JPH0687867A - Cephalosporin derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound having low toxicity, excellent in oral absorbing properties and safety and useful as an antimicrobial agent, etc. CONSTITUTION:The compound of formula I (R<1> and R<3> are H or lower alkyl; R<2> is H or a group hydrolyzable in vivo), e.g. 7beta-{2-(2-aminothiazol-4-yl)-2-[(Z)- hydroxyimino]acetamido}-3-(2-propionyl)thio-3-cephem-4-carboxylic acid. Furthermore, this compound of formula I is obtained by reacting, e.g. a compound of formula II (R<5> is methyl, ethyl, etc.) with a compound of formula III (R<6> is monochloroacetyl, formyl, H, etc.; R<7> is protecting group of hydroxyl group or lower alkyl) in the presence of a condensing agent such as N,N- dichlorohexylcarbodimide and deprotecting the resultant reactional product.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel cephalosporin derivative having a substituted thio group at the 3-position. More specifically, the present invention relates to a novel compound, an oral cephalosporin derivative having strong antibacterial activity and a salt thereof.

2. Description of the Related Art Cephalosporin antibiotics are extremely effective drugs as therapeutic agents for bacterial infections because they have excellent antibacterial activity and high safety. In recent years, in particular, a lot of research and development have been carried out because a cephem derivative having an aminothiazolyl group on the 7-position amino group has a strong antibacterial activity and a broad antibacterial spectrum.

The present inventors have also disclosed a cephem derivative excellent in oral absorption in JP-A-1-308289.

Many cephalosporin type anti-substances useful as medicines are known, but most of them are administered parenterally because of poor oral absorbability. Among the oral cephalosporins currently in clinical use, cephalexin and cefaclor have a phenylglycylamino group at the 7-position and show high oral absorption, but their antibacterial activity is Is significantly inferior to Gram-negative bacteria compared to cephalosporins.

Recently, an oral cephalosporin agent has been developed in which a carboxylic acid at the 4-position is esterified to improve the oral absorbability as a so-called prodrug. By introducing an aminothiazolyl group at the 7-position, the antibacterial activity against Gram-negative bacteria was strengthened compared to cephalexin, etc., but the antibacterial activity against Gram-positive bacteria was rather decreased, and the oral absorbability was not so high. It has some drawbacks such as poor quality.

Means for Solving the Problems As a result of intensive studies aimed at solving the above problems, the present inventors have synthesized a novel cephalosporin derivative having strong antibacterial activity, high oral absorption and low toxicity. And succeeded in completing the present invention.

That is, the present invention has the formula (I)

[0005]

[Chemical 2]

(Wherein R ¹ and R ³ represent a hydrogen atom or a lower alkyl group, and R ² represents a hydrogen atom or a group that can be hydrolyzed in vivo), and a cephalosporin derivative It is a non-toxic salt.

The in-vivo hydrolyzable group in the present invention means 5-methyl-1,3-dioxacyclopent-4-, which is known in the prodrug technology of β-lactam agents.
En-2-one-4-ylmethyl group, acetoxymethyl group, pivaloyloxymethyl group, 1-pivaloyloxyethyl group, 1-acetoxyethyl group, 3-phthalidyl group, 1- (cyclohexyloxycarbonyloxy) Examples thereof include an ethyl group and a 1- (isopropoxycarbonyloxy) ethyl group. Further, the lower alkyl group represented by R ¹ and R ³ is a methyl group, an ethyl group, a propio group or the like.

On the other hand, the non-toxic salt of the compound represented by the formula (I) of the present invention means a pharmacologically acceptable one,
For example, salts with inorganic bases such as sodium, potassium, magnesium, ammonium, salts with organic bases such as triethylamine and cyclohexylamine, salts with basic amino acids such as arginine and lysine, minerals such as sulfuric acid, hydrochloric acid and phosphoric acid. Salt with acid or acetic acid, lactic acid, tartaric acid,
Examples thereof include salts with organic acids such as fumaric acid, maleic acid, trifluoroacetic acid, paratoluenesulfonic acid and methanesulfonic acid.

In the compound represented by the formula (I), R ¹
A hydrogen atom, a preferable example of R ² is a hydrogen atom, a pivaloyloxymethyl group, or 1-
Β such as (isopropoxycarbonyloxy) ethyl group
-Groups known in the lactam drug prodrug technology,
R ³ can be a hydrogen atom, and the non-toxic salt can be a maleate salt.

Further, the compound represented by the formula (I) of the present invention has geometrical isomers (E-form and Z-form) derived from the oximino group at the 7-position side chain. Included, but preferably Z-form.

The compound of the formula (I) of the present invention can be produced, for example, by the production method I shown in the following chemical formulas 3 and 4 or the production method II shown in the chemical formulas 5 and 6.

Production Method I

[0013]

[Chemical 3]

[0014]

[Chemical 4]

[In the reaction routes of Chemical formulas ³ and 4, R ¹ and R ³ are
R ⁴ has the same meaning as described above, and represents a protective group for an amino group such as a phenylacetyl group, a phenoxyacetyl group, a trityl group, a phthaloyl group, a formyl group, and a benzoyl group.

