JPS59167576A - Beta-lactam compound - Google Patents

Abstract

NEW MATERIAL:The beta-lactam compound of formula I (X is CH2, S or O; Y is OH, acyloxy or amino; A is phenyl, naphthalene or heterocyclic group; R1 is H, OH, methoxy or alkyl; R2 is H, halogen, methoxy, etc.; R3 is H, alkali metal, etc.; R4 and R5 are H, alkyl, or together with bonded C atom form cycloalkylidene; l is 0-3; m is 0 or 1; n is 1-5). EXAMPLE:(6R,7S)-7-[2-( 2-Aminothiazol-4-yl )-2-syn-(3,4-diacetoxy-benzoyloxyimino) acetamido]-1-azabicyclo[4,2,0]oct-2-ene-8-oxo-2-carboxylic acid. USE:Bactericide and disinfectant for Gram-positive bacteria, Gram-negative bacteria, etc. PREPARATION:The objective compound of formula I can be prepared e.g. by condensing the novel carboxylic acid of formula II (Z is amino, etc.; Y<1> is Y, etc.) or its reactive derivative with the compound of formula III, and eliminating the protecting group from the resultant compound of formula IV.

Description

Detailed Description of the Invention The present invention is based on the general formula (I) (wherein, X is CH2 (methylene group), S (sulfur atom),
or 0 (oxygen atom), Y is a hydroxyl group, acyloxy group, amine group, or substituted amine group, A is a tuunyl group, naphthalene group, or a monocyclic or bicyclic heterocyclic group, R
1 is a hydrogen atom, a hydroxyl group, a methoxy group, or a lower alkyl group, and the crow is a hydrogen atom, a halogen atom, a methoxy group, or a CH2R2' [However, R2' is a hydrogen atom, an azido group,
An acyloxy group, a carbamoyloxy group, a pyridinium group, a substituted pyridinium group, or a substituted or unsubstituted heterocyclic thio group (heterocycle refers to a 5- to 6-membered ring having 1 to 4 0, S, or N heteroatoms) represents a heterocycle], R3 represents a hydrogen atom, an alkali metal, an alkaline earth metal, an organic ammonium group, or an ester residue;
4, R5 each represents a hydrogen atom, a lower alkyl group, or a cycloalkylidene group together with the carbon atom to which they are bonded, l is O or an integer of 1.2 or 3,
m Id, 0 or 1, n represents an integer of 1.2.3.4 or 5), and further has the general formula (n) (provided that
2 represents an amino group or a protected amine group, Y" represents a protected hydroxyl group or a protected amino group in addition to Y as defined above, and A, R4, R, 1, d, m and n are The present invention relates to a novel carboxylic acid represented by (synonymous with the above) and its reactive derivative.

Although many β-lactam antibiotics are being developed to provide excellent chemotherapeutic agents for the treatment of various bacterial infections, we have also made great efforts to search for better and more useful compounds. We have synthesized many β-lactam compounds in which the carbacephem nucleus is nine cores and the amine group at the 7-position of a cephalosporin or its related skeleton is acylated with various acyl groups. A β-lactam compound represented by the general formula (I) having an acyl group derived from a carboxylic acid is widely used in Durham-negative bacteria, including Pseudomonas aeruginosa, Pseudomonas cepachia, and various Enterobacteria, in addition to Durham-positive bacteria. The present invention was completed based on the discovery that it has a strong antibacterial effect.

The present invention will be explained in more detail below.

In Y of the compound represented by the general formula (I), the acyloxy group means a linear or branched lower acyloxy group having 1 to 6 carbon atoms, and the substituent of the substituted amine group is 1 to 6 carbon atoms.
-6 linear or branched lower acyl groups are exemplified.

Among the groups represented by A, monocyclic heterocycles include furyl, chenyl, pyrrolyl, oxazolyl, isoxasilyl, imidazolyl, pyrazinyl, thiazolyl, isothiazolyl, triazolyl, and thiadiazolyl groups. , tetrazolyl group, IH-pyranyl group, pyridinyl group, pyrimidinyl group, triazinyl group, etc., and examples of the bicyclic heterocyclic group include chromonyl group, chromonyl group, naphthyrisinyl group, quinolinyl group, inquinolinyl group, etc. .

The lower alkyl group in R1 group means a linear or branched lower alkyl group having 1 to 6 carbon atoms, the halogen atom in R2 group is chlorine or bromine, and the acyloxy group in R2' group is , means a lower acyloxy group having 2 to 6 carbon atoms; substituents for the substituted pyridinium group include a carbamoyl group, carboxy group, and cyan group; substituents for the heterocyclic thio group include 1 to 5 carbon atoms; Lower alkyl group, hydroxyl group, oxo group, amino group, nitro group, (Part 2) q
CO2H1 (part 2), So, H, (C'H2), -N(
Examples include lower alkyl group)2. However, q is 1~
Represents an integer of 3. The heterocycle includes all 5- or 6-membered heterocycles containing 1 to 4 N and O1S atoms, and preferred examples include a tetrazolyl group, thiadiazolyl group, triazolyl group, and triazinyl group.

The alkali metal and alkaline earth metal in the R3 group are metals that form the counter cation of the carboxylate anion (COO-), examples of the former include sodium, potassium, etc., and examples of the latter include magnesium, calcium, barium, etc. be done.

Examples of counter-cation groups include ammonium groups of organic amines such as basic amino acids.

The ester residue represented by R3 is, for example, a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R7 is a lower alkyl group having 1 to 6 carbon atoms or a phenyl group. ) or the lower alkyl group of formulas R4 and R5 is a lower alkyl group having 1 to 5 carbon atoms, and the cycloalkylidene group means a cycloalkylidene group having 3 to 6 carbon atoms.

2 in general formula (I[) represents an amine group or a protected amine group, and examples of the protecting group include trityl group, formyl group, chloroacetyl group, bromoacetyl group, 2.2
Examples include general amine protecting groups such as a 2-to-17 chloroacetyl group, a t-butyloxycarbonyl group, and a benzyloxycarbonyl group. Protecting groups for the hydroxyl group in Y include formyl group, chloroacetyl group, bromoacetyl group, 2,2.2-trichloroethoxycarbonyl group, tetrahydropyranyl group, methoxymethyl group, ethoxyethyl group, trimethylsilyl group, t -Butyl-dimethylsilyl group, etc. are exemplified, and examples of protecting groups for amino groups include polmyl group, acetyl group, chloroacetyl group, bromoacetyl group, 2,2.2-trichloroethoxycarbonyl group, and t-butyloxycarbonyl group. Examples include.

Examples of reactive derivatives of carboxylic acids represented by general formula (Il) include acid chlorides, acid halides such as acid bromide, acid anhydrides, mixed acid anhydrides, acid azides, and active esters. It means all carboxylic acid-conducting conductors that can form an acyl compound with the 7-position amine group of or its analogs.

The β-lactam compound represented by general formula (1) can be produced by the following method.

(Method A) (1) A compound represented by the general formula (I) (however, R
In addition to the above R3, 3° is a t-butyl group, a benzyl group, a p-
nitrobenzyl group, benzhydryl group, trityl group) For the first step of condensation, general methods for acylation of penicillin and cef-allosporin are applied, and the main methods include acid halide method, acid anhydride method ( (including the dicyclohexylcarbodiimide method), the mixed acid anhydride method, the active ester method, or the acid azide method. In this case, the acid chloride of carboxylic acid (II) can be prepared using phosphorus pentachloride, thionyl chloride or oxalyl chloride as a chlorogenating agent.

The 7-amine compound (1) can be used as such or as an inorganic acid salt such as hydrochloride, hydrobromide, phosphate or as an organic acid salt such as trifluoroacetate, methanesulfonate, or as a - It is also possible to use it as a silyl derivative.

The acylation (condensation) reaction is carried out in a water-containing or slightly aqueous solvent at a temperature of -500 DEG to +50 DEG C., if necessary in the presence of a base or other acid scavenger. Examples of solvents include halogenated hydrocarbons such as methylene chloride, ethers such as tetrahydrone, esters such as ethyl acetate, amides such as dimethylformamide, sulfoxides such as dimethyl sulfoxide, acetonitrile, acetone, or water. They may be used alone or in combination.

As the base, organic tertiary amines such as triethylamine and dimethylaniline, and inorganic bases such as sodium bicarbonate and potassium carbonate are used, and as scavengers, oxirane compounds such as ethylene oxide and propylene oxide are used.

Among the compounds represented by the general formula (1), cephalosporins where X is S are widely known compounds, and oxacephalosporins where X is O are J, Med, CMm, 2
0.55B1977), 22.757 (19”79)
, J, Am, Chem, Sac,, 1 (Roe, 4
403, (1979), etc., and carbacephems in which X is CH2 are disclosed in JP-A No. 5
No. 4-128591, No. 55-87791, No. 55-
It can be produced by the method described in No. 108872 and No. 56-61377.

The Rakuji process is the elimination process of the pus-retaining group, and the intermediate (IV
) after isolation and purification or without isolation and purification.
, yL, h Functional groups in I (hydroxyl group, amino group,
This can be carried out by removing the protective group (carboxyl group) by a conventional method. For the removal method, methods appropriate for the protecting groups of hydroxyl group, amine group, and carboxyl group are applied, and each of them is described in "Pr.
otgctiveGroups in Organic
Chemistry (1973, Plenum
It can be carried out according to the method detailed in Sections 2.3.4 and 5 of 2003, Press).

Method B) (V) (vI) In the first step, the hydroxyimino compound represented by the general formula (V) is treated with a reactive alkylating agent (Tsume O) or an acylating agent (Tsume O) represented by the general formula (VI). l=0, m-1)
This is the process of condensing with.

In the case of 1f-O, Q represents a chlorine, bromine, iodine atom, or a sulfonate group such as a mesyloxy group or a tosyloxy group, and in the case of A=O1m = 1, it represents a reactive derivative of phosphoric acid. Halides, acid anhydrides (including those produced by carbodiimides, etc.),
Examples include mixed acid anhydrides and active esters.

The condensation is carried out in a solvent in the presence of a base if necessary.
Although it can be carried out at a temperature within the range of 50°C, it is preferably carried out at a temperature of 5°C or lower in order to suppress the formation of anti-isomers.

As the base and solvent used, the bases and solvents used in the condensation reaction of Method A are used.

The compound represented by the general formula (V) is known, and X=C
A method for producing H is described in JP-A-56-49381. A group of compounds represented by the general formula (YI) are also known [Chemisier Berichte, Danyu B, 791 (1928)]
Reference].

The carboxylic acid represented by the general formula (n) can be produced by the following method.

(Vl) (VI) (However, R8
represents a hydrogen atom or a protecting group for canopivoxyl group) This condensation reaction can be carried out in the same manner as in Method B) for producing the compound represented by the general formula (I). i; Hc), Q is a chlorine, bromine, iodine atom or a sulfonate such as a mesyloxy group or a tosyloxy group;
A reactive derivative of a carboxylic acid in which l=O1m= is used, and examples of the reactive derivative include acid halides, acid anhydrides (including those produced with carbodiimides, etc.), mixed acid anhydrides, and active esters. . The condensation is carried out in the solvent used in the above method B), if necessary in the presence of a base.
Although it can be carried out at a temperature in the range of 50°C to +50°C, it is preferably carried out at a temperature of 5°C or lower in order to suppress the formation of anti-isomers.

In the case of 4≠0, the protective group R8 for the lupoxyl group is a group that can be removed with an alkali, acid or Lewis acid, i.e., a lower alkyl group such as methyl, ethyl, t-butyl group, benzyl, p-methoxybenzene, etc. Examples include arylmethyl groups such as /zyl, p-nitrobenzyl, diphenylmethyl, and triphenylmethyl groups, and in the case of l-0, m = 1, t-butyl, benzyl, p- which can be eliminated with acid or Lewis acid. Methoxybenzyl, p-nitrobenzyl, diphenylmethyl, triphenylmethyl groups, etc. are used.

The reaction of the decarboxylated protecting group can be carried out at a temperature of -50° to +50°C under general ester dissociation reaction conditions, but it is preferably carried out at a temperature of 10°C or lower to avoid isomerization to the anti-type.

Of course, this condensation reaction can also be carried out with a free carboxylic acid in which R8 is a hydrogen atom.

The compound of the present invention has strong antibacterial activity against Gram-positive and Gram-negative bacteria, and is useful as a bactericidal agent and as a component of a disinfectant in the treatment of various infectious diseases, and is similar to general cephalosporin agents. It is formulated with various carrier materials, excipients, diluents, etc., and administered as an injection, an oral drug, or a crude drug depending on the dosage form.

Examples of the present invention are shown below.

Example 1゜2-(2-)ditylaminothiazol-4-yl)-2
-Production of syn-(3,4-diacetoxybenzoyloxyimino)acetic acid: Produced by the following steps 1)-3).

1) Production of diphenylmethyl 2-(2-)lytylaminothiazol-4-yl)-2-syn-hydroxyiminoacetate: 2-(2-tritylaminothiazol-4-yl)-2
-Syn-hydroxyiminoacetic acid 8,58 f to tetrahydrone run 100! ! The mixture is suspended in L1, and diphenyldiazomethane is added while stirring at room temperature until the red color of the reaction solution disappears. Thereafter, 1 portion of acetic acid was added, and the mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine, saturated sodium bicarbonate solution, and saturated brine in this order, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude ester. The obtained ester was subjected to silica gel column chromatography [Wakogel (manufactured by Wako Tsumugi Co., Ltd.) C-100].
The product was purified using a developing system of n-hexane-ethyl acetate 3:1 (■/■) to obtain an ester compound in 6.07 r and a yield of 51 cm.

NMR (CDCl, )δ: 7.13 (25,H,
m), 7.07 (IH.

s), 6.10 (IH, g) 2) Preparation of diphenylmethyl 2-(2-)ditylaminothiazol-4-yl)-2-syn=(3,4-diacetoxybenzoyloxyimino)acetate Nidiphenyl Methyl 2-(2-)rithylaminothiazol-4-yl)-2-syn-hydroxyiminoacetate 9107n9 was dissolved in anhydrous methylene chloride 1. Dissolve in oml,
Add 0.230 mJ of triethylamine while stirring while cooling with water. To this solution, 385.6 μl of 3.4-diacetoxybenzoic acid was suspended in anhydrous methylene chloride, and while stirring, 33 μl of phosphorus pentachloride was added.
After adding 71nfl and reacting for 30 minutes, the acid chloride obtained by concentration under reduced pressure is added.

