom, a and b are 0
Or represents an integer of 1. ) or a salt thereof, or a reactive derivative at the hydroxyl group, and optionally removing the amino-protecting group, hydroxy-protecting group and/or carboxy-protecting group. (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1, R^2, R^3, R^4, R^5, R
^6, R^7, R^8, X, a, b, and the bond of the wavy line have the same meanings as above. ) A method for producing a cephalosporin derivative represented by (33) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents a hydrogen atom or an amino protecting group,
R^2 and R^3 represent a hydrogen atom, a methyl group, a carboxyl group, or a protected carboxyl group, and R^4 and R^5 represent a hydrogen atom, or R^4 and R^5 together represent an oxygen atom. , R^6 and R^7 represent a hydroxyl group, an acetoxy group, or a protected hydroxyl group, and R^8
represents a hydrogen atom or a carboxy protecting group, X represents a methine group or a nitrogen atom, and the wavy line bond represents an anti (ant
i) type or syn type bond, and a and b represent an integer of 0 or 1. ), a salt thereof, a compound thereof, and/or a hydrate of the salt as an active ingredient. (34) The active ingredient is (6R,7R)-7-[2-(2-
amino-4-thiazolyl)-2-[Z-[3,4-bis-(p-toluenesulfonyloxy)phenyl]oximino]acetamide]-3-[(2-carboxy-5-
Methyl-s-triazolo[1,5-a]pyrimidine-7
-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, salts thereof, hydrates thereof and/or hydrates of salts The formulation according to claim 33, which is (35) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-(1-(3,4
-dihydroxybenzoyl)-1-methylethyl]oxyimino]acetamide]-3-[(2-carboxy-5
-Methyl-s-triazolo[1,5-a]pyrimidine-
7-yl)thiomethyl]-8-oxo-5-thia-1-
34. The preparation according to claim 33, which is azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (36) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[1-(5-acetoxy-4-hydroxypyridin-2-yl)carbonyl-1-methylethyl]oxyimino]acetamide]
-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]
-8-oxo-5-thia-1-azabicyclo [4.2.
0] The preparation according to claim 33, which is oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (37) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[1-carboxy-2-(3,4-diacetoxyphenyl)ethyl]oximino]acetamide]-3-[(2-carboxy-
5-Methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1
-Azabicyclo[4.2.0]oct-2-ene-2-
34. The preparation according to claim 33, which is a carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (38) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[1-carboxy-2-(3,4-dihydroxyphenyl)ethyl]oximino]acetamide]-3-[(2-carboxy-
5-Methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1
-Azabicyclo[4.2.0]oct-2-ene-2-
34. The preparation according to claim 33, which is a carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (39) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[(R)-carboxy(3,4-diacetoxyphenyl)methyl]oximino]acetamide]-3-[(2-carboxy-5
-Methyl-s-triazolo[1,5-a]pyrimidine-
7-yl)thiomethyl]-8-oxo-5-thia-1-
34. The preparation according to claim 33, which is azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (40) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-diacetoxyphenyl)methyl]oximino]acetamide]-3-[(2-carboxy-5
-Methyl-s-triazolo[1,5-a]pyrimidine-
7-yl)thiomethyl]-8-oxo-5-thia-1-
34. The preparation according to claim 33, which is azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (41) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-diacetoxyphenyl)methyl]oxyimino]acetamide]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo- Claim 33 which is 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt formulation. (42) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[(R)-carboxy(3,4-dihydroxyphenyl)methyl]oximino]acetamide]-3-[(2-carboxy-5
-Methyl-s-triazolo[1,5-a]pyrimidine-
7-yl)thiomethyl]-8-oxo-5-thia-1-
34. The preparation according to claim 33, which is azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (43) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[(S)-carboxy(3,4-dihydroxyphenyl)methyl]oximino]acetamide]-3-[(2-carboxy-5
-Methyl-s-triazolo[1,5-a]pyrimidine-
7-yl)thiomethyl]-8-oxo-5-thia-1-
34. The preparation according to claim 33, which is azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (44) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[carboxy(
3,4-dihydroxyphenyl)methyl]oxyimino]acetamide]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5 -thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt; formulation. (45) The active ingredient is (6R,7R)-7-[2-(2-
Amino-4-thiazolyl)-2-[Z-[1-carboxy-1-(3,4-diacetoxyphenyl)-1-methylethyl]oximino]acetamide]-3-[(2
-carboxy-5-methyl-s-triazolo[1,5-
a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]octo-
34. The preparation according to claim 33, which is 2-ene-2-carboxylic acid, a salt thereof, a hydrate thereof and/or a hydrate of a salt. (46) The active ingredient is (6R,7R)-7-[2-(2-
amino-4-thiazolyl)-2-[Z-[1-carboxy-1-(3,4-diacetoxyphenyl)-1-methylethyl]oximino]acetamide]-3-[(2-
Carboxy-5-methyl-s-triazolo[1,5-a
[pyrimidin-7-yl)thiomethyl]-8-oxo-
5-thia-1-azabicyclo[4.2.0]octo-2
-ene-2-carboxylic acid, its salts, its hydrates and/or
or a hydrate of a salt thereof.