R ⁵ is a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, a vinyl group, an allyl group, an ethynyl group, a methoxymethyl group, an ethoxymethyl group, a 1-methoxyethyl group, a methylthiomethyl group. , Carboxymethyl group, carboxyethyl group, t-butoxycarbonylmethyl group, 2- (t-butoxycarbonyl) ethyl group, benzyl group, paranitrobenzyl group, bis-
(4-methoxyphenyl) methyl group, 3,4-dimethoxybenzyl group, trityl group, phenethyl group, phenacyl group, 2,2,2-trichloroethyl group, trimethylsilyl group, 4-hydroxy-3,5-di (t -Butyl) means a protective group for a carboxyl group such as a benzyl group, a phenyl group, a tolyl group and a xyl group.

R ⁶ is a protecting group for an amino group such as a monochloroacetyl group, a formyl group, a benzyloxycarbonyl group, a paranitrobenzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, a t-butoxycarbonyl group and a trimethylsilyl group, or Indicates a hydrogen atom.

R ⁷ is formyl group, acetyl group, propionyl group, methoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, benzoyl group, toluoyl group, benzenesulfonyl group, tosyl group, phenyl group, 4-methoxybenzyl group. Group, a 2,4-dimethoxybenzyl group, a trityl group, a tetrahydropyranyl group, and other hydroxyl-protecting groups, or a lower alkyl group.

R ⁸ represents the above-mentioned in-vivo hydrolyzable group. W, A and B are each a leaving group such as a halogen atom (eg, chlorine atom, bromine atom, iodine atom), methanesulfonyloxy group, trifluoromethanesulfonyloxy group, diphenylphosphoryloxy group, paratoluenesulfonyloxy group. . ]Less than,
Each step will be described.

Step a: A known compound of the formula (II) is dissolved in an organic solvent which does not participate in the reaction and stirred with 1.0 to 1.2 molar equivalent of sodium hydrosulfide in the presence of a base.
Obtain the mercapto form. The reaction temperature is -50 to 100 ° C, preferably -40 to 5 ° C. Reaction time is 10 minutes to 4
The time is preferably 10 minutes to 1 hour.

Then, the 3-mercapto compound obtained by the above operation is not isolated but in the same system in the presence of a base, the compound of formula (II
1.0-2.0 molar equivalents of the compound of I) are added and stirred at a reaction temperature of -50-100 ° C, preferably -25-50 ° C to obtain the 3-thio-substituted form of formula (IV).

The reaction time varies depending on the kind of the base used, the kind of the compound of the formula (III) and the reaction temperature, but is 10 minutes to 5 hours, usually 10 minutes to 2 hours.

In the above, a suitable organic solvent is N,
Examples thereof include N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, acetonitrile, tetrahydrofuran and dichloromethane, and these can be used alone or in combination.

Preferred bases are diisopropylethylamine, N, N-dimethylaminopyridine,
Organic bases such as N, N-dimethylaniline and triethylamine can be mentioned, and the optimum amount thereof is 1.0 to 2.0 molar equivalents relative to the compound of formula (II).
Further, the 3-mercapto compound obtained by the above operation can be used in the next reaction after isolation.
That is, in the presence of a base and an organic solvent similar to the above,
A 3-mercapto compound and a compound of formula (III) can be reacted to obtain a 3-thio-substituted compound of formula (IV). The reaction conditions and the like are the same.

Step b: Next, the protecting group of the amino group at the 7-position of the compound of formula (IV) obtained in the above step a is removed by a method commonly used in the field of β-lactam chemistry. The compound of (V) is obtained.

For example, the protecting group R of the compound of formula (IV)
^{When 4} is a phenoxyacetyl group, a phenylacetyl group or a benzoyl group, the compound of the formula (IV) is dissolved in dichloromethane or benzene, and phosphorus pentachloride of 1.5 to
Add 2.0 molar equivalents and 2.0-3.0 molar equivalents of pyridine, and stir at -40 to 30 ° C for 30 minutes to 3 hours. Then, a large excess of methanol or isobutyl alcohol is added at -50 to 20 ° C, and the mixture is stirred for 30 minutes to 2 hours,
Further, add a large excess of water, and at -50 to 20 ° C for 30 minutes to 1
Stir for hours to obtain the compound of formula (V).

When the protecting group R ⁴ of the compound of formula (IV) is a trityl group, the compound of formula (IV) is dissolved in a solvent that does not participate in the reaction (eg ethyl acetate), and the mixture is cooled with ice.
Paratoluenesulfonic acid monohydrate is added in an amount of 1.0 to 1.5 molar equivalents, and the mixture is stirred for 1 to 5 hours to obtain the paratoluenesulfonic acid salt of the compound of formula (V).

The paratoluene sulfonate can be treated with a base as required to give a free compound of the formula (V).

Step c: From the compound of formula (V) to formula (VI
To obtain a compound of formula (I), a compound of formula (V) is reacted with a 2-aminothiazoleacetic acid derivative of formula (VI) or a compound of formula (V) is reacted with a compound of formula (VI).
Reacting a reactive derivative of the compound of.

Here, the condensing agent includes N, N-dicyclohexylcarbodiimide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, carbonyldiimidazole, diphenylphosphoric acid azide, Vilsmeier reagent and the like.

The reactive derivative of the compound of the formula (VI) means an acid halide (for example, an acid chloride or bromide of the formula (VI)), an acid anhydride (for example, a symmetrical acid anhydride of the compound of the formula (VI)). Or mixed acid anhydride with ethyl chlorocarbonate, diphenylphosphoric acid, methanesulfonic acid, etc.),
Activated esters (eg, esters with para-nitrophenol, thiophenol, N-hydroxysuccinimide, 1-oxybenzotriazole, etc.) and the like.