After reacting for 1 hour, the mixture was diluted with 20 ml of chloroform, washed successively with saturated sodium bicarbonate solution, water, and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain 3.4-diacetoxybenzoyl compound 1.13f.

NMR (CDCI!a) δ: 7.5-7.1 (27
H,m), 7.0 (IH,'d, J=9Hy,
), 6.80 (iH+ a ), 2.30 (3H
,,s),2.27(3H,5)3)2-(2-tritylaminothiazol-4-yl)-2-syn-(3,
Preparation of 4-diacetoxybenzoyloxyimino)acetic acid Nidiphenylmethyl 2-(2-1 lythylaminothiazol-4-yl)-2-syn-(3,4-diacetoxybenzoyloxyimino)acet-) 1.13 ' f 5 ml of anhydrous methylene chloride.

Dissolve 880 ml of aluminum chloride in 4 ml of anhydrous nitromethane and add dropwise to the solution under water-cooling and stirring. 20 minutes after dropping, the reaction solution was diluted with ethyl acetate 5011II!
The mixture is diluted with water, washed once with IN hydrochloric acid and twice with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Toluene 2 to the residue
07d was added and ground, and the toluene layer was removed by decantation to obtain carboxylic acid 649~. Furthermore, an equivalent amount of n-hexane is added to the toluene layer, and the resulting precipitate is collected to further obtain carboxylic acid 1007rLy.

NMR (DMSO-d, )δ: 7.9-7.8(2
H, m), 7.6-7,'l (17H, m), 2.
27 (6H, s) I % x 1 (KBr): 3.43
5.1790.1775 (sh,), 1750 (sh
, PA 1600 Example 2゜2-(2-tritylaminothiazol-4-yl)-2
-Production of syn-(3,'4-diacetoxybenzoyloxyimino)acetic acid (alternative method): Anhydrous chlorination of 4.297 of 2-(2-tritylaminothiazol-4-yl)-2-syn-hydroxyiminoacetic acid Methylene 5'Orttlj
2.77 r of triethylamine under stirring under cooling with water.
After adding and dissolving ytl, 3.4-diacetoxybenzoic acid 2
．． The acid chloride prepared from No. 347 in the same manner as in Example 1-2) was dissolved in 10 mA of anhydrous methylene chloride and added dropwise.

One hour after the dropwise addition, the reaction solution was washed once with IN hydrochloric acid and twice with saturated brine, dried over sulfuric acid, and concentrated under reduced pressure to obtain a crude carboxylic acid. The residue was crushed by adding ether, and −
After stirring in ether overnight, the mixture was taken in a furnace to obtain 5.31 p of carboxylic acid. Both IR and NMR of this compound were consistent with those obtained in Example 1-3).

Example 3゜2-(2-formylamino-thiazol-4-yl)-
Preparation of 2-syn-(3,4-diacetoxybenzoyloxyimino)acetic acid: 2-(2-formylamino-thiazol-4-yl)-
215 % (1 mmol) of 2-syn-hydroxyiminoacetic acid and 306% (2,2 mmol) of triethylamine were dissolved in 4 d of dichloromethane, and 3,4-
A solution of 256 ml (1 mmol) of diacetoxybenzoyl chloride in dichloromethane (3 d) is added. 30 minutes under water cooling,
After stirring at room temperature for 30 minutes, the reaction solution was poured into water, adjusted to pH 1 with 10% hydrochloric acid, and extracted twice with ethyl acetate. Wash with brine, dry with mirabilite, and concentrate under reduced pressure. The residue was triturated in ethyl acetate-hexane (1:1) and recrystallized from chloroform-methanol to obtain 150 μm of the desired compound.

NMR (CD30D) δ: 8.57 (IH, s), 8
．． 2-7.7 (2H, m), 7.5-7.3 (2H, m
), 3.3 (6H,s)IRE” (KBr)
: 3150(br), 1795, aX 1782.1775.1750.1559 Example 4゜(6R,78)-7-1:2-(2-aminothiazol-4-yl)-2-syn-(3, Preparation of 4-diacetoxybenzoyloxyimino)acetamidocou-1-azabicycloC4,20]oct-2-ene-8-oxo-2-carboxylic acid: 2-(2-)cutyl-aminothiazol-4-yl)-2 -Syn=(3,4-diacetoxybenzoyloxyimino)acetic acid 1.239 was suspended in 20 ml of anhydrous methylene chloride, cooled to -30°C, added phosphorus pentachloride with stirring, and then heated to room temperature over 30 minutes. After returning to the same temperature, it was concentrated under reduced pressure, and 30 g of anhydrous tetrahydrofuran was added to the residue to prepare an acid chloride solution. (6R, 78)
325 μl of -7-amino-1-azabicyclo[4,2,0:]]oct-2-ene-8-oxo-2-carboxylic acid was suspended in 15 μg of tetrahydrofura/15- and water under ice-cooling with stirring, and the mixture was purified with triethylamine. Dissolve at H8.0. The above acidic acid solution was added dropwise to this solution while simultaneously adding triethylamine to maintain the pH at 7.5 to 8.5.

After dropping and reacting for 30 minutes, adjust the pH to 2.0 with IN hydrochloric acid.
Add ethyl acetate and collect the liberated organic layer.

Then, the aqueous layer was extracted twice with ethyl acetate, and the organic layers were collected, dried with sulfuric acid, dried over IJum, and concentrated under reduced pressure. Ether was added to the residue, and after pulverization, the mixture was stirred in ether for 30 minutes, the ether was removed by decantation, 50% acetic acid was added, and the mixture was heated and stirred at 60° C. for 30 minutes. Thereafter, it was concentrated under reduced pressure, and 40 mL of ether and 20 mL of ethyl acetate were added to the residue, and after stirring for 30 minutes, the organic layer was removed by decantation, and the residue was dissolved in dimethyl sulfoxide. ) 25- column chromatography and elute with a gradient of water washing and draining to water/methanol = 1:4 (V/V) to obtain acyl compound 322.

NMR (DMS 0-do + CDa OD ) δ:
8.15-7.95 (2H, m), 7.43CIH,
d, J=9Hz), 7,20(IH,s), 6.37
(IH,m), 5.63 (IH,d,' J=4.
5Hz), 4.10-3.30 (IH,m), 2.
30 (6H, s), 2.50-1.40 (4H, m) xR? '''' (KBr): 3450.178
0.1750 (sh), aX 1730 (sh), 1670.1640.1545 Example 5゜(6R,78)-7-[2-(2-aminothiazole-
Production of 4-yl)-2-sheer(3,4-diacetoxybenzoyloxyimino)acetamidocou-1-azabicyclo[4,2,0)oct-2-ene-8-oxo-2-carboxylic acid (alternative method) : 2-(2-formylaminothiazol-4-yl)-2
-Syn-(3,4-diacetoxybenzoyloximino)acetic acid 1 a'omg (0.30 mmol) was dissolved in 3 ml of anhydrous tetrahydrofuran, and under cooling with dry ice and carbon tetrachloride, 50 μl of triethylamine (0.36 mmol) was dissolved in 3 ml of anhydrous tetrahydrofuran.
mmol).

Phosphorus pentachloride 6279 (0.30 mmol) was added to this solution and stirred for an additional hour at the same temperature to prepare an acid chloride tetrahydrofuran solution.

(6R,7S)-7-amino-1-azabicyclo[4,
2,0: ] ] Octo-2-1-8-oxo-2-carbo/acid (30 μm (0.15 mmol)) was purified with I/C in 15 dl of water and 0.8 mli of tetrahydrofuran, and the pH was adjusted by adding triethylamine under water cooling. to 7.8. The solution was adjusted to pH 7.5-8. with triethylamine while stirring under water cooling.
The acid chloride solution was added dropwise while maintaining the temperature at 0°C, and the mixture was further stirred at 0°C for 30 minutes. Add 15 g of water, wash with ethyl acetate, and add 1.5 g of the aqueous solution. Adjust the pH to 2.0 with ON hydrochloric acid. Extract twice with ethyl acetate/nato-2-hydrofuran (3/1), wash with brine, dry with sodium chloride, and concentrate under reduced pressure. The residue was triturated in ethyl acetate, and the precipitate was filtered and dried to give (6R,78)-7-[2-(2-formyl-aminothiazol-4-yl)-2-syn-(3,4-di acetoxybenzoinooxyimino) acetamidocy 1-
45 μl of azabicyclo[4,2,O)oct-2-ene-8-oxo-2-carboxylic acid are obtained. 40rng of the formyl compound obtained above was mixed with 2g of methanol and 0.15g of concentrated hydrochloric acid.
Stir with the mixture of f and stir at room temperature for 1 hour. The solution is brought to pH 6.0 with aqueous NaHCO3 and concentrated under reduced pressure. Adjust the pH of the residue to 2.0 and add Diamond Ion H.
Purification with P-10 (water to water:methanol=1:8) yields the title compound 19■. The physical property values were in good agreement with those obtained by the method of Example 4.

Example 6 (su,78)-7-'(2-(2-aminothiazol-4-yl)-2-syn-(3,4-diacetoxybenzoyloxyimino)acetamide cy-1-azabicyclo[4,2 ,0]oct-2-ene-8-oxo-2-
Production of carboxylic acid (alternative method): Produced by the following steps 1) to 3).

1) Diphenylmethyl (6R,7S)-7-(:2-(
2-)Ritylaminothiazol-4-yl)-2-syn-hydroxyiminoacetamide]-1-azabicyclo[4,2,0'3oct-2-ene-8-oxo-2-
Preparation of carboxylate: 2-(2-1 lythylaminothiazol-4-yl)-2
-Syn-(1-methoxy-1-methyl)ethoxyiminoacetic acid 6.3f was dissolved in 30g of anhydrous tetrahydrone, cooled to -20°C, 1.7f of triethylamine was added with stirring, and then 2.57f of phosphorus pentachloride was added. Add and react for 30 minutes to prepare an acid chloride solution.

On the other hand, 1.51 of (6R+78)-7-amino-1-azabicyclo[:4,2.0:]]oct-2-ene-8-oxo-2-carboxylic acid was suspended in 50 μl of tetrahydrofuran and 50 μl of water, and the mixture was cooled with water. pH with triethylamine under stirring
Dissolve as 8.0. The previously prepared acid chloride solution is added dropwise to this solution while simultaneously adding triethylamine to maintain the pH between 7.5 and 9.0. 30 minutes after dropping, add salt until saturated, and adjust to pH 2 with IN hydrochloric acid.
The organic layer released was collected and the aqueous layer was extracted twice with a mixed solvent of tetrahydrofuran and ethyl acetate equivalent. The organic layer was collected and washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude acyl compound 10. 3 get f. This crude acyl body 10.3F was directly mixed with 50 g of acetone and 50 g of IN hydrochloric acid.
Add the liquid, dissolve and leave for 40 minutes. The water is drained 50rIL
After adding e and distilling off only acetone under reduced pressure, it was extracted twice with a mixed solvent of tetrahydrone-ethyl acetate equivalent, the organic layer was collected, dried over sodium sulfate, and concentrated to obtain the crude hydroxyiminoacyl compound 7,32F. obtain. This crude hydroxyiminoacyl compound 7.32 f was converted into tetrahydro7ran 5
Dissolve the solution in 50 g of ethyl acetate and add diphenyldiazomethane until the red color of the reaction solution disappears. Thereafter, the reaction solution was evacuated under reduced pressure, and the residue was washed three times with n-hexane, and then subjected to silica gel column chromatography (Wakogel C'-2
001001 Solvent n-hexane-ethyl acetate 3: I
V/V) to obtain 83,711 g of the desired diphenyl methyl ester.

NMR (C'D3C7) δ near, 6-7.0 (25L m), 6.93 (H(,s)
, 6.75 (IHl, s), a+6 (tHxm), 5.
30 (LH, a-41J=5.6Hz) + 3.8'0
(IH, m), 2.4-1.3 (4H, m) 2) diphenylmethyl (6R,7S)-7-(2-(2
-tritylaminothiazol-4-yl)-2-syn-
(3,4-diacetoxybenzoyloxyimino)acetamido-1-azabicycloC4,aO)oct-2
-En-8-oxo-2'-carboxylate: diphenylmethyl (6R,
7s)-7-(z-(1=)rithylaminothiazol-4-yl)-2-syn-hydroxyiminoacetamide]-1-azabicyclo(4,2,O]]oct-2-ene-8-oxo-2carboxy Dissolve 151.8 sg of the acid chloride in anhydrous methylene chloride 3H, add 30μ of triethylamine while stirring under water cooling, add the acid chloride prepared from 57.1 to 9 of 3,4-diacetoxybenzoic acid dissolved in 2P of methylene chloride, React for 1 hour.Then, the reaction solution was washed 3 times with water, dried over sodium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (silica gel 202,
NIA was performed with n-hexane-ethyl acetate (2:1 vyt) to obtain 151 g of the desired benzoyl compound.

NMR (CDOR3) δ: 8.0-7.8 (7H, m)t 7.6-7.0
(26H, m).

6.90 (IH, s), 6.70 (, IH, s), 6.
43 (IH.

m), 5°50 (IL dd, J=9,5Hz), 2
．． 5-1.0 (4H, m), 2.27 (6H, 5) 3)
(6R,7s)-7-(2-(2-aminothiazole-
Preparation of 4-yl)-2-syn-(3,4-diacetoxybenzoylcarbonyloxyimino)acetamido-1-azabicyclo(4,2,0)oct-2-ene-8-oxo-2-carboxylic acid: Diphenylmethyl (6R,
7s,)-7-[-(2-)ditylaminothiazole-
Anhydrous chlorination of 4-yl)-2-syn-(3,4-diacetoxybenzoyloxyimino)acetamido-1-azabicyclo(4,2,0)oct-2-ene-8-oxo-2-carboxylene) 151119 methylene 1 m
Dissolve in 0.1 m of anisole and 1 m of trifluorotetraacetic acid.
Add d and leave at room temperature for 1 hour.

Thereafter, it was concentrated under reduced pressure, ethyl acetate was added to the residue again, and after concentration under reduced pressure, 2 g of 50% acetic acid water was added, and the mixture was heated and stirred at 50° C. for 1 hour. Thereafter, it was concentrated under reduced pressure, the residue was washed with ether, the residue was dissolved in dimethylformamide, and chromatographed on silica gel (silica gel 51. Ethyl acetate:acetic acid 10:1 v7).
After purification with t), the carboxylic acid 4
Obtain 1 mg. Both the NMR and IR spectra of this product matched those obtained in Example 4.

Example 7 (4S, 6R, 7S)-7-('2-(2-aminothiazol-4-yl)-2-syn-(3°4-diacetoxybenzoyloxyimino)acetamido-1-azabicycloC4, 2,0]] Preparation of oct-2-ene-8-oxo-2-carboxylic acid: 2 = (2-,)riflaminothiazol-4-yl)-2-syn=(3,4-diacetoxybenzoyloxyimino)acetic acid 649 my anhydrous tetrahydrone 4
Pentachloride with 151 μl of triethylamine under stirring and cooling at -20'C! Add Jy208m9 and react for 30 minutes to prepare an acid chloride solution. On the other hand (4S,
6 R,7B )-7-amino-1-azabicyclo[
4,2,0) Oct-2-ene-4-hydroxy-8-
Oxo-2-carboxylate 100xy is suspended in 7 grams of tetrahydro and 10 grams of water, and while stirring while cooling with water, triethylamine is added to adjust the pH to 8.0 and dissolve. Then, the acid chloride solution prepared earlier is added dropwise while stirring while cooling with water while simultaneously adding triethylamine to maintain the pH at 7.5 to 9.0. After dropping, react for 30 minutes and pip with IN hydrochloric acid.
Adjust H to 2.0, add ethyl acetate, collect the liberated organic layer, extract the aqueous layer twice with ethyl acetate, collect the organic layer, wash with saturated brine, dry over sodium sulfate, and concentrate under reduced pressure. Ether is added to the residue, the mixture is ground, and the ether layer is removed by decantation to obtain a crude acyl compound. Add 50 d of 50% acetic acid water and 5 d of methanol to this, and heat to 50°C.
After heating and stirring for 1 hour, the mixture was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, and the ethyl acetate layer was extracted again with water. The aqueous layer was collected, washed with ethyl acetate, and concentrated under reduced pressure. The residue was purified with 20 ml of Diaion HP-10, and the ethyl acetate layer was extracted with water. Fractions eluted with methanol were collected to obtain 5 mg of acyl compound a.

NMR (cD3oD) δ: 8.0-7.7(2I(,m), 7.6-7.a(x
H, m), 7.30 (IH, s), 6.27 (LH,
d, J=6Hz), 5.63(, IH, d, J=5H2
), 2.30 (6H, S), 2.2 to 1.5 (2H, m
) Engineering R)”-1 (KBr): ax 3550.3400,3330+ 1780,1760
+1660.1620 Example 8 7-(2-(2-aminothiazol-4-yl)-2-
Syn-(4-diacetoxybenzoyloxyimino)
Preparation of 2-(2-tritylaminothiazol-4-yl)-2
-Syn-(3,4-diacetoxybenzoyloxyimino)acetic acid 70019 was suspended in anhydrous tetrahydrofuran and triethylamine 111 was cooled at -20°C with stirring.
Add 208 μl of phosphorus pentachloride and react for 30 minutes to prepare an acid chloride solution. On the other hand, 7-amino-3-(1
-Methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 185JF was suspended in 7 parts of tetrahydrofuran and 7 parts of water, and the pH was adjusted to 8.0 with triethylamine while stirring under water cooling, and dissolved. Thereafter, the previously prepared acid chloride solution is added dropwise while simultaneously adding triethylamine so as to maintain the pH of the reaction solution at 7.5 to 9.0. After reacting for 30 minutes after dropping, adjust the pH to 2.0 with IN hydrochloric acid, add ethyl acetate, collect the liberated organic layer,
The aqueous layer was further extracted twice with ethyl acetate, the organic layer was collected,
Wash with saturated brine, dry over sodium sulfate, and concentrate under reduced pressure. Ether is added to the residue and pulverized, the ether is removed by decantation, and 7 QmJ of 5096 acetic acid is added to the obtained crude acyl compound, followed by heating and stirring at 50° C. for 30 minutes.

After that, it was concentrated under reduced pressure, and the residue was washed with a mixed solvent of ether and ethyl acetate equivalents, then dissolved in dimethyl sulfoxide, charged to 15- of Diaion Hp-io, and mixed with water to water/
Elution was carried out with a gradient of methanol = 5/1 η to obtain 35 μ of the acyl compound. This acyl body is again Diaion H
Purification is performed using P-10101Le in the same manner as above to obtain the desired acyl compound 19mFl.

NMR (CD30D) δ: 8.0-7.7 (ZH, m), 7.4-7.2 (2H
, m), 5.87 (IHI at J=45Hz),
5.15 (IHI d, J=45H2), 3.9
7 (3H9s) + 2.28 (6Hr e )1
RI>Cl1l-1(KBr): ax 3430.1780, 1750(S)], ), 1650
After adding ether to 19 m9 of the obtained acyl body and pulverizing it, the ether was removed by decantation, and ether was again added to the residue, stirred and washed, and then removed by ether gold decantation. The residue is dried under reduced pressure to obtain purified acyl compound 121#.

NMR (DMSOa, + CD30D,) δ: 8-0
5-7.90 (IL m) * 7.95 (I H,
s) + 7-44 (IH, a, J=s, xHz),
7.17(xH,S)+5.92(LH,a, ,
T,, -5,0Hz), 5.19(IH,d, J=
5.0H2), 4.46 (IHI a, J=13.
4H2) + 4.25 (IHIa, J=13.4H2)
, 3.94 (3H, s), 3.73 (IH.

s), 3.70 (IH, S) 12.31 (3H, El
) + 24.29 (3H, 5) IR'i)"-1' (KBr): ax 3450+ 33501 2950.1780.16
80°16351 1615 Example 9 2-(2-)ditylaminothiazol-4-yl)-2
-Nnn-(3,4-bisdihydroxypyranyloxyphenyl-1-yl)methoxyiminoacetic acid, production of triethylamine salt It is produced by the second steps 1) and 2).

1) Ethyl 2-(2-)ditylaminothiazole-4-
Preparation of ethyl)-2-syn-(3,4-bisdihydroxypyranyloxyphenyl-1-yl)methoxyiminoacetate: Ethyl 2-(2-)ditylaminothiazol-4-yl)-2-syn-hydroxy Dissolve 3.25f of iminoacetate in 20m of hot water dimethylformamide, add anhydrous ether yxo, mt, and add 60q6 of iminoacetate under stirring under water cooling.
3,4-bisdihydropyranyloxypenzyl chloride prepared from 3,4-bisdihydropyranyloxybenzyl alcohol 2-847 prepared according to Reference Example 2 after adding 430 μ of oil-dispersed sodium hydride. Dissolve in dimethyl sulfoxide 101 and add.

After that, it was returned to room temperature, stirred overnight, diluted with ethyl acetate, and diluted with water.
Wash twice with saturated sodium bicarbonate solution, dry over sodium sulfate, and concentrate under reduced pressure. The residual liquid was subjected to silica gel column chromatography (Wako gel C-2'00200f, n-hexane-ethyl acetate-3:IV/V) to obtain substituted oximino compound 1.1.
Get 52.

NMR (CDCff13) δ near, 5-6.8 (18H+, m) r 6.50 (IH,
e), 5.40 (2H1m), 5.17 (2H,s)
,ts7(2H,q.

J=6.6H2), 4.2~3.5(4)(,m),
2. 'z ~1.3 (12H, m), 1.23 (3H
, q, J=6.6H2) 2) Ethyl 2-(2-1-ditylaminothiazol-4-yl)-2-syn-(3,4
-bisdihydroxypyranyloxyphenyl-1-yl)methoxyiminoacetate 1.15F in dioxane 5
Add 2.17 g of an aqueous solution containing IN sodium hydroxide, start stirring and refluxing, add 1 ml after 2 hours, remove after 6 hours, and 1 mA after 8 hours.

After 10 hours, stirring and refluxing were started.After 6 hours, 2d each, an IN sodium hydroxide aqueous solution was added, refluxed for an additional hour, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was cooled with water. While stirring, adjust the pH to 2.0 with IN hydrochloric acid and extract twice with ethyl acetate. After washing the ethyl acetate layer with saturated brine, drying and filtration with sodium simulant, triethylamine l
ml was added to the filtrate and concentrated under reduced pressure to obtain 1.241 of the desired carboxylic acid triethylamine salt. Continue as is and move on to the next example 1
o for acylation.

Example 10 (6R,78)-7-(:2-aminothia□sol-4
-yl)-2-syn-(3,4-dihydroxyphenyl-1-yl)methoxyiminoacetamide]-1-azabicyclo(4,2,01 oc)-2-xno-8-oxo-2-carboxylic acid. Preparation of Sodium Salt 2-(2-)Dithylaminothiazol-4-yl)-2-syn-(3,4-bisdihydroxypyranyloxyphenyl-1-yl) prepared according to Example 9 620,211 g of triethylamine methoxyiminoacetic acid salt was dissolved in 7 ml of anhydrous tetrahydrochloride, cooled to -20°C, and 104 ml of phosphorus pentachloride was added with stirring, followed by reaction for 30 minutes to prepare an acid chloride solution. On the other hand, (6R,78)-7-amino-1
-Azabicyclo(4,2,0':loct-2-ene-
8-one-2-carvone (980 μg) to 10 μg of tetrahydrofuran and 10 μg of water! The mixture is made cloudy, and the pH is adjusted to 8.0 with triethylamine under stirring while cooling with water. To this solution, add the acid chloride solution prepared earlier to pH with triethylamine.
7. Add dropwise at the same time to keep the temperature between 5 and 9.0. After the dropwise addition and reaction for 30 minutes, carboxylic acid triethylamine salt 650111? Then, add the acid chloride solution prepared in the above manner in the same manner and allow to react for an additional 30 minutes. After adjusting the pH to 2.0 with IN hydrochloric acid, ethyl acetate was added to separate the layers, and the aqueous layer was further extracted twice with ethyl acetate.

The organic layer was collected, washed with saturated brine, and then diluted with sulfuric acid). After drying over IJum, it was concentrated under reduced pressure. The residue was ground in ether and the ether was removed by decantation. The obtained powder was diluted with ether.
After washing twice and drying, 50 to 10 parts of acetic acid were added, heated and stirred at 60°C for 1 hour and 30 minutes, and concentrated under reduced pressure. Add 2 rJ of saturated sodium bicarbonate solution to the residue to dissolve it, and wash twice with ethyl acetate. This solution was purified using 15 pages of Diaion HP-10, and the two fractions eluted with 25% methanol water were collected to obtain the desired acyl compound, 23.1 πg.

NMR (D20) δ near, 03 (4H, m), '6.27 (IH, t, J = 3
H2).

5.47 (IHI a, , T=4.5H2), 5.
15 (2H, brs) + 2.5 ~ L 5 (4L, m
) Engineering Rshic″” (KBr): aw 3300.1770 (sh),, 1755.1750 (
sh) Example 11 7-(2-(2-aminothiazol-4-yl)-2-
Preparation of syn-(a,4-diacetoxybenzoyloxyimino)acetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid: 2-(2-)ditylamino-4-thiazolyl)-2-syn-( 3,4-diacetoxybenzoyloxyimino)
145 gg of acetic acid is dissolved in 5 ml of anhydrous tetrahydrofuran, and 3 L of ethylamine (5 μm) and 49.5 μm of phosphorus pentachloride are added to the solution while stirring and cooling at -30°C. Thereafter, the reaction solution is allowed to react for 1 hour while stirring under water cooling to prepare an acid chloride solution.

On the other hand, 7-amino-3-acetoxymethyl-3cephem-
4-carboxylic acid 97.2 = y to tetrahydrofuran 5
The mixture was suspended in 5 d of water and adjusted to pH with triethylamine while stirring under water cooling.
Adjust to 9.0 and dissolve.

The previously prepared acid chloride solution is added dropwise to this amino acid solution, and triethylamine is added at the same time to keep the pH of the reaction solution at 7.5-9.0. After the dropwise addition, the reaction mixture was allowed to react for 30 minutes, the pH was adjusted to 2.0 with 1N maric acid, and the reaction solution was extracted three times with ethyl acetate.

The organic layers were combined, washed twice with saturated brine, dried over hot sodium sulfate, and concentrated under reduced pressure by 6%. 50% acetic acid water 2 to the residue
Add 0'ml of the mixture, heat and stir at 60°C for 1 hour, and then concentrate under reduced pressure. The residue was ground in ether 20g and the ether layer was removed by decantation to obtain a crude acyl compound. The crude acyl compound was dissolved in a small amount of dimethyl sulfoxide, charged to a column of DIAION HP-1012, and eluted with a gradient of water to water-methanol (115 yen/refill) to obtain the acyl compound 271f? .