When an acid chloride is used as the reactive derivative of the compound of formula (VI), the compound of formula (VI) is first dissolved in a solvent that does not participate in the reaction and then at -30 to -10 ° C in the presence of a base. 1.0 to 1.1 molar equivalents of phosphorus pentachloride are added and stirred for 10 to 30 minutes to prepare an acid chloride of the compound of formula (VI).

A solution prepared by dissolving 0.7 to 1.0 molar equivalent of the compound of the formula (V) in a solvent which does not participate in the same reaction as described above is added within the range of -30 to 0 ° C, and the mixture is added for 10 to 30 minutes. Stir to obtain the compound of formula (VII).

The preferred solvent in this step is dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide and the like. Further, suitable bases are pyridine, triethylamine, N, N-dimethylaminopyridine, N, N-dimethylaniline, diisopropylethylamine and the like, and the usage amount thereof is 4.0 to 5.5 with respect to the compound of the formula (V). It is a molar equivalent.

As a reactive derivative of the compound of the formula (VI), a mixed acid anhydride of the compound of the formula (VI) with phosphorus oxychloride will be described as an example. First, the compound of the formula (V) and 1.0
~ 1.3 molar equivalents of the compound of formula (VI) are dissolved in a solvent which does not participate in the same reaction as above. -20 to -5 ℃
2.0 to 4.0 molar equivalents of base and 1.0 to 3.0 molar equivalents of phosphorus oxychloride are added, and the mixture is stirred in the range of −20 to 0 ° C. for 10 to 30 minutes to obtain the compound of formula (VII). To obtain the compound of

The preferred solvent in this step is ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, dichloromethane, chloroform and the like. Also suitable bases are pyridine, triethylamine, diisopropylethylamine and the like.

As a reactive derivative of the compound of formula (VI), a mixed acid anhydride of the compound of formula (VI) with methanesulfonic acid will be described as an example. First, the compound of formula (VI) is used as a solvent which does not participate in the reaction. And methanesulfonic acid chloride at 1.0 to 1.1 in the presence of a base at -70 to -30 ° C.
Add a molar equivalent and stir for 20-40 minutes to prepare a mixed acid anhydride of the compound of formula (VI).

To this, in the presence of a base, 0.5 to 0.7 molar equivalent of the compound of formula (V) was added within the range of -70 to -30 ° C, and the mixture was stirred for 20 to 40 minutes to obtain the compound of formula (VII). Obtain the compound.

Preferred solvents in this step are N, N-dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane, chloroform and the like. Suitable bases are diisopropylethylamine, triethylamine, N, N-dimethylaniline, N, N-dimethylaminopyridine, pyridine and the like, and the amount thereof is 1.0 to 2.2 with respect to the compound of formula (V). It is a molar equivalent.

The active ester of the compound of formula (VI) with 1-oxybenzotriazole will be described as an example of the reactive derivative of formula (VI). First, the compound of formula (V) is not involved in the reaction. It is dissolved in a solvent, 1.0 to 1.1 molar equivalents of the active ester form of formula (VI) is added at 0 to 40 ° C., and the mixture is stirred for 5 to 20 hours to obtain a compound of formula (VII).

The preferred solvent in this step is N, N-dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane, chloroform and the like.

Step d: Next, in order to obtain the compound of the formula (VIII) from the compound of the formula (VII) obtained in the above step c, the protecting group of the compound of the formula (VII) is introduced in the field of β-lactam chemistry. It is eliminated by commonly used methods such as hydrolysis and reduction.

(1) Hydrolysis Hydrolysis is generally preferably carried out in the presence of an acid, and examples of such an acid include inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, formic acid, acetic acid and trifluoro. Organic acids such as acetic acid, methanesulfonic acid, benzenesulfonic acid, and paratoluenesulfonic acid can be mentioned.

Further, in place of the above acid, boron trifluoride,
Lewis acids such as boron trifluoride / etherate, aluminum chloride, antimony pentachloride, ferric chloride, tin chloride, titanium tetrachloride, zinc chloride and acidic ion exchange resins may be used.

When the above organic acid or Lewis acid is used, it is desirable to carry out it in the presence of a cation trapping agent such as anisole. Preferred solvents for hydrolysis are, for example, water, methanol, ethanol,
Tetrahydrofuran, N, N-dimethylformamide,
Examples include dioxane, dichloromethane, nitromethane and the like.

When the above-mentioned acid is a liquid, it can be used as a solvent itself.

(2) Reduction Reduction is carried out by chemical reduction or catalytic reduction method.
Examples of the reducing agent used in the chemical reduction include zinc,
Metals such as iron and formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid,
Combinations with organic or inorganic acids such as hydrobromic acid are mentioned. Examples of the catalyst used in the catalytic reduction include platinum black, platinum oxide, palladium black, palladium carbon, Raney nickel and the like.

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, methanol, ethanol, acetic acid, tetrahydrofuran, N, N-dimethylformamide, dioxane, or a mixture thereof.

The reaction temperature for the above-mentioned hydrolysis and reduction is not particularly limited, but it is usually carried out under cooling or under heating.

Step e: The compound of formula (X) has the formula (VII)
A compound of formula (IX) is reacted with a compound of formula (IX) in the presence of a base or a salt of a compound of formula (VIII) is added to a compound of formula (I)
It can be obtained by reacting the compound of X).