3350.1780.1750(sh), 1ctso,
1670°1615.154O NMR (DMSOa-6-aD3oD) δ: 8.2-7
．． 8 (2L m)t 7.6-7.2 (IH, m),
7.16(IH,s)t 5.93(IH,dl J=
4.8Hz')+5.19(IH,d, J==4.
8H2), 5.07 (IH, 6, J = 13.2H2)
) + 4.74 (IH, a, J=13.2Hz), 3.
72 (IH.

dl J=20Hz)+3.40(IHI a, J
=2oH2)+2.30(6H,e)t 2.04(3
H,S) Example 12 (48,6R,78)-7-(2-(2-aminothiazol-4-yl)-2-syn-(3,4-diacetoxybenzoyloxyimino)acetamide]-4 -methoxy1-azabicycloC4,a O)oct-2-ene-
8-okine-22-(2-)ditylaminothiazole-
4-yl)-2-cy-(a,4-diacetoxybenzoyloxyimino)acetic acid aomy is dissolved in 4-side anhydrous tetrahydrofuran, and 71 μm of triethylamine is added under cooling to -20°C. Then phosphorus pentachloride 11011
g and stirred for 1 hour under water cooling to obtain an acid chloride solution. On the other hand, it was manufactured according to Reference Example 4 (48.
6R,7s)-7-Aξ-4-methoxy-1-azabicyclo[4,2,0:]]octo-2-ene-8-oxo-2-carboxylic acid 107 Mixture of 6- water and 6-tetrahydrofuran The above acid chloride solution is added dropwise while maintaining the pH of the solution at 7.5 to 8.0 by adding triethylamine while stirring and cooling with water. Thereafter, stirring was performed for 1 hour at the same temperature. Next, under water cooling, the pH was adjusted to 2 with 0.5N hydrochloric acid, and then extraction was performed twice with ethyl acetate.

The organic layer was washed once with saturated brine and then dried with mirabilite. The solvent is distilled off under reduced pressure. Ten volumes of 50% aqueous acetic acid were added to the resulting residue, and the mixture was stirred at 50°C for 45 minutes. Concentrate the reaction solution,
The resulting residue is thoroughly crushed with ether and the solid matter is filtered off. Dissolve this in 14 dimethyl sulfoxide and 20-
Using Diamond Ion HP-10, it is adsorbed onto Nine Kasim,
The 7-lactone containing the target product eluted with water-methanol (2:3) is condensed under reduced pressure to obtain 911 g of crude powder. This product was crushed with a mixture of 2-2 μm of ethyl acetate and 2 μm of ether, and the solid material was removed in an oven to obtain 78 μm of the desired product as a powder. Yield 25.8% NMR (CD30D) δ: 1.4-2.4 (2H1m), 2.31 (6L brs
), 3.33 (3L s), 3.84-4.16 (2
H,Xl), 5.72 (IH.

cl+ J=5.5H2), 6.42 (IHI cl,
J=5.4Hz).

7.29 (IH, s), 7.37-8.05 (3H, m
) 1790 (ah), 1780, 1770.1760 (
sh).

1620-1690 Example 13 2-(2-)Ritylaminothiazol-4-yl)-2
-Production of syn-(3I4-diacetoxybenzoylmethoxyimino)acetic acid: Produced by the following three steps.

13-1) Synthesis of diphenylmethyl 2-(2-tritylaminothiazol-4-yl)-2-syn-(3,4-dihydroxybenzoylmethoxyimino)acetate Nidiphenylmethyl 2-(2-)ditylaminothiazole- 4-yl)-2-syn-hydroxyiminoacetate
) 571 '11g to 5m anhydrous dimethyl sulfoxide
1 and suspend anhydrous potassium carbonate 570119. On the other hand, 37311 g of chloroacetylcatechol was added to 100 g of water.
382 γ g of borax was added to N with stirring, and when the reaction solution became transparent, it was concentrated under reduced pressure to dryness, and further dried over phosphorus pentoxide under reduced pressure to obtain the borate form of clotetraacetylcatechol. Add to suspension.

After stirring the reaction solution at room temperature for 13 hours, it was diluted with ethyl acetate, and I
After washing twice with N hydrochloric acid and five times with saturated brine, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure 6 times. The residue is purified by silica gel column chromatography and n-hexane/ethyl acetate=2/1 (V/'v) to obtain the desired product.

Yield 506 my (68 inches) NMR (CDC13) δ near, 6-6.7 (29) (, m)t 6. zo(xh,
s) + s, t.

(IH2s), 6.27 (IH9s), 5.31 (2H
+ 5) 13-2) diphenylmethyl 2-(2-tritylaminothiazol-4-yl)-2-syn-(3,
Synthesis of 4-diacetoxybenzoylmethoxyimino)acetate Nidiphenylmethyl 2-()ditylaminothiazole-
4-yl)-2-syn-(3,4-dihydroxybenzoylmethoxyimino)acetate 506■ to pyridine 4
Dissolve the solution in the solution and add 0.5 ml of acetic anhydride and leave it overnight. Thereafter, the reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with an aqueous solution of IN hydrochloric acid and saturated brine, dried over anhydrous sulfuric acid, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and n-hexane/ethyl acetate-2/1 (v/v) to obtain the target product 508Hp.

NMR (CDC73) δ: 8.9 ~ 8.6 (2H, m) + 7-5 ~ 7.2
(25H+m).

7.10 (IH, S), 6.23 (IH, s), 5.3
3 (2H.

s), 2.28 (6H, s) Engineering RV'"-" (KBr): 21I] aX 3400.3070, 3040, 2930.1785° 1750.1715.1610 13-3) 2- (2-) Dithyl Aminothiazole-4
Synthesis of -yl)-2-syn-(3,4-diacetoxybenzoylmethoxyimino)acetic acid Nidiphenylmethyl 2
-(,2-)ditylaminothiazol-4-yl)-
2-Syn-(3,4-diacetoxybenzoylmethoxyimino)acetate) 42019 was dissolved in methylene chloride 5- and nitromethane 5-anisole 0.5- and aluminum chloride 334119 was dissolved in nitromethane 3- and added dropwise under stirring while cooling with water. do. After the dropwise addition, the mixture was stirred for 5 minutes, diluted with ethyl acetate, washed twice with IN hydrochloric acid, and further washed three times with saturated brine. The aqueous layers were combined and extracted with ethyl acetate, the ethyl acetate layer was washed three times with saturated salt, and combined with the previous ethyl acetate layer.
(Anhydrous sulfuric acid) After drying with IJum, concentrate under reduced pressure and collect the residue.
- Wash twice with hexane to obtain the target compound. Yield 31
911? (95ch) NMR (CDCj?8) δ: 8.0~7.7 (2L m), 7.5~e, s (
16H, m).

6.72 (IH, s), 5.40 (2H, s), 2.3
0 (6H.

S) Heel Ji can-1 (KBr).

ax 3450.3070, 1780, 1715.1600 Example 14 (6R,7s)-7-[-(2-aminothiazole-4
-yl)-2-syn-(3,4-diacetoxybenzoylmethoxyimino)]]]acetamido1-azabicyclo 4.2t O:]]Production of oct-2-ene-8-oxo-2-carboxylic acid: 2-(2- ) dithylaminothiazol-4-yl)-2
-Syn-(3,4-diacetoxybenzoylmethoxyimino)acetic acid (363 μm) was dissolved in anhydrous tetrahydrofuran (59 μm) and triethylamine (59.4 μm) was added thereto with stirring.
Refrigerate to °C.

Thereafter, 39.4 mg of phosphorus pentachloride F was added and stirred for 30 minutes to prepare an acid chloride solution. On the other hand (6R978)-
7-7 Mi/-1-7 Zahishiku 0 [4,2,0) Oct-
2-ene-8-oxo-2-carboxylic acid 18219 was suspended in 5 d of tetrahydrofuran and 5 d of water, and dissolved at pH 9.0 using triethylamine while stirring under water cooling.

The previously prepared acid chloride solution is added dropwise to this solution, but at this time triethylamine is added until the pH of the reaction solution is 7.4-9.
．． Drop simultaneously to maintain 0. After dropping, the reaction was allowed to proceed for 1 hour, and the pH was adjusted to 2.0 with IN hydrochloric acid, and the reaction solution was diluted with ethyl acetate for 3 hours.
The organic layers were combined and washed twice with IN hydrochloric acid and then three times with saturated saline. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure, and 10 g of 50% acetic acid solution was added to the residue, and the mixture was heated at 60°C.
After heating and stirring for an hour, concentrate under reduced pressure. After washing the residue twice with ether, it was dissolved in dimethyl sulfoxide and added to Diaion HP.
After charging IOl0IIIJ and washing with water, methanol/
Elute with a gradient of water and 5/z (v/v) to obtain the acyl compound 105119.

NMR (DMSOds + CD30D) δ: 8.0~
7.8 (2L m)+ 7.40 (I H+ (
11J” 7.5H2)+6, go(t[,s),
6.3o(xH,m), 6.51(IH.

d, J=5.2Hz)+5.37(2H,S),4.
95-4.65 (I H7m), 2-28 (6H+
g)+2.6~1.2 (4L m)IR>
"-" (KBr): ax 3300.2920,1770,1680,1630°535 Example 15 (6R,'7S) -7-(: 2-(2-aminothiazol-4-yl)-2-syn -(3,4-dihydroxybenzoylmethoxyimino)]]acetamido 1-azabicyclo2,0:l oct-2-ene-8
-Production of oxo-2-carboxylic acid sodium salt: (6R,78)-7-[:2-(2-amatsunothiazol-4-yl)-2-syn-(3+4-diacetoxybenzoylmethoxyimino)]] Acetamide 1-azabicycloC4,2,0)oct-2-ene-8-oxo-
2-carboxylic acid 43289 in 20 ml of water and 2 methanol
0yl, and while cooling with water and stirring, add saturated aqueous sodium hydrogen carbonate solution to adjust the pH to 7.0 and dissolve. Then, add a solution diluted with concentrated ammonia water to pH 10.5.
The reaction temperature was raised to room temperature and stirred for 20 minutes. After that, acetic acid was added to adjust the pH to 7.5, and the residue was concentrated under reduced pressure, and the residue was dissolved in a saturated aqueous sodium bicarbonate solution.
Charge the column chromatograph with IO50m and elute with a gradient of water to water-methanol=1/1 (v/v) to obtain 174 mg of the target compound after concentration under reduced pressure.

NMR (D20) δ near, 61-7.37 (2H, m), 6.98 (IH,
e), 6.85 (IH, a, J=8H2), 6.16
(IH, m), 5.48 (II (, d, J=4.9H2
), 5.38 (2L s), 402-3.82 (IHI
m), 2.3-1.6 (4Ht m) I R9 Tomi a
x (KBr): 3200, x75o (sh), 1745, 1680, 1
66011590, 1535 Example 16 7-[:'2-(2-aminothiazol-4-yl)-
2-syn-(3,4-diacetoxybenzoylmethoxyimino)]]acetamido 3-acetoxymethyl 3-
Production of cephem-4-carboxylic acid: Dissolve 332 μl of 2-()rithylaminothiazol-4-yl)-2-syn-(3,4-diacetoxybenzoylmethoxyimino)acetic acid in 5 μg of anhydrous tetrahydro7ran. Add 69μ of triethylamine to 20"C while stirring while cooling, and then add phosphorus pentachloride 10419 and stir for 20 minutes to prepare an acid J-ride solution.Meanwhile, add 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid. 200 to 9 was suspended in 5 ml of tetrahydrofuran and 5 ml of water, and while stirring while cooling with water, triethylamine was added to adjust the pH to 9.0 and dissolve to obtain an amino acid solution.

The above acid chloride solution is added dropwise to this amino acid solution while stirring while cooling with water. At this time, triethylamine is added at the same time to maintain the pH of the reaction solution at 7.4 to 9.0.

After dropping, react for 30 minutes, adjust the pH to 2.0 with IN hydrochloric acid,
Extracted three times with ethyl acetate, collected the organic layer, and extracted with saturated saline solution three times.
After washing twice, dry with anhydrous sodium sulfate. After filtration, the mixture was condensed under reduced pressure, 50 g of vinegar and 20 g of purified water were added to the residue, heated and stirred at 60° C. for 1 hour, and then concentrated under reduced pressure to obtain a crude acyl compound. After washing the crude acyl body twice with ether, it was dissolved in DM80 and charged onto a column of Diaion HPIOIQm.
Elution with a gradient of 115 (v/y) methanol yields 50 ml of the desired compound.

NMR (pnsoag + CD30D) δ: 8.0~
7.8 (2H, m), 7.44 (IH, cl, J=
8.3H2).

6.84 (IH, s), 5.87 (IH, d, J=4.
9H2).

5.41 (2H, 8), 5.18 (IH, a, J=4.
9Hz).

5.05 (IHI at J=12.9Hz), 4.7
2(LH, (1°J=12.9Hz), 3.'6B(I
H, a, J = 18.3H2).

3.43 (IHld, 'J = 18.3Hz)P
2.31 (6H9s).

2.04 (3H, S) Engineering R Shitomi: deception KBr): 3330.2940.1780.1750 (sh).

1690.1630,1600,1540 Example 17 7-[2-(2-aminothiazol-4-yl)-2-
Syn-(3,4-diacetoxybenzoyloxyimino)]]acetamido-3-1-carboxymethyl-IH
-Production of 2-(2-tritylaminothiazol-4-yl)-2-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid
-Syn-(3,4-diacetoxybenzoyloxyimino)acetic acid (308 µm) was dissolved in 3 d of anhydrous tetrahydrofuran and 611 g of triethylamine was added while cooling at -70°C. Then, 105 µm of phosphorus pentachloride was added and stirred at 0°C for 1 hour. Prepare a dioxylic acid chloride solution.

On the other hand, 7-amino-3-(1-carboxymethyl-IH
-tetrazol-5-ylthiomethy)-3-cephem-
4-carboxylic acid 100 pieces with tetrahydrone run 5 TIL
1 and 5 d of water, and while cooling to 0°C, add triethylamine to adjust the pH to 9.0 and dissolve. The acid chloride solution prepared earlier is added dropwise to this solution, but at this time, the p
Triethylamine is simultaneously added dropwise to maintain H between 7.5 and 9.0. After the dropwise addition, the reaction mixture was allowed to react for 30 minutes, and then IN hydrochloric acid was added to adjust the pH to 2.0, followed by extraction three times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried with sodium sulfate, and concentrated under reduced pressure. 50% acetic acid (20%) was added to the residue, heated and stirred at 60°C for 1 hour, and then concentrated under reduced pressure.

Then, the residue is dissolved in a small amount of dimethyl sulfoxide, purified with a Diaion HPIOIQm column, and eluted with a gradient from water to water-methanol 115 (VJ) to obtain the acyl compound 65119.

NMR (DM80d6+CD30D) δ:s, os
~7. c+t(xu, m), 7. c+6(xH,
B), 7.42-7.32 (IH, m), 7.18 (
LH, s), 5.93 (IH, (11J=4.9Hz)
,5.25(2H,s),s,xc+(xa,d.

J=4.9Jl), 4.55(IH,a, J=13.8
H2) 14.24(IL (1,, T=13.8I(Z
), 3.72 (II(,8).

3.68 (LH, s), 2-32 (3H, s), 2.
30 (3H, 5) IRQ "-" (KBr): ax 3200.1780.1755 (day h), 1700,1
640゜615 Antibacterial activity by Mueller-Hinton agar dilution method (M
The ICμ resistance) is shown in the following table.

Example 18゜1-(2-1-ditylaminothiazol-4-yl)-
Method for producing 2-syn-(1-(3,4-diacetokibenzoyl)ethyl)oxyiminoacetic acid It is produced through the following steps 1) and 2).

1) Production of diphenylmethyl 2-(2-1 lythylaminothiazol-4-yl)-2-syn-[1-(3,4-diacetoxybenzoyl)ethyl]oxyiminoacetic acid Lytylaminodiazol-4-yl)-2-syn-hydroxyiminoacetate
Dissolve 1.25 g in 5 ml of anhydrous dimethyl sulfoxide and add anhydrous sodium carbonate9. Suspend and stir Olg.

On the other hand, 1-bromoethyl-(3,4-dihydroxyphenyl)ketone 13. 10.1 g of borax was added to 500 ml of Ogwo water under stirring with stirring, and when the reaction liquid became clear, it was concentrated to dryness under reduced pressure.

Further, it is dried with phosphorus pentoxide under reduced pressure to obtain a borate form of catechol, which is added to the above suspension. After stirring the reaction solution at room temperature for 2 hours, it was diluted with ethyl acetate and washed with IN hydrochloric acid.
Wash twice with saturated brine, dry the m-layer over anhydrous sodium sulfate, and concentrate under reduced pressure to 1/3 volume. Add 17.8 ml of acetic anhydride and 24.1 ml of triethylamine to the concentrated solution,
After standing for a period of time, the two reaction solutions were added to a saturated aqueous sodium hydrogen carbonate solution.
After washing with IN hydrochloric acid and three times with saturated brine, it is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The IA residue was chromatographed on a silica gel column using cyclohexane/ethyl acetate-3/
1 (V/V) to obtain 20 g of the target compound 7.

NMR (DC13) δ: 8.0-7.7 (21
1,m).

7.5-7.1 <2611. m), 7.08
(ill, s).

6.22-(ill,s), 5.50(II
l, q, J=611z).

2.26 (611,s), 1.50 (311
,s)2)2-(2-tritylaminothiazole-
Diphenylmethyl 2-(2-tritylaminothiazol-4-yl)-2- produced by 4-yl)-2-syn-(1-(3,4-diacetoxybenzoyl)ethyl]oxyiminoacetic acid (■) Shin-(1-(3,
7.20 g of 4-diacetoxybenzoyl)ethyloxyiminoacetic acid was dissolved in 60 ml of anhydrous methylene chloride and 60 ml of nitromethane, and the mixture was cooled with water and stirred with 5.0 g of aluminum chloride.
Dissolve 5 g in 60 ml of nitromethane and add dropwise. After dropping, stir for 5 minutes, dilute with ethyl acetate, and dilute with IN hydrochloric acid.
Wash twice and then with saturated saline. The organic layer is dried over anhydrous sodium sulfate and then concentrated under reduced pressure. 60 ml of n-hexane and 60 ml of ether were added to the residue, stirred, powdered, and collected to obtain 3.77 g of the desired carboxylic acid.

NMR (CDCl2) δ: 8.1-7.7
(211,m).

7.5-7.2 (16H, m), 6.68
(IIl, s).

5.62 (IIl, q, J=6Hz),
2.27 (611,s).

1.57 <3H, d, J=6Hz) Example 19゜(6R,,7S)-7-(2-(2-aminothiazol-4-yl)-2-syn-C1-(3゜4- diacetoxybenzoyl)ethyl]oxyimino)acetamide 1-
-1-Asa Donkuro [4°2.0] Octo-2-En-
Production of 8-oxo-2-carboxylic acid 2-(2-1-ditylaminothiazol-4-yl)-2-syn-[1-(3,4-diacetoxybenzoyl)ethyl] synthesized in Example 18 ogishiminoacetic acid 3.7
Dissolve 7 g in 30 ml of anhydrous tetrahydrofuran, add 0.7 ml of triethylamine under water cooling, add 1.1.6 g of phosphorus pentachloride with stirring, and stir for an additional 30 minutes to prepare an acid chloride solution.

On the other hand, (6R,7S)-7-amino-1-azabicyclo(
4,2,0) Oct-2-ene-8-oxo-2-carboxylic acid2. Suspend OOg in 20 ml of tetrahydrofuran and 20 ml of water, and adjust the pH to 9.0 using triethylamine while stirring while cooling with water. The acid chloride solution prepared previously is added dropwise to this solution. At this time, I-ethylamine is added at the same time so that the pH of the reaction solution is maintained at 7.4 to 9.0. After dropping, react for 1 hour and adjust to pH 2.0 with IN hydrochloric acid.
The reaction solution was extracted three times with ethyl acetate, the organic layers were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Then add 100 ml of acetic acid to the residue and 3 ml of methanol.
0ml and 100ml of water were added, heated and stirred at 50°C for 1 hour, and then concentrated under reduced pressure.

The residue was washed twice with ether to obtain a crude acyl compound.

The crude acyl compound was dissolved in dimethyl sulfoxide and charged onto a Diaion HP-1020 (lmlO column).
Fractions eluted with water-methanol 1/3 (V/V) were collected to obtain 570 mg of the target compound.

NMR (DMSOd-s +CO300) δ:8
．． 2-7.7 (2t1.m), 7.4
(IH, d, J=8.111z), 6
．． 80 (IQ, s), 6.33 (IIl,
m).

6.7-6.4 (2H, m), 2.30
(6H,s).

1.5 (1 (311d, J = 6Hz) IR,>,'','(cm-'): 3350.2950.
1780.1690゜645 Example 20゜2-(2-)rithylaminothiazol-4-yl)-2
-Shin-(1-(3,4-Shea I Kishihen Soil)
-1-Methylethyl] Oxyiminoacetic acid is produced through the following steps 1), 2), and 3).

1) Synthesis of diphenylmethyl 2-(2-tritylaminothiazol-4-yl)-2-syn-(1-(3,4-di-doxyhensoyl)-1-medyl-edyl)oxyiminoacetate 2,-, 3.42 g (6.0 mmole) of diphenylmethyl (1-tritylaminothiazol-4-yl)-2-synhydroxyiminoacetate is dissolved in 12 ml of anhydrous dimethyl sulfoxide, and 2.ssg of anhydrous potassium carbonate is suspended. on the other hand.

1-Bromo-1-methylethyl 3,4-dihydroxyphenylketone (J, Med, Chem, 7°17
8 (1964)) was suspended in 10 ml of water and 1.56 g of porcelain sand was added with stirring. When the reaction solution becomes a homogeneous solution, it is condensed under reduced pressure and toluene is added several times and evaporated to dryness to obtain the corresponding borate. This was added to the above suspension, stirred at room temperature for 16 hours, diluted with 100 ml of ethyl acetate, washed twice with ON hydrochloric acid, and then washed three times with saturated saline. After drying the organic layer with Glauber's salt, it was concentrated under reduced pressure to obtain a residue of 4.7
g to silica gel chroma I-(silica/,,'/l/1
60 g, developing solution hexane/ethyl acetate = 4/1 = 1.
2ρ, s/1=1.2i, 2/1=1.57!
/fraction-17-18ml). Fractions 106 to 17o are combined and concentrated under reduced pressure to obtain 1.8 g (yield: 40%) of the above-mentioned target compound.

IR9”r-beast (cm'): 1759.1
750.1740-1600. 1540.70O NMR (CDCl2) δ: 6.18 (I
II, S ), 1.40 (611, s ) 2) 2-(2-)ditylaminothiazol-4-yl)-2-syn-(1-(3,4-diacetoxybenzoyl)-1-methyl Synthesis of diphenylmethyl ethyldioxyiminoacetate 2-(2-tritylaminothiazol-4-yl)-2-syn-[1-(3,4-
5 ml of pyridine of diphenylmethyl 1-methylethyldioxyiminoacetate (903)
Add 1 ml of acetic anhydride and stir at room temperature for 6 hours.

Add 50 ml of ethyl acetate and wash with 1.0 N HCA and saturated saline. After drying Glauber's salt, concentrate under reduced pressure to obtain a residue of 1.1
get g. Tridylation with hexane-ether affords the desired compound 970.mu. (yield 96%).

IRQ”:=c, y, (cm-’): 1
784, 1780-1758゜1750, 1695.1
54O NMR (CDCl2) δ: 7.9 (21+
, m), 7.0(,IH,d, J=7.51
1z), 6.40 (1)1. s).

2.26 (3H,s), 2.20 (3H,s
), 1.48(611,s) 3)l-(2-)ditylaminothiazol-4-yl)
Synthesis of -2-syn-(1-(3,4-diacetoxybenzoyl)-1-methylethyl]oxyiminoacetic acid 2-(2-tritylaminothiazol-4-yl)-2-syn- (1-(3,4-diacetoxybenzoyl)-1-methylethyldioxyiminoacetate 950 μm of diphenylmethyl acetate was dissolved in 6 ml of methylene chloride, 6 ml of nitromethane, and 0.5 ml of anisole. While cooling with water and stirring, 451 μm of aluminum chloride was dissolved in 4. ml of nitromethane. Dissolve and add dropwise. After dropping, stir for 5 minutes and add ethyl acetate.
Add 0m1 and INHC7! .

Wash with saturated saline. After drying the Glauber's salt, concentrate under reduced pressure to obtain a residue of 1
．． Obtain 02 g. Tritylation was performed with 10 ml of hexane to obtain the desired compound 785 (yield: 100%).

rR>:, p; (cm-'): 1782.177
5.1515°1205,70O NMR (CDC13) δ: 8.1 (21L m
), 6.22(IH,s), 2.23(3
H,s), 2.13 (3H,S)1.21 (
6t1. s) Example 21 (6R,7S)-'l-(2-(2-aminothiazol-4-yl)-2-syn-(1-(3゜4-diacetoxybenzoyl)-1-methylethyl) oximinoacetamide)-1-azabicyclo (4,2,0) Oct-2-ene-8-oxo-2-carboxylic acid triethylamine salt 2-(2-trideraminothiazole-4- yl)-2-syn-(1-(3,4-cyacetoxybenzoyl)-1-methylethyl]oxyiminoacetic acid (0.59 g) in 4 ml of anhydrous tetrahydrofuran.
To this, 239 μl of triethylamine was added while stirring under water cooling, and 198 μβ of phosphorus oxychloride was added thereto. Water cooling 3
The mixture was stirred at room temperature for 30 minutes to prepare an acid chloride THF solution.

(6R,7S)-7-amino-1-azabicyclo(4,
2,0) Dissolve 80 mg of oct-2-ene-8-oxo-2-carboxylic acid in 2 ml of water and 2 ml of THF, add triethylamine under water cooling, and adjust H to 7.5. This was cooled with water and adjusted to pH 7.0 to 7.5 with triethylamine.
Add the acid chloride solution dropwise while maintaining the temperature. 4 at 0℃
After stirring for 0 minutes, add LNHCI to adjust the pH to 2. After saturation with common salt, the mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain 620 ml of crude acyl compound.

Dissolve this crude acyl compound in 3 ml of methanol/water (10/1), adjust the pH to 1.5 with ], 0 NH (1!), and dissolve at 50°C.
Stir for 30 minutes. pH 7.0 with triethylamine
After that, concentrate under reduced pressure. After tritylation with ether, purification with Diaion HP-10.

HP 1060cc Water 60ml Water/Methanol-2/ 160ml; 1/16
0m11/260m1; 1/360m1; 11
560 inl fraction 7-8 ml Fractions 42 to 48 were combined and concentrated under reduced pressure to obtain the desired compound 108 (yield 34%).

IR＞E";;(cm-'): 1792.17
85.1780.1690°1518, 1205.7
0O NMI? (CD300) δ: 8.06 (21
1, m > , 7.30 (III.

d, J=811z), 6.77(IH,s),
6.07(]H,m).

5.48 (III, d, J=4.5Hz)
, 3.9 (IIl, m).

3.17 (611,q, J=7.5Hz)
, 2.28 (6)1. s).

1.67 (311, s), 1.63 (311,
s), 1.28 (911°t, J = 7.5H
z) Example 22゜(6R,7R)-7-(2-(2-aminothiazole-
4-yl)-2-syn-(1-(3゜4-diacetoxybenzoyl)-1-methylethyl]oxyiminoacetamide)-3-(1-carpocyzmedyl-5-tetrazolyl)thiomethyl-△3- Preparation of cephemu-4-carboxylic acid l-(2-tritylaminethiazol-4-yl)-2-syn-(1-(3,
1 g of 4-diacetoxybenzoyl)-1-methylethyl oxyimino vinegar was added to 10 ml of anhydrous tetrahydrofuran.
Add 202μl of triethylamine dissolved in and stir -1
Cool to 5°C. Thereafter, 335 μp of phosphorus oxychloride was added and stirred for 60 minutes to prepare an acid chloride solution.

On the other hand, (6R,7R)-7-amino-3-(1-carboxymethyl-5-tetrazolyl)thiomethyl-△3
- 538 ml of cephemu-4-carphonic acid was suspended in 20 ml of tetrahydrofuran and 20 ml of water, and dissolved at pH 7.7 using triethylamine under stirring under water cooling.