Suitable bases for this reaction include triethylamine, diisopropylethylamine, N, N-
It is an organic base such as dimethylaminopyridine or an inorganic base such as sodium hydrogen carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide.

The salt of the compound of formula (VIII) is a salt with a metal such as silver, sodium, potassium, calcium or magnesium.

This reaction will be described by taking the sodium salt as an example of the salt of the compound of formula (VIII).
The sodium salt of the compound of formula (IX) is dissolved or suspended in a solvent that does not participate in the reaction, and 1.0 to 2.0 molar equivalents of formula (IX)
-50 to 50 ° C, preferably -30 to
Stir at 20 ° C. for 5 minutes to 2 hours, preferably 10 minutes to 1 hour. A suitable solvent in this reaction is acetone,
Chloroform, dichloromethane, tetrahydrofuran,
Acetonitrile, diethyl ether, methanol, ethanol, benzene, N, N-dimethylformamide,
N, N-dimethylacetamide, dimethyl sulfoxide,
Hexamethylphosphoric triamide, water, etc.

The compound (X) can also be obtained by the production method II shown in Chemical formulas 5 and 6.

Production Method II

[0056]

[Chemical 5]

[0057]

[Chemical 6]

[In the reaction pathway of Chemical formula 5, R ^{3 to} R ⁸ have the same meanings as described above. The compound of the present invention can be orally administered in the dosage form of tablets, pills, capsules, granules and the like produced according to a conventional formulation technique.

In each of the above formulations, the usual bulking agent,
Additives such as binders, pH adjusters and solubilizers can be used.

The dose of the compound of the present invention to a treated patient may vary depending on the patient's age, type of disease and condition, etc., but is usually 10 to 3000 mg per day.
It can be administered in several divided doses.

INDUSTRIAL APPLICABILITY The compound of the formula (I) of the present invention and its non-toxic salt show not only strong antibacterial activity against various pathogenic bacteria including Gram-positive and negative bacteria, but also excellent oral absorbability, and It has low toxicity and is useful as an antibacterial agent for oral administration.

Next, the results of the antibacterial activity, oral absorption test and single dose toxicity test of the compound of the present invention are shown.

Test Example 1 An antibacterial test against various bacteria was carried out by the agar plate dilution method (inoculum size: 10 ⁶ cells / ml), and the results shown in Table 1 below were obtained.

[0063]

[Table 1]

(Note) A: Compound obtained in Example 1 (d) B: Cefixime (sodium salt, known compound) C: Cefdinir (sodium salt, known compound) D: 7β- {2- (2-amino) (Thiazol-4-yl)
-2-[(Z) -hydroxyimino] acetamide} -3
-Allylthio-3-cephem-carboxylic acid sodium salt

Test Example 2 The time course of the blood concentration after oral administration to ICR male mice (4 weeks old, 1 group, 3 mice) was examined.

Drug dose: 20 mg / kg (5% gum arabic suspension) Quantitative method: Bioassay method (test bacteria: Bacillus cereus S1101) The results are shown in Table 2.

[0067]

[Table 2]

(Note) E: Compound obtained in Example 2 F: Cefdinir (sodium salt)

Test Example 3 ICR male mice (4 weeks old, 1 group, 3 mice) were used to examine the mortality rate after a single administration.

Administration route: intraperitoneal administration volume; 50 ml / kg (physiological saline) dose: 4,000 mg / kg observation period; 14 days after administration The results are shown in Table 3.

[0071]

[Table 3]

(Note) G: Compound H obtained in Example 1 (d); 7β- {2- (2-aminothiazol-4-yl)
-2-[(Z) -hydroxyimino] acetamide} -3
-Allylthio-3-cephem-carboxylic acid sodium salt

EXAMPLES Next, the production method of the compound of the present invention will be explained in more detail with reference to examples.

Example 1 (a) 3.0 g (5.6 mM) of 7β-phenylacetamide-3-methanesulfonyloxy-3-cephem-4-carboxylic acid paramethoxybenzyl ester was added to 20 ml of N, N-dimethylformamide. Dissolved at 70 ° C at -10 ° C
% Sodium hydrosulfide 630 mg (6.7 mM) N, N
-Dimethylformamide 10 ml solution and diisopropylethylamine 1.1 g (8.4 mM) were added.

After stirring for 30 minutes at the same temperature, 1.34 g (12.2 mM) of propargyl bromide was added, and the mixture was further stirred for 1 hour under ice cooling.

After the reaction, 100 ml of 0.5% hydrochloric acid was added,
200 ml of ethyl acetate was extracted and 100 ml of saturated saline was added.
After washing with 2, it was dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: dichloromethane = 1: 2) to give 7β-phenylacetamide-3.
1.8 g of-(2-propynyl) thio-3-cephem-4-carboxylic acid paramethoxybenzyl ester was obtained.