The acid chloride solution prepared earlier is added dropwise to this solution, but at this time triethylamine is added until the pH of the reaction solution is 7,
Add dropwise to maintain the temperature between 0 and 8.5. After the dropwise addition, the reaction mixture was allowed to react for 1 hour, and the pH was adjusted to 2.5 with INm acid, and the reaction solution was extracted three times with ethyl acetate, and the organic layers were combined and washed three times with saturated brine. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, 80 ml of methanol/water (10/1) was added to the residue, and the pH was adjusted with IN hydrochloric acid.
After heating and stirring at 50°C for 1 hour, the mixture was adjusted to pH 7.0 with triethylamine and concentrated under reduced pressure. 1 water to the residue
'Add 2 ml of Oml dimethyl sulfoxide, Il salt,
Adjust to pif 2.0 with acid and concentrate under reduced pressure. Dissolve the residue in dimethyl sulfoxide and add Diaion HP-1050.
After charging to 0ml and washing with water, reduce the methanol/water ratio to 1.
Elute by varying the volume from 115 to 2/1,
The above compound 382■ is obtained.

NMR (DMSOd-6, CD300) δ; 8.
2-8.0 (2H, m) 7.30 (IH, d,
J=8. '7Hz), 6.8 (Ill, s
).

5.83 (IH, d, J = 5.2Hz),
5.22 (211,s).

5.16 (Il, d, J=5.211z),
3.35~4.80 (411, m) 2.27 (6
11,s), 1.60 (611,s)xR
)'''(cm-'): 3400.1775.1
675.525 to 1620゜hα Example 23゜(6'R,7R)-7-(1-(2-aminothiazol-4-yl)-2-syn-(1(3゜4-diacetoxybenzoyl) -1-methylethyl]oxyiminoacetamide) -1-(]-pyridiniummethyl)-3-cephem-4-carboxylate 2-(2-tritylaminothiazol-4-yl synthesized according to the method of Example 20) )-2-syn(1-(3,4
-Diacetoxybenzoyl)=1-methylethyl]oxyiminoacetic acid (2.44 g) was dissolved in 35 ml of anhydrous methylene chloride and cooled to -20°C with stirring. Phosphorus pentachloride 1.77
g and stirred at the same temperature for 50 minutes. To the resulting solution, 105 ml of diisopropyl ether was added and stirred for 40 minutes under water cooling. The deposited precipitate was collected by filtration.

On the other hand, N,N- containing 2.52ml of triethylamine
Dimethylacetamide 18ml/acetonitrile 1Bm
(6R,7R)-7-amino-3 in a mixture of l
A stirred suspension of 11.32' g of -(1-pyridinium methyl) 3-cephem-4-carboxylic acid digroup i was cooled to -10°C. A solution of the precipitate obtained above dissolved in 35 ml of anhydrous methylene chloride is added dropwise to this cold suspension over 10 minutes. The mixture was heated at -10°C for 30 minutes and then at room temperature for 40 minutes.
Stirred for 0 minutes. After adding 1 ml of methanol to the reaction solution, it was concentrated under reduced pressure, and the resulting N,N-dimethylacetamide solution was added dropwise to 180 ml of water with stirring.

After stirring for 1 hour under water cooling, the precipitate was collected by filtration, and 30% of chloroform was added.
Dissolve in 0ml. Wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure.

Add 50 ml of 50% aqueous acetic acid (V/V) to the resulting residue and stir at 50°C for 1 hour. The precipitated insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. Dissolve the residue in dimethyl sulfoxide, charge it to 500 ml of Diaion HP-10, add 1000 ml of water, water/methanol-4/
110100O, water/methanol-2/1900m
1. Elute in the following order: water/methanol-1/12,500ml; water/methanol-1/22,000ml.

Both fractions containing the target compound were concentrated under reduced pressure to obtain 630 mg of the title compound.
(yield 24%).

IR) ”:Q2;,, (cm-'): 340
0.1780.1680.1630°1540, 121
O NMR (DMSOd-6, CD300) δ (ppm
): 9.5-9.0 (211, m), 8.4
~8.7 (IIl, m).

8.3~7.8 (4t1.m), 7.4~
7.2 (111,,m).

6.75 (0,411,s), 6.67 (0
, 611, s), 5.79 (IH, d, J-4
,911z), 5.7~5.2 (21L m
).

5.15 (11(,d, J-4,911z),
3.0-3.8 (21!, m).

2.29 (6H, s), 1.58 (2,41+,
s), 1.54 (3,6t's) Example 24゜(6R,rx)-r,-(2-(2-aminothiazol-4-yl)-2-syn-[1-(3, 4-diacetoxybenzoyl)-1-methylethyl]oxyiminoacetamide)-3-acetoxymethyl-3-cephem-4
-Production of carboxylic acid: 2-(2-tritylaminothiazol-4-yl)-2-syn-(1-(3,
1.732 of 4-diacetoxybenzoyl)-1-methylethyl]oximinoacetic acid was dissolved in 2 of anhydrous tetrahydrofuran.
5- and cooled to -10°C with stirring. After adding 0.35 μm of triethylamine, 521 μm of phosphorus pentachloride was added and stirred at the same temperature for 30 minutes to prepare an acid chloride solution.

On the other hand, 7-amitusephalosboranic acid 730μ (purity 9
2.9%) with 25 m of water and 25 m of tetrahydrofuran.
1 and adjust the pH to 9.5 with triethylamine.

The acid chloride solution obtained above is added dropwise to the resulting solution over 20 minutes. The pH at the time of dropping is adjusted to 8 to 8.5 using triethylamine. After stirring for 40 minutes under water cooling, the pH of the reaction solution was adjusted to 2.5 with 6N hydrochloric acid and extracted twice with ethyl acetate. After washing three times with saturated brine, dry the sodium sulfate and concentrate under reduced pressure. 20 ml of acetic acid was added to the resulting residue to dissolve it, and then the mixture was heated to 55°C. Add 20 minutes of water over 10 minutes and stir for another 30 minutes at the same temperature. The precipitated insoluble matter is separated by e and concentrated under reduced pressure. After adding water to the resulting residue, it is extracted twice with ethyl acetate. After washing twice with saturated saline, dry the sodium sulfate and concentrate under reduced pressure. Dissolve the residue in dimethic acid sulfoxide, charge it to Diaion HP-10150-, and add 300 ml of water.
Water/methanol=172 aood, water/methanol=
Elute in the order of 1/660 (lay/), collect fractions containing the target product, distill off methanol under reduced pressure, and extract the resulting aqueous solution twice with ethyl acetate.

After drying the mirabilite, the sardine was concentrated under reduced pressure to obtain 790q of the title compound (yield: 45
%).

NMR (CDC7s-CDsOD) δ: 1.67 (6
H,s).

2.07(3H,B), 2.23(3I(,8)',
2.25(3I(.

S), 3.36, 3.66 (2H, AE (1, J=19
H2).

4.89.5.13 (2H, ABq, J=14Hz
), 5.12 (IH, d, J=5Hz), 5.
93 (IH, d, J = 5Hz), 6.67 (IH
, S), 7.2'2 (IH, d, J=9Hz),
7.9-8.1(2H,m)rR)):',X(xBr
, ) : 3300.1780.1695°1685(
Sh), 1630.1540 Example 25゜(6R,7R)-7-(2-(2-aminothiazole-
Preparation of 4-yl)-2-syn-[-(a,4-dihydroxybenzoyl)-1-methylethyl]oxyiminoacetamide)-3-acetoxymethyl-3-cephem-4-carboxylic acid sodium salt: Example (6R,7R)-7- synthesized according to the method of 24
[:2-(2-aminothiazol-4-yl)-2-syn-[-(a,4-diacetoxybenzoyl)-1-methylethyl]oxyiminoacetamide]-3-acetoxymethyl-3-cephem -4-carboxylic acid 14.08
After adding 550 d of methanol to F and cooling the resulting solution on ice, 0.79 ml of concentrated aqueous ammonia (28%) is added.

After stirring at the same temperature for 1.5 hours, concentrated hydrochloric acid was added to adjust the pH to about 7. The reaction solution was condensed under reduced pressure, and aqueous sodium bicarbonate was added to the resulting residue to dissolve it, and then the mixture was charged into a Diaion HP-101t. Elute in the order of 2 t of water, 5 t of water/methanol - 9/1 3 t, and 372 t of water/methanol, and concentrate both fractions containing the target product under reduced pressure to obtain the title compound 9.101 (
Yield: 71%).

NMR (D20) δ: 1.62 (6H, s), 2.
07 (3H.

s), 3.31, 3.62 (2H, ABq, J=17H
z).

4.68.4.89 (2H, ABq, J = 12H
z), 5.17 (IH, cl, J=5Hz), 5.
82 (IH, d, J=5H2), 6.82 (IH, E+
), 6.87 (IH, d, J=9Hz), 7. '5
~7.8 (2H,m)IR)):',X(KBr)
: 3300.1780.1670゜1600.153
0 Example 26゜(6R,7R)-7-(2-(2-aminothiazole-
4-yl)-2-syn-(1-(3,4-dihydroxybenzoyl)-1-methylethyl]oxyiminoacetamide'J-3-(4-sulfoethylpyridinium)-
Preparation of methyl-3-cephem-4-carboxylate sodium salt (6R,7R)-7- Synthesized according to the method of Example 25
[,,2-(2-aminothiazol-4-yl)-2-
Syn-[1-3,4-dihydroxybenzoyl)-1-
After adding 2.5 d of water to 321 kg of methyl ethyl (oxyiminoacetamide)-3-acetoxymethyl-3-cephem-4-carboxylic acid sodium salt and 187 ~ of 2-(4-pyridyl)ethanesulfonic acid, bicarbonate was added. Gradually add 84q of sodium hydrogen. 2. Add sodium iodide to the resulting solution. Add Of and stir at 75°C for 2.5 hours. After cooling to room temperature, charge to Diamond Ion HP-1050g/. Water 200g, water/methanol-971z
Elute in the following order: ov, water/methanol = 6/1 1ooy, and water/methanol = 3/1100, and both fractions containing the target product are concentrated under reduced pressure to obtain 90ff of a crude product. After dissolving this substance in water, charge it again to HP-1010d and add 4 liters of water.
Elute in the order of 0-1 water/methanol=5/140m, and concentrate the fraction containing the target product under reduced pressure to obtain the title compound 44 (yield: 12%).

NMR (D20) δ: 1.54 (3H,s),
1.60 (3H.

s), 3.24 (4H, s), 3.0-3.7 (2H,
m).

5.22 (IH, d, J=5Hz), s, o
~5.7 (2I (, Shizuku m), 5.84 (IH, d,
J=5Hz), "6.77 (IH.

s), 6.6-6.8 (IH', m), 7.
4-7.8 (2H, m).

7.9 (2H, d), 8.7 (2H, d) IRQ''''
(KBr): 3400,1780,1670°ax 1610.1540 Example 27°(6R,7R)-7-(2-(2-7minothiazol-4-yl)-2-syn-[1-(3,4 -dihydroxybenzoyl)-1-methylethyl]oxyiminoacetamide') -3-(: (1゜2,5.6-tet2hydro-2-methyl-5,6-thioxo as di)riazin-3-yl )-thiomethyl-3-cephem-4-carbo/acid disodium salt production: 2-(2-tritylaminothiazol-4-yl)-2
-Syn-[1-(3,4-diacetoxybenzoyl)-
1-Methylethyl]oxyiminoacetic acid 4.91 ? (
7.10 mmole) was dissolved in anhydrous tetrahydrofuran 76%, and 1.671 mmole of phosphorus pentachloride was dissolved under ice-acetone cooling.
(8.02 mmole) and stir for 30 minutes. Add 1.12 m/(8,03 mm) of triethylamine to this solution.
ole) and stirred at 0°C for 20 minutes to obtain an acid chloride solution.

On the other hand, (6B, 7R) ~7-amino-3・-[(1゜2
, 5,6-tetrahydro-2-methyl-5,6-thioxoaS-)riazin-3-yl)-thiomethylcou3
-cephem-4-carboxylic acid 2.67f (7,19m
mole) was suspended in 761 L of water, and a 1N aqueous sodium hydroxide solution was added to adjust the pH to 7.5 to make a solution. To this, 29% of tetrahydrofuran is added, and the above acid chloride solution is added dropwise over about 15 minutes while stirring while cooling with water. During this time, adjust the pH to 6.5~ with 1N sodium hydroxide aqueous solution.
Keep it at 8.0. After dropping, the mixture was stirred for 1.5 hours while cooling with water. Add 2N hydrochloric acid to the reaction solution to adjust the pH to 1.5. water 20
After adding 0d and further sodium chloride, the mixture is extracted five times with ethyl acetate. After washing the ethyl acetate layer with saturated saline,
Dry with sodium sulfate and concentrate under reduced pressure to give a yellow solid 6.20
get f. Add this to a 1:3 solution of water and methanol at 240 ml.
Suspend in TILl and adjust the pH to 1.0 by adding 6N hydrochloric acid. After stirring at room temperature for 4.5 hours, 1N sodium hydroxide solution was added to the yellow reaction mixture to adjust the pH to 7.5, and the mixture was concentrated under reduced pressure to remove methanol. Adjust the pH'H to 7.5 again and wash twice with ethyl ether. Add a small amount of n-butanol to the aqueous layer and concentrate under reduced pressure to about 80%. Add this red solution to Diaion HP-10 (Mitsubishi Kasei) 450+d
Refine with. After washing with 1.6 tons of water, water: methanol 10
:1 to 8:1 were combined and concentrated under reduced pressure to obtain the desired product as a yellowish white solid, 1.32? (1,73 mmol
e).

NMR (D20) δ: 7. ．． 8-7.5 (2H, m)
, 6.87 (LH.

s), 6.9-6.7 (IH, m), 5.78 (
IH, d, J=4.5H2), 5.17 (IH,
d, J=4.5Hz), 4.33(IH, d, J
= 13.2'Hz), 4.03 (IH, d, J = 13.
2H2), 3.8-3.4 (2H, m), 3.57
(LH,s).

1.62 (6H, 5) IR)) Meng x (KBr) :'ai! oo, 1785
(s), 177s.

1670.1600.1550 Example 28゜7-42-(2-aminothiazol-4-yl)-2-
Syn-(1-(3,4-dihydroxybenzoyl)-1
-methylethyl]oxyiminoacetamide]-3-(
s-carboxymethyl-4-methyl-thiazole-2-
Production of thiomethyl-3-cephem-4-carboxylic acid disodium salt: Box 2-(2-1 lytylaminothiazol-4-yl)-2
-Syn-(1-(3,4-diacetoxybenzoyl)-
7.463 F of 1-methylethyl]oxyiminoacetic acid is dissolved in 80 of anhydrous tetrahydrofuran, 2.02 of triethylamine is added thereto, and the mixture is cooled to -15 DEG C. with stirring. Add 1.56% of phosphorus oxychloride to this and stir for 1 hour to prepare an acid chloride solution.

On the other hand, 4.336 F of 7-amino-3-(5-carboxymethyl-4-methylthiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid was suspended in 170 d of tetrahydro7ran and 140 d of water, and cooled in water. Dissolve to pH 8 using triethylamine under stirring. The acid chloride solution prepared previously is added dropwise to this solution. At this time, triethylamine is simultaneously added dropwise so that the pH of the reaction solution is maintained at 7.5 to 8.5. After completion of the dropwise addition, the mixture was stirred for 30 minutes under water cooling, and the pH was adjusted to 7 with 1N hydrochloric acid. Tetrahydrofuran was distilled off under reduced pressure, and the remaining aqueous solution was adjusted to pH 2.5 with 1N hydrochloric acid.

The precipitate generated here was collected with P, washed with water, and then treated with 200 d of methanol.
Suspend in 20 dlc of water. pH1.4 with 1N hydrochloric acid
After stirring at 45-50° for 40 minutes, adjust the pH to 7.0 with triethylamine and concentrate under reduced pressure to about 80 ml.

The resulting precipitate is washed with P and water, and 30 d of dimethyl sulfoxide is added to the combined solution f and the washing solution, and the mixture is concentrated under reduced pressure to a concentration of about 60 ml. Concentrated hydrochloric acid was added to this solution to adjust the pH to 2, and the solution was subjected to chromatography using Diaion HP-10 (Mitsubishi Kasei) 14.

After washing with water, it was developed in a water-methanol system by increasing the methanol content sequentially, and water: methanol = 1 = 6.
Concentrate both fractions eluted with methanol to give 3.079
A yellowish white solid is obtained.

This was dissolved in 120-methanol and stirred with water cooling for 2.
Add 1.0-8% ammonia water.

After stirring for several hours, add 304 ml of water and adjust the pH to 6 with 1N hydrochloric acid.
Then methanol is distilled off under reduced pressure. The remaining aqueous solution was adjusted to pH 9.0 with 1N sodium hydroxide, and the Diamond Ion HP
-10 (Mitsubishi Kasei) 250- chromatography. After washing with water, developing with water-methanol-3:1,
The eluted fractions are concentrated to give 1.50 r of the title compound as the disodium salt.

NMR' (D20) δ: 7.7-6.9 (3H, m)
, 6.85(IIF(,e), ,5.82(x
H, a, J=5Hz), 5. x6(ILcl,σ
=5)(Z), 4.35, 3.85C2H.

ABq, J = 13Hz), a, a 9.3.3
3 (2H, ABq.

J=17Hz), &62(2H,' s), 2.26(
3H.

s), 1.63 (6H, s) I R9m,, (KBr)' 3430.1790
．． 1785.

1770.1670, 1590.1540 Example 29゜7-(2-(2-aminothiazol-4-yl)-2-
Syn-(1-(3,4-diacetoxybenzoyl)-1
-Methyl-ethoxyimino])acetamido-3-(neesulfomethyltetrazol-5-yl)thiomethyl-
Preparation of 3-cephem-4-carboxylic acid: Ac 2-(2-)ditylaminothiazol-4-yl)-2
-Syn-(1-(a,4-diacetoxybenzoyl)-
Dissolve 5.01 ml of 1-methyl-ethoxyimino]acetic acid in 50 d of anhydrous tetrahydrofuran, cool with stirring in an ice-salt bath, add 1.5 d of triethylamine and 2.279 d of phosphorus pentachloride, and stir for 30 minutes to prepare an acid chloride solution. do. Thereafter, 50% of tetrahydrofuran was added to an aqueous solution of 50% containing 2.041% of 7-amino-3-(1-sulfomethylnato2zol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, and the mixture was stirred under water cooling. An acid chloride solution of p
Add dropwise while simultaneously adding triethylamine to maintain H7.5 to B.5. After stirring for 30 minutes after the dropwise addition, the pH was adjusted to 1.5 with IN hydrochloric acid, and the reaction solution was extracted three times with ethyl acetate.

The organic layers were combined, washed twice with saturated brine, dehydrated with sodium sulfate, filtered through a sieve, and concentrated under reduced pressure. After adding 50 g of ethyl ether to the residue and pulverizing it, the supernatant was removed by decantation. After repeating this operation 5 times, drying under reduced pressure and adding 5% acetic acid to the residue.
04 and water 50M1. Add 20 liters of methanol and heat to 50°C.
After heating and stirring for 30 minutes, the mixture was concentrated under reduced pressure. Add 50 d of ethyl ether to the residue, triturate it, remove the supernatant by decantation, dissolve in 10w11 dimethyl sulfoxide,
Diaion) (P-10300mJO column was charged and eluted with water-water/methanol-1/2 gradient end to obtain 920 ml of acyl compound.

NMR (DMSOa-6+ CD30D) δ: 8.2~
7.9(2Lm), 7.30(1)(,a,,T=9H
2), a93 (1a, S).

6.87 (IH, a, J = 5.II (Z), 5.22 (
2H,s).

5.17 (IH, d, J = 5.IHz), 3.77 (2
H, m).

Z29 (6H, s), 1.67 (3H, s), 1.64
(3H,5)IR):x(KBr): 3320.
1785.1700°1650.1640 Example 7-(2-(2-aminothiazol-4-yl)-2-
Syn-[1-(3,4-dihydroxybenzoyl)-1
-methyl-ethoxyimino])acetamido-3-(1
-Sulfomethyltetrazol-5-yl)thiomethyl-
Preparation of 3-cephem-4-carboxylic acid sodium salt nia-(2-(2-aminothiazol-4-yl)-2-syn-1:1-(3,4-diacetoxybenzoyl)-1
-methyl-ethoxyimino])acetamido-3-(1
-Sulfomethyltetrazol-5-yl)thiomethyl-
840 g of 3-cephem-4-carboxylic acid are stirred in 30 g of water, and sodium hydrogen carbonate is added to adjust the pH to 7.6 with stirring. Stir for 3 hours while adding sodium hydrogen carbonate to adjust the pH to 7.5 or higher. After that, Diamond ion 30
After charging to 0d and washing with 300d of water, add 500d.
After washing with 9% methanol water (d), the fractions eluted with 16.7% methanol water are collected and concentrated under reduced pressure to obtain deacetoxy compound 327 Misaki.

NMR (D20) a 2 7.7-7.4 (2H,
m), 6.87 (IH.

(1, J=9Hz), 6.83 (IL 8), 5.80
(IH, (1°J=5.4Hz), 5.53 (2H, 8
), 5.13 (IH, (1°J=5.4H2), 4.4
3 (IH, 6, J=15Hz), 4.13 (IH, cl
, J=15Hz), 3.73(IH,d,,T,~16
．． 5H2), 3.40 (IL cl, J=16.5H2
), 1.63 (6H,s) I R9;2,-,' (KBr)23500.
1790 (sh), 1775°1770 (E3h
), 16B5, 1600.1540 Reference Example 1゜(6R178)-7-(2-(2-aminothiazole-
4-yl)-2-syn-benzyloxyiminoacetamide]=1-azabicyclo(4,2,0)oct-2
Preparation of -ene-8-oxo-2-carboxylic acid: 2-(2-)rithylaminothiazol-4-yl)-2
- Suspend 490 μt of syn-benzoyloxyiminoacetic acid in anhydrous methylene chloride, cool at 30° C., add 126 μt of triethylamine and 191 μt of phosphorous pentachloride with stirring,
Let it return to room temperature for 30 minutes. Thereafter, it is concentrated under reduced pressure, and the residue is dissolved in 1 ONl of tetrahydrone run to prepare an acid chloride solution. On the other hand, 170 μl of (6R178,)-7-amino-1-azabicyclo(4,2,0)oct-2-ene-8-oxo-2-carboxylic acid was suspended in 15 m of tetrahydrofuran and 15 d of water, and triethylamine was stirred under water cooling. Dissolve the acid chloride solution prepared earlier and adjust the pH of the reaction solution to 7.5 with triethylamine.
．． Drop while adding at the same time to keep the temperature between 5 and 8.5.

After dropping, adjust the pH to 2.0 with IN hydrochloric acid for 30 minutes, add ethyl acetate to separate the layers, extract the aqueous layer twice with ethyl acetate, combine the organic layers, wash twice with saturated brine, dry over sodium sulfate, and concentrate under reduced pressure. do. Add 50ml of 50X acetic acid to the residue, heat and stir at 60°C for 1 hour, concentrate under reduced pressure, add 20g of ethyl acetate and stir for 30 minutes, then remove the solvent by decantation and dry. The obtained powder was dissolved in dimethyl sulfoxide, charged to 10- of Diaion H'P-1O, and eluted with a gradient from water to 80% methanol/water to obtain acyl compound 193.

NMR (CD, OD) δ: 8.2 to 7.8 (2
H, m), 7.7-7.3 (3H, m), 7.20 (
IH, S), 6.46 (IH, m).

5.67 (IH, d, J=5Hz), 4.1-3.75
(IH, m).

2.4~1.3 (4H, m) IR So:X (KBr) + 3300.1760.16
80°1660.1630.1540 Reference example 2 3.4-bisdihydropyranyloxybenzyl following 1)
, 2).

1) Production of 3.4-bisdihydropyranyloxybenzyl alcohol: 3.4-dihydroxybenzoic acid7. or 1 ethanol
Process a catalytic amount of p-toluenesulfonic acid dissolved in 80 d of methylene chloride, fill a Soxhlet extractor with Molecular Sieves 3A (manufactured by Wako Pure Chemical Industries, Ltd.) and react under heating under reflux for 3 hours. Obtain the ethyl ester. This crude ethyl ester was dissolved as it was in 70d of anhydrous ether, and 9.2% of 43-dihydrobilane
After adding a catalytic amount of p-toluenesulfonic acid and reacting at room temperature for 3 hours, 2 tul of 2,3-dihydropyran was added.
Add and react overnight. Thereafter, 100 d of anhydrous dimethyl cellosolve was added, and then lithium aluminum hydride 3.42F was added little by little and stirred for 1 hour. After draining the water, ethyl acetate was added to separate the layers, and the aqueous layer was further extracted three times with ethyl acetate. The rooted layer was combined, washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 3001, n-hexane-ethyl acetate (3:2 V/V) to obtain 44 sq. of the desired 3,4-dihydropyranyloxybenzyl alcohol.

2) Production of 3.4-bisdihydrobicinyloxybenzyl chloride: 44-bisdihydropyranyloxybenzyl alcohol 2,84f produced according to Reference Example 2-1 above was mixed with anhydrous ether 60- and pyridine 54. 1.7 d of thionyl chloride was dissolved in 20 d of anhydrous ether and added dropwise while stirring and cooling with water.

After dropping, the reaction mixture was allowed to react for 1 hour, washed once with saturated saline and twice with water, dried over sodium sulfate, and concentrated to obtain the desired 3,4-dihydroxybenzyl chloride.

Reference Example 3 Antibacterial activity by dilution method on Mueller-Hinton agar (MI
Cμri/go) is shown in the following table.

Reference example 4゜(48,6R,78)-7-amino-4-methoxy-1
-Azabicyclo(4,2,'O)octo-2-nin-8
-Production of oxo-2-carboxylic acid = 4-1) (a) = cis-7β-phthalimide 4α-methoxy-1-azabicyclo[4,aO)oct-2-ene-8-oxo-2-
Production of carboxylic acid, tert-butyl ester: (to)-cis-7β-7thalimido 1-azabicyclo(4,2,O)oct-2- produced in the same manner as in Reference Example 5
To 1.231 g of ene-8-okyne-2-carboxylic acid, tertiary butyl ester, 62 m/m of anhydrous carbon tetrachloride, 0.59 F of N-gromosuccinimide, and 0.19 F of azobisisobutyronitrile were added, and the mixture was stirred. Heat under reflux for 40 minutes.

Next, after lowering the temperature of the reaction solution to 70°C, anhydrous methanol IC1
Add m and heat to reflux for 20 minutes. After concentrating the reaction solution under reduced pressure,
5d of ethyl acetate, 10% of ether, n-hexane/
When 15d was added and the precipitated crystals were taken f, the target object was 0.8
Get 79. (65.5%) The physical properties of this material are as follows.

■R-(xBr): 1soo(sh), x79s(s
h).

1780.1735.1725 (sh) NMR (CDC
ta) δ: 7.82 (4H, m), 6.40 (IH
.

d, J+=5Hz), 5.70 (H, d, J=6Hz
).

3.87-4.20(2I(,m), 3.37(3I
(, s), 1.1-2.2 (2H, m), 1.5.
7(9I(,8)4-2)(to)-cis-7β-phthalimido-4α-methoxy1-azabicyclo[4,2,0
)-Oct-2-ene-8-oxo-2-carboxylic acid: (to)-cis-7β-7thalimide 4α-hydroxy-1-azabicyclo[4λ0] produced by 02H 4-1)
150 kg of oct-2-ene-8-oxo-2-carboxylic acid, tert-butyl ester is dissolved in 2 parts of anhydrous methylene chloride, 24 parts of trifluoroacetic acid is added to this, and the mixture is allowed to stand at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and further ethyl acetate was added and concentrated under reduced pressure twice. The resulting residue was washed with ether to obtain 119q of the desired product as a white powder. (9
2,0%) tn-1 1Rνmax (KBr): 1805 (sh), 1
800', 1790°1730 (sh), 1725 NMR (CDCta-CI) aOD) δ near, 85 (4
H, m).

6.55 (IH, 6, J = 5Hz), 5.75 (I
H, a.