NMR (DMSO-d ₆ ) δ (ppm); 3.
28 (1H, t, J = 2.5Hz), 3.49 and 3.57 (2H, ABq, J = 14Hz), 3.73
(1H, dd, J = 2.5,17Hz), 3.75 (3H, S), 3.82 (1H, dd, J = 2.5,17H
z), 3.83 and 3.90 (2H, ABq, J = 17Hz), 5.12 and 5.21 (2H, AB
q, J = 12Hz), 5.14 (1H, d, J = 4.5Hz), 5.64 (1H, dd, J = 4.5,8.5H
z), 6.92 (2H, d, J = 8.5Hz), 7.17 ~ 7.39 (7H, m), 9.13 (1H, d,
(J = 8.5Hz)

IR ^KBr ν _max (cm ^-1 ); 3269,3031,295
8,1780,1698,1655,1614,1537,1517,1497,1455,1391,136
0,1288,1247,1228,1173,1119,1090,1032

(B) 7β-phenylacetamido-3- (2-purpinyl) thio-3-cephem-4-carboxylic acid paramethoxybenzyl ester obtained in (a) above.
Dissolve 65 g (3.2 mM) in 20 ml of anhydrous dichloromethane, 0.51 g (6.5 mM) of pyridine under ice cooling.
And 1.02 g (4.9 mM) of phosphorus pentachloride were added, and the mixture was stirred at room temperature for 1.5 hours.

Then, under ice-cooling, 1.45 g (19.6 mM) of isobutyl alcohol was added, and the mixture was stirred at the same temperature for 1 hour, then 5 ml of water was further added, and the mixture was stirred for 30 minutes.

After the reaction, the organic layer of the reaction solution was saturated with saline (5 m).
It was washed with 1 and dried over anhydrous magnesium sulfate.

The solvent was concentrated (about 5 ml), the residue was added dropwise to 80 ml of diisopropyl ether, and the precipitated powder was collected by filtration to give 7β-amino-3- (2-propynyl) thio-3-cephem-4-. 1.0 g of hydrochloride of carboxylic acid paramethoxybenzyl ester was obtained.

NMR (DMSO-d ₆ ) δ (ppm);
3.34 (1H, t, J = 2.5Hz), 3.75 (3H, S), 3.82 and 3.97 (2H, AB
q, J = 16.5Hz), 3.89 (2H, d, J = 2.5Hz), 5.07 (1H, d, J = 4.5Hz),
5.17 (2H, bS), 5.25 (1H, d, J = 4.5Hz), 6.92 (2H, d, J = 8.5Hz),
7.34 (2H, d, J = 8.5Hz), 9.23 (3H, bS)

IR ^KBr ν _max (cm ^-1 ); 3436,3271,289
8,2649,1772,1694,1613,1586,1516,1467,1401,1367,129
1,12151176,1134,1116,1030

(C) 7β-amino-3 obtained in (b) above
-(2-Propinyl) thio-3-cephem-4-carboxylic acid paramethoxybenzyl ester hydrochloride 980 mg
(2.3 mM) and 2- (tritylaminothiazole-4)
1.75 g (2.5 mM) of sodium salt of -yl) -2-[(Z) -trityloxyimino] acetic acid was dissolved in 30 ml of tetrahydrofuran and cooled to -20 ° C.

To this was added 546 mg of pyridine (6.9 mM).
And phosphorus oxychloride 705mg (4.6mM) added-
The mixture was stirred at 15 to -5 ° C for 20 minutes.

After the reaction, 50 ml of water was added, and ethyl acetate 1 was added.
After extracting with 00 ml and washing with 50 ml of saturated saline,
It was dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: n-hexane = 1: 2) to give 7β- {2- (2-tritylaminothiazol-4-yl). 1.82 g of 2-[(Z) -trityloxyimino] acetamide} -3- (2-propynyl) thio-3-cephem-4-carboxylic acid paramethoxybenzyl ester were obtained.

NMR (DMSO-d ₆ ) δ (ppm);
3.28 (1H, t, J = 2.5Hz), 3.75 (3H, S), 3.80 (2H, d, J = 2.5Hz),
3.78 and 3.88 (2H, ABq, J = 17Hz), 5.19, (2H, bs), 5.25 (1H,
d, J = 4.5Hz), 5.77 (1H, dd, J = 4.5,8.5Hz), 6.66 (1H, S), 6.93
(2H, d, J = 8.5Hz), 7.06-7.42 (32H, m), 8.77 (1H, bS), 9.85
(1H, d, J = 8.5Hz)

IR ^KBr ν _max (cm ^-1 ); 3286,3057,178
6,1729,1688,1613,1516,1493,1448,1386,1360,1249,121
9,1175,1116,1085,1034

(D) 7β- {2- (2) obtained in (c) above
-Tritylaminothiazol-4-yl) -2-
[(Z) -Trityloxyimino] acetamide} -3-
(2-Propinyl) thio-3-cephem-4-carboxylic acid paramethoxybenzyl ester 1.77 g (1.7
3 mM trifluoroacetic acid and anisole 0.1.
To a mixed solution of 62 ml and dichloromethane (6.2 ml) was added under ice cooling, and the mixture was stirred for 1.5 hours.

The reaction solution was added with 64 ml of diisopropyl ether.
It was dripped in and the precipitated crystal was collected by filtration. Then, the crystals were dissolved in 6.2 ml of formic acid and stirred at room temperature for 1 hour,
The insoluble matter was filtered off and the filtrate was washed with disopropyl ether 7
It was dripped into 7 ml. The precipitated crystals were collected by filtration to give 7β-
{2- (2-aminothiazol-4-yl) -2-
[(Z) -Hydroxyimino] acetamide} -3- (2
650 mg of formate salt of -propynyl) thio-3-cephem-4-carboxylic acid was obtained.

This formate salt was suspended in 10 ml of water, 356 mg (4.2 mM) of sodium hydrogencarbonate was added and dissolved, and then subjected to Toyopearl (HW-40F) column chromatography (eluting solvent: water) to obtain 7β- Sodium salt of {2- (2-aminothiazol-4-yl) -2-[(Z) -hydroxyimino] acetamido} -3- (2-propynyl) thio-3-cephem-4-carboxylic acid 500
mg was obtained.