J=5.5'Hg), 3.9~4.3 (2H, m
), 3.40(3H,s), 1.2~'lL3
(2H,m)4-3)(to)-cis-7β-amino-
Production of 4α-methoxy-1-azabicyclo(4,2,0)oct-2-ene-8-oxo-2-carboxylic acid: cis-7β-7thalimide 4α- produced by 4-2) Methoxy-1-azabicycloC4,2,0:]
] Octo-2-ene-8-oxo-2-carboxylic acid 119
Dissolve (1) in 1.9 mJ of 0.2N sodium hydrogen carbonate solution, add 30 μt of hydrazine hydrate and 270 μt of water under water cooling.
A solution consisting of was added over 15 minutes and allowed to react for 1 hour. The pH of this reaction solution was adjusted to 1.5 using IN hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. Take advantage of the precipitated crystals and adjust the pH of the oral fluid to 3.5 with 0.2N sodium hydrogen carbonate.
Adjust to. The resulting solution was concentrated under reduced pressure to 2+d,
This product is purified twice using Diaion HP-10 (30d), and both fractions containing the target substance eluted with water are collected, and the solvent is distilled off under reduced pressure to obtain white powder 52 Misaki. (Yield 70.5%) IR)),”, (KBr): 180
0.1790 (sh).

1620 (1540-1590) NMR (D20) δ: 6.23 (IH, d, J=5.
4Hz).

4.92 (IH, d, J=5.4Hz), 3.9-4.
3 (2H.

m), 3.47 (3H, 8), 2.3-2.5 (IH,
m).

1.71 (IH,aaa,J,=13.8.4.2
．． 3.9Hz)4-4)(t)~cis-7β-7enylacetamide 4α-methoxy-1-azabicycloC4
, 2゜0] Production of oct-2-ene-8-okino-2-carboxylic acid: (t)-cis-7β-amino-4α-methoxy-1-azabicyclo[4] produced by 4-3) , λ0] Octo-2-dyne-8-oxo-2-carboxylic acid 4209 was dissolved in 50% tetrahydrofuran aqueous solution 80+ml, and while stirring in water, added sodium hydrogen oxide powder to adjust the pH of the solution to 7.
．． Adjust to 5. While maintaining the pH of the reaction solution at 7.3 to 7.5 with a saturated aqueous sodium bicarbonate solution, 7d'Q of a tetrahydro-tetrasilane solution containing 2.3d of phenylacetyl chloride is added dropwise at the same temperature. After stirring at the same temperature for 1 hour, the precipitate was separated by f, and the f solution was concentrated under reduced pressure.
Tetrahydrofuran is distilled off. After washing twice with ethyl acetate, the pH of the aqueous layer was adjusted to pH 1.5 with IN hydrochloric acid, and then extracted three times with ethyl acetate.

After evaporating the solvent, the residue was dissolved in methanol, and the pH was adjusted to 7.8 with a saturated aqueous sodium bicarbonate solution, and then methanol was evaporated under reduced pressure.

The resulting aqueous solution was passed through a 200 m Diaion HP-10 column, and after washing the column with 500 m of water, both fractions containing the target substance eluted with water-methanol (10:1 v/v) were collected. The solvent is distilled off under reduced pressure. The obtained residue was dried under vacuum in the presence of phosphorus pentoxide to obtain 480 tons of the desired white powder.
Get y. (Yield 72.1X) The physical properties of this product are as follows.

on-” IRνmax (KEr): 1770 (sh), 1
760°1660.160O NMR (CD30D) δ: 7.30 (5H, brs)
, 6.23 (IL d, J=5.5H2), 5.35
(IH,a,J=5.4H2), 3.7~4.0(2H
, I), 3.60 (2H, 8).

3.37 (3H, 8), 1.80-2.17 (IH, m
).

1.27-1.67 (IH, m) 4-5) (48,6R,78)-7-amino-4-medoxy 1-azabicyclo(4,2,0]oc)-2-ene-8- Production of oxo-2-carboxylic acid: (1) Preparation of bacterial cell disruption solution (a) Kluyvera citrophilaA as a culture starter of microorganisms having optical selective deacylation ability
TCC21285 [Mycological description by J, General
Applied Microbio'logy 3.
28-31 (1957)].

As a seed medium, an aqueous solution containing 1% polypeptone, 1% yeast extract, 0.5% meat extract, 0.5% monosodium glutamate, and 0.25% table salt was adjusted to pH with 5N-NaOH.
A solution adjusted to 7.0 was used. 1 platinum loop of seed fungus for 50m
The cells were inoculated into a 10 m long seed medium in a large test tube, and cultured with shaking at 30°C for 24 hours. The entire volume of this seed medium was placed in a 2-t pleated Erlenmeyer flask.
Inoculate at 0d and culture by shaking at 30°C.

The fermentation medium used had the same composition as the seed medium.

(b) Counterfeiting of disrupted bacterial cell solution After 24 hours of the main culture described above, bacterial cells are taken out from the fermentation solution by centrifugation and washed twice with 50 d of 0.9% saline.

The cells are suspended in 1/3°M phosphate buffer. The bacterial cell concentration was 40 q/d, and the bacterial weight was calculated in terms of dry bacterial cells. Put 10 tons of the above suspension into a large 50-mm test tube, and
The microbial cells were disrupted by ultrasonication at 0.00 W for 2 minutes to prepare a microbial cell disruption solution. For this treatment, an ultrasonic generator model UR200P manufactured by Tomy Seiko Co., Ltd. was used.

(2) Preparation of substrate solution (t)-cis-7β- prepared in the same manner as in Reference Example 4-4)
Add 480 kg of phenylacetamide-4α-methoxy-1-azabicyclo[4,2,0]-]octo-2-ene-8-oxo-2-carboxylic acid, sodium salt to 22 d of 1/30M phosphate buffer (pH 6,5). .

At this time, the compound did not dissolve, but it dissolved when 2N-NaOH was added little by little and the pH was then adjusted to 6.5 again. Finally, deionized water was added to adjust the content to 24-.

(3) Enzyme reaction Add 24d of the above bacterial cell disruption solution to the substrate solution 24°C and
Perform the enzyme reaction for 80 minutes.

(4) After the isolation and purification of the target product, remove the bacterial cells from the reaction solution by centrifugation.
The supernatant was adjusted to pH 3.0 with 2N hydrochloric acid. Next, the reaction solution was charged into a column (column diameter: 2.6 on, height: 38 cm) filled with 200-diaion HP-10. Elution is performed with deionized water, and Sgl is fractionated. The target product is eluted in the 7-rakusion from 190d to 230d. This fraction was concentrated under reduced pressure and lyophilized.
A white powder of 107.7fnf (71, IN) is obtained.

The physical properties of this material are as follows.

[α)j''=-86.0° (C20.25, 1M phosphate buffer, pH 7) IR and NIAR spectra are in good agreement with the corresponding 8-isomer.

Reference example 5゜(a)-cis-7β-phthalimido-1-azabicyclo [
4,2IO] Production of oct-2-ene-8-oxo-2-carboxylic acid, tert-butyl ester: 5-1) Cis-4
-(3,3-dimethoxy-1-propen-1-yl)-
3-7 thalimidole 2-oxoazetidin-1-yl-α
-Production of diethylphosphonoacetic acid, tertiary butyl ester:
α-Amino-α-diethylphosphonoacetic acid, tert-butyl ester 20 F (74.8 mM) was dissolved in ethyl acetate 160
4,4-dimether-trans-2 in this solution.
- Add gucinal 11.43f (82.3mM),
Heat to 0°C for 10 minutes. When the solvent is concentrated under reduced pressure at a bath temperature of 50°C, the thick base is obtained as an oil. To this was added 250 g of anhydrous methylene chloride, and to this solution was added triethylamine xz7v (s9.smM) under water-cooling and stirring.
Add. Next, in this reaction solution, 18.41 (82
, 3mM) over 1 hour. After dropping, remove the ice water bath and continue stirring for 2 hours until the temperature reaches room temperature. Next, the insoluble matter in the reaction solution was removed by e-pricking, and the P solution was diluted with 100% saturated saline.
Next, wash twice with a solution consisting of 25 m/ml of saturated aqueous sodium hydrogen sulfite solution and 25 m/ml of water, and then twice with saturated brine. After drying the layer i over anhydrous sodium sulfate, the solvent was distilled off to obtain a 46F oil (hereinafter abbreviated as crude acetal compound). This crude acetal compound was purified by silica gel chromatography (Wako gel - 200, 2t, elution: H-hexane-ethyl acetate 1:2v/v) (as a diastereomer mixture of about t:1) to obtain the target compound 3.
1.8F (75% yield) is obtained as a crystalline oil.

ENGR SigF (c!n-") '" 790 (s
h), 178'0 *1775.173O NMR (CDCZa) δ: 1.30-1.5
a (m, 15H).

2.98 (8,3/2H), a, ol (8,3/2H)
, a, os(s, 3/2H), 3.10(s, 3
/2H), 4.06-4.41 (m, 4H), 4.
61 ((1, J=5Hz, 17”2H).

4.62 (cl, J=5Hz, 1/2H), 4.81~
5.04 (m.

IH), 4.99 (d, J=24Hz, '1/2H)
, 5.02 ((1, J=24H2, 1/2H), s.5
1-5.74 (m, 2H).

5.9-6.2 (m, IH), 7.68-7.9
2 (m, 4H)5-2) cis-4-(3-oxo-
1-propen-1-yl)-3-7 thalimido 2-oxoazetidin-1-yl-α-diethylphosphonoacetic acid,
Production of tertiary butyl ester: In a solution in which the crude acetal compound 462 obtained in 5-1) was dissolved in a mixed solvent consisting of 400 d of methylene chloride and 20 d of acetone, the mixture was cooled with water and stirred.
Add 7.19 g of p-toluenesulfonic acid monohydrate and continue stirring for 1 hour and 30 minutes. Water is added to the reaction solution, and the organic layer is washed with water, then twice with saturated brine, once with saturated deuterated water, and then three times with saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvent is distilled off to obtain 35f oil (hereinafter abbreviated as crude aldehyde compound). This crude aldehyde compound was chromatographed on silica gel (
Purification with Wakogel C-200,600yd, elution: n-hexane:ethyl acetate 1:1 v/v) yielded the desired product 28.37 (yield 72) as a diastereomer mixture.
．． 7%) as a crystalline oil.

The physical properties of this material are as follows.

CHCL s IRν (cfn-”): 1790 (sh), 17
80°ax 1730, 1695 NMR (CDC7:l) δ: 9.5 (LH,a,
J=8. OH2).

7.8 (4H, br), 6.9-7.4 (IH, m)
, 5.9-6.3 (IH, m), 5.7 (IH, m)
, 5.1(IH, (1°J=23H2), 4.Q ~4
．． 5 (5H, m), 1.5 (9H.

θ), 1.4 (6H, t, J=71Hz)5-3)
Out-cis-7β-7 thalimido 1-azabicyclo(4,
2,0) Production of oct-2-ene-8-oxo-2-carboxylic acid, tert-butyl ester: cis-4-(3-oxo-1-propen-1-yl obtained in 5-2) )-3-phthalimido-2-oxoazetidin-1-yl-α-diethylphosphonoa' acid, tert-butyl ester 602 was dissolved in dimethoxyethane 600M, 5% palladium on carbon 30V was added, and hydrogenated at 40°C for 3 hours with stirring. Through gas. After the reaction, the catalyst was separated, and then lof of diazabicyclooctane was added to the reaction solution, and the mixture was left at room temperature overnight.

1 t of chloroform was added to this reaction solution, washed with dilute hydrochloric acid and water, concentrated under reduced pressure, and the residue was treated with ethyl acetate to obtain colorless needle-shaped crystals. Take f and 29.69
(70%) of the object is obtained.

The physical properties of this material are as follows.

1:R))0H”3(cn+-”):1800.17
80.1735°ax 635 NMR (CD(43)δ near, 82(4H, m), 6.
35 (IH.

m ), 5.64 (I H, cl, J ~5.0
HZ), 3.88. (I Hrm), 1.67-45
8 (4H, m), 1.57 (9H, s) Reference Example 6゜The antibacterial activity MIC (μ2/go) of the compound obtained in Example 19 by the dilution method on Meeller-Hinton agar is shown in the following table. .

Staphylococcus aureus Smith 12.5 E. coli Joule 0.2 Klebsiella
Pneumoniae Y-600,39Se-yThia marcesans '['-550,78 Proteus vulgaris 6897 0.1 Enterobacter cloacani F1870 3.13 Pseudomonas aeruginosa 145 0.39 Sanada 325-5, Hiratsuka City 0 Inventor Fumio Suzuki 1566-47 Nara-cho, Midori-ku, Yokohama 0 Inventor Motoo Yamazaki 3-6-6 Asahi-cho, Machida City 0 Inventor Kiyomi Sato Kamo 58-1 755-

Claims (4)

[Claims] (1) General formula (1) (However, X is CH2, S, 0, Y is a hydroxyl group, acyloxy group, amino group, or substituted amine group, A is a phenyl group, naphthalene group, or a monocyclic or bicyclic hetero group) cyclic group, R1 is a hydrogen atom, hydroxyl group, methoxy group, or lower alkyl group, R2 is a hydrogen atom, halogen atom, methoxy group or CH2R2° [however, R2' is a hydrogen atom, an azide group, an acyloxy group, a carbamoyloxy group; group, pyridinium group, substituted pyridinium group, or substituted or unsubstituted heterocyclic thio group (however, heterocycle refers to 1 to 4 0, S
, represents a 5- to 6-membered heterocyclic ring having a hetero atom of H], R3 is a hydrogen atom, a prucari metal, an alkaline earth metal, an organic ammonium group, or an ester residue, and R4 and R5 are each a hydrogen atom. , represents a cycloalkylizo/group together with a lower alkyl group or the carbon atom to which they are bonded, l is an integer of 0 or 1.2, or 3, m is 0 or 1, and n is 1.2.3 .4t or an integer of 5). (2) Claim 1 represented by the general formula (Vlll) \ C-A-(Y)n A β-lactam compound in which l=O1m=1. (3) General formula (■) (However, 2 represents an amino group or a protected amine group, and Y
' represents Y as defined above, a protected hydroxyl group or a protected amino group, and A1R4, R5J, m and n are defined as defined above) or a reactive derivative thereof. (4) In claim 3 represented by the general formula (IX) (wherein Z, A, Y" and n have the same meanings as above), l=0, m=
1 or a reactive derivative thereof.