NMR (DMSO-d ₆ ) δ (ppm);
3.13 (1H, t, J = 2.5Hz), 3.47 (1H, dd, J = 2.5,16Hz), 3.36 (1H,
dd, J = 2.5,16Hz), 3.56and 3.67 (2H, ABq, J = 17Hz), 4.98 (1
H, d, J = 4.5Hz), 5.59 (1H, dd, J = 4.5,8Hz), 6.65 (1H, S), 7.12
(2H, bS), 9.41 (1H, d, J = 8Hz), 11.30 (1H, S)

IR ^KBr ν _max (cm ^-1 ); 3283,1762,166
2,1608,1533,1395,1353,1183,1046

Example 2 420 mg of the sodium salt obtained in Example 1 (d) above
(0.9 mM) N, N-dimethylformamide 7 ml
The solution was dissolved in, and 287 mg (1.2 mM) of pivaloyloxymethyl iodide was added under ice cooling and stirred for 1 hour.

After the reaction, 30 ml of water was added and ethyl acetate was added to 5
The extract was extracted with 0 ml, washed with 30 ml of saturated saline and dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the residue was treated with Sephadex LH.
It was subjected to -20 column chromatography (elution solvent; acetone), and 7β- {2- (2-aminothiazole-4)
-Yl) -2-[(Z) -hydroxyimino] acetamido} -3- (2-propynyl) thio-3-cephem-4
-Carboxylic acid pivaloyloxymethyl ester 255 m
g was obtained.

NMR (DMSO-d ₆ ) δ (ppm);
1.16 (9H, S), 3.30 (1H, t, J = 2.5Hz), 3.80 (1H, dd, J = 2.5,17H
z), 3.83 and 3.91 (2H, ABq, J = 17Hz), 3.87 (1H, dd, J = 2.5,1
7Hz), 5.22 (1H, d, J = 4.5Hz), 5.75 (1H, dd, 4.5,8Hz), 5.78 a
nd 5.90 (2H, ABq, J = 6Hz), 6.69 (1H, S), 7.14 (2H, bS), 9.48
(1H, d, J = 8Hz), 11.31 (1H, S)

IR ^KBr ν _max (cm ^-1 ); 3435,2975,178
1,1754,1674,1616,1531,1481,1460,1371,1283,1217,115
8,11311110,1029

Example 3 280 mg (0.51 mM) of the pivaloyloxymethyl ester compound obtained in the above Example 2 was dissolved in 1 ml of acetone, and 110 mg of paratoluenesulfonic acid monohydrate (0.1%).
(58 mM) was added, and the mixture was stirred at room temperature for 10 minutes. After the reaction, the reaction solution was added dropwise to 10 ml of diisopropyl ether. The precipitated crystals were collected by filtration to give 7-β {2- (2-aminothiazol-4-yl) -2-[(Z) -hydroxyimino] acetamide} -3- (2-propynyl) thio-3.
-Cephem-4-carboxylic acid pivaloyloxymethyl ester 230 mg of 1 molecule paratoluenesulfonic acid salt was obtained.

NMR (DMSO-d ₆ ) δ (ppm);
1.16 (9H, S), 2.29 (3H, S), 3.31 (1H, t, J = 2.5Hz), 3.83 (1H, d
d, J = 2.5,7Hz), 3.87 (1H, dd, J = 2.5,7Hz), 3.88 (2H, bS), 5.2
5 (1H, d, J = 4.5Hz), 5.75 (1H, dd, J = 4.5,8Hz), 5.78and 5.90
(2H, ABq, J = 6Hz), 6.87 (1H, S), 7.12 (2H, d, J = 8Hz), 7.47 (2
H, d, J = 8Hz), 8.51 (3H, bS), 9.70 (1H, d, J = 8Hz), 12.10 (1H,
S)

IR ^KBr ν _max (cm ^-1 ); 3412,2975,178
5,1756,1641,1530,1481,1459,1372,1280,1214,1161,112
5,1110,1034,1010

Example 4 280 mg (0.51 mM) of the pivaloyloxymethyl ester compound obtained in the above Example 2 was added to 0.7 m of acetonitrile.
It was dissolved in 1, and a solution of maleic acid (62 mg, 0.53 mM) in acetonitrile (2.3 ml) was added. The mixture was allowed to stand at room temperature for 2 minutes, then, diisopropyl ether (3 ml) was further added, and the mixture was allowed to stand for 1 hour.

The precipitated crystals were collected by filtration, and 7-β {2- (2
-Aminothiazol-4-yl) -2-[(Z) -hydroxyimino] acetamido} -3- (2-propynyl)
250 mg of 1-molecule maleate salt of pivaloyloxymethyl thio-3-cephem-4-carboxylic acid was obtained. NMR (DMSO-d ₆ ) δ (ppm); 1.16 (9H,
S), 3.30 (1H, t, J = 2.5Hz), 3.75-3.95 (4H, m), 5.22 (1H, d, J
= 4.5Hz), 5.75 (1H, dd, J = 4.5,8Hz), 5.78 and 5.90 (2H, AB
q, J = 6Hz), 6.25 (2H, S), 6.71 (1H, S), 7.28 (2H, bS), 9.50 (1
H, d, J = 8Hz), 11.40 (1H, S)

IR ^KBr ν _max (cm ^-1 ); 3284,2976,178
4,1756,1662,1627,1531,1365,1110

Example 5 500 mg of the sodium salt obtained in Example 1 (d) above
(1.1 mM) 5 ml of N, N-dimethylformamide
The mixture was dissolved in water, 1-iodoethylisopropylcarbonate (392 mg, 1.5 mM) was added under ice cooling, and the mixture was stirred for 45 minutes.

After the reaction, 30 ml of water was added and ethyl acetate was added to 5
The extract was extracted with 0 ml, washed with 30 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to Sephadex LH-20 column chromatography (eluting solvent; acetone) to give 7β- {2- (2-aminothiazol-4-yl) -2-[(Z) -hydroxy. Imino] acetamido} -3- (2-propynyl) thio-3-cephem-4-carboxylic acid 1- (isopropyloxycarbonyloxy) ethyl ester (230 mg) was obtained.

Acetone (1.5 ml) was added to the ester product, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals are collected by filtration,
97 mg of one of the diastereomeric isomers
Obtained.

NMR (DMSO-d ₆ ) δ (ppm);
1.23 (3H, d, J = 6Hz), 1.25 (3H, d, J = 6Hz), 1.48 (3H, d, J = 6H
z), 3.31 (1H, bS), 3.82 (1H, d, J = 17Hz), 3.85 (2H, bS), 3.92
(1H, d, J = 17Hz), 4.78 (1H, m), 5.20 (1H, d, J = 5Hz), 5.73 (1H,
d, J = 5,9Hz), 6.69 (1H, S), 6.80 (1H, q, J = 6Hz), 7.13 (2H, b
S), 9.47 (1H, d, J = 9Hz), 11.30 (1H, S)

IR ^KBr ν _max (cm ^-1 ); 3293,2986,178
5,1760,1697,1621,1531,1448,1378,1354,1294,1267,122
6,1163,1122,1101,1074,1043

Example 6 One of the diastereomeric isomers (NM) of Example 5 was concentrated by concentrating the filtrate obtained by filtering the crystals precipitated in Example 5 above.
From the R spectrum, about 25% of the isomer of Example 5 is contained) 1
33 mg was obtained.

NMR (DMSO-d ₆ ) δ (ppm);
1.24 (6H, d, J = 6Hz), 1.48 (3H, d, J = 5.5Hz), 3.31 (1H, bS), 3.
85 and 3.93 (2H, ABq, J = 17Hz), 3.86 (2H, bS), 4.80 (1H, m),
5.22 (1H, d, J = 5Hz), 5.78 (1H, dd, J = 5,8.5Hz), 6.68 (1H, S),
6.76 (1H, Q, J = 5.5Hz), 7.13 (2H, bS), 9.48 (1H, d, J = 8.5Hz),
11.32 (1H, S)

IR ^KBr ν _max (cm ^-1 ); 3290,2983,176
2,1672,1616,1531,1377,1271,1218,1167,1101,1074,104
Four

Example 7 216 mg of diastereomeric isomer obtained in Example 5
(0.38 mM) was dissolved in 10 ml of acetone, 48 mg (0.42 mM) of maleic acid in methanol was added, and the mixture was concentrated to about 3 ml at room temperature.

Next, 5 ml of diisopropyl ether was added to this concentrated solution and the mixture was left standing for 1 hour. The precipitated crystals were collected by filtration to give 7β- {2- (2-aminothiazol-4-yl) -2-[(Z) -hydroxyimino] acetamide}.
-3- (2-propynyl) thio-3-cephem-4-carboxylic acid 1- (isopropyloxycarbonyloxy)
203 mg of the maleic acid salt of ethyl ester was obtained.

NMR (DMSO-d ₆ ) δ (ppm);
1.23 (3H, d, J = 6Hz), 1.25 (3H, d, J = 6Hz), 1.48 (3H, d, J = 5.5H
z), 3.31 (1H, t, J = 2.5Hz), 3.83 and 3.91 (2H, ABq, J = 17H
z), 3.85 (2H, d, J = 2.5Hz), 5.20 (1H, d, J = 4.5Hz), 5.73 (1H, d
d, J = 4.5,8Hz), 6.24 (1H, S), 6.70 (1H, S), 6.81 (1H, q, J = 5.5
Hz), 7.23 (3H, bS), 9.49 (1H, d, J = 8Hz), 11.37 (1H, S)

IR ^KBr ν _max (cm ^-1 ); 3293,2985,178
5,1761,1696,1622,1530,1378,1355,1294,1268,1226,116
4,1102,1075,1043

Example 8 (a) The 7β-amino-3-obtained in (b) of Example 1
700 mg of (2-propynyl) thio-3-cephem-4-carboxylic acid paramethoxybenzyl ester hydrochloride
(1.6 mM) and 2- (tritylaminothiazole-4)
839 mg (1.8 mM) of sodium salt of -yl) -2-[(Z) -methoxyimino] acetic acid was dissolved in 20 ml of tetrahydrofuran and cooled to -20 ° C.

To this, 390 mg of pyridine (4.9 mM)
And phosphorus oxychloride 503mg (3.3mM) added-
The mixture was stirred at 15 to -5 ° C for 20 minutes. After the reaction, 50 ml of water
Was added, and the mixture was extracted with 100 ml of ethyl acetate, washed with 50 ml of saturated saline and then dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: n-hexane = 1: 1) to give 7β- {2- (2-tritylaminothiazol-4-yl). -2-[(Z) -methoxyimino] acetamide} -3- (2-propynyl) thio-3
-1.1 g of cephem-4-carboxylic acid paramethoxybenzyl ester were obtained.

NMR (DMSO-d ₆ ) δ (ppm);
3.27 (1H, t, J = 2.5Hz), 3.65-3.92 (4H, m), 3.74 (3H, S), 3.8
1 (3H, S), 5.13 and 5.19 (2H, ABq, J = 12Hz), 5.16 (1H, d, J =
4.5Hz), 5.64 (1H, dd, J = 4.5,8Hz), 6.74 (1H, S), 6.92 (2H, d,
J = 8.5Hz), 7.17 ~ 7.42 (17H, m), 8.81 (1H, bS), 9.55 (1H, d, J
= 8Hz)

IR ^KBr ν _max (cm ^-1 ); 3328,2937,178
1,1730,1683,1613,1516,1448,1386,1362,1285,1248,122
0,1174,1117,1037,1003

(B) 7β- {2- (2) obtained in (a) above
-Tritylaminothiazol-4-yl) -2-
[(Z) -Methoxyimino] acetamide} -3- (2-
1.0 g (1.2 mM) of propynyl) thio-3-cephem-4-carboxylic acid paramethoxybenzyl ester was added to a mixed solution of 3.0 ml of trifluoroacetic acid, 0.6 ml of anisole and 3.0 ml of dichloromethane under ice cooling. 1
The mixture was stirred for 20 minutes at room temperature.

After the reaction, the reaction solution was added dropwise to 50 ml of diisopropyl ether, and the precipitated crystals were collected by filtration to give 7β-
{2- (2-aminothiazol-4-yl) -2-
580 mg of trifluoroacetic acid salt of [(Z) -methoxyimino] acetamide} -3-propargylthio-3-cephem-4-carboxylic acid was obtained.

This trifluoroacetic acid salt was suspended in 5 ml of water, and 257 mg (3.1 mM) of sodium hydrogencarbonate was added to dissolve the trifluoroacetic acid salt, followed by subjecting to Toyopearl (HW-40F) column chromatography (elution solvent: water). 7β- {2
-(2-aminothiazol-4-yl) -2-[(Z)
454 mg of the sodium salt of -methoxyimino] acetamido} -3- (2-propynyl) thio-3-cephem-4-carboxylic acid was obtained.

NMR (DMSO-d ₆ ) δ (ppm);
3.12 (1H, t, J = 2.5Hz), 3.47 (1H, dd, J = 2.5,16Hz), 3.54 and
3.68 (2H, ABq, J = 17Hz), 3.63 (1H, dd, J = 2.5,16Hz), 3.83 (3
H, S), 4.98 (1H, d, J = 5Hz), 5.57 (1H, dd, J = 5,8.5Hz), 6.73 (1
H, S), 7.12 (2H, bS), 9.54 (1H, d, J = 8.5Hz),

IR ^KBr ν _max (cm ^-1 ); 3401,3274,176
2,1657,1607,1535,1391,1353,1181,1128,1040

Example 9 400 mg of the sodium salt obtained in Example 8 (b) above
(0.8 mM) to N, N-dimethylformamide 6.0
It was dissolved in ml, 265 mg (1.1 mM) of pivaloyloxymethyl iodide was added under ice cooling, and the mixture was stirred for 1 hour.

After the reaction, 30 ml of water was added and ethyl acetate was added to 5
The extract was extracted with 0 ml, washed with 30 ml of saturated saline and dried over anhydrous magnesium sulfate.

The solvent was distilled off and the residue was treated with Sephadex LH.
It was subjected to -20 column chromatography (elution solvent; acetone), and 7β- {2- (2-aminothiazole-4)
-Yl) -2-[(Z) -methoxyimino] acetamido} -3- (2-propynyl) thio-3-cephem-4
-Carboxylic acid pivaloyloxymethyl ester 272m
g was obtained.

NMR (DMSO-d ₆ ) δ (ppm);
1.16 (9H, S), 3.30 (1H, t, J = 2.5Hz), 3.80 (1H, dd, J = 2.5,17H
z), 3.84 (3H, S), 3.85and 3.92 (2H, ABq, J = 17Hz), 3.87 (1H,
dd, J = 2.5,17Hz), 5.22 (1H, d, J = 4.5Hz), 5.75 (1H, dd, J = 4.
5,8.5Hz), 5.78 and 5.90 (2H, ABq, J = 6Hz), 6.78 (1H, S), 7.
21 (2H, S), 9.61 (1H, d, J = 8.5Hz)

IR ^KBr ν _max (cm ^-1 ); 3285,2975,178
0,1755,1672,1618,1536,1481,1461,1372,1283,1218,115
8,1130,1110,1034

In accordance with the procedure and reaction conditions disclosed in Examples 1 (a)-(d) and Example 2, the following Example 1
0 (a)-(d) and the compound of Example 11 were obtained.

Example 10 (a) 7β-Phenylacetamido-3- (2-butynyl) thio-3-cephem-4-carboxylic acid paramethoxybenzyl ester NMR (DMSO-d ₆ ) δ (ppm); 1.78 (3H, t, J = 2.
5Hz), 3.50 and 3.57 (2H, ABq, J = 14Hz), 3.66-3.77 (2H,
m), 3.75 (3H, S), 3.85 (2H, bS), 5.12 and 5.20 (2H, ABq, J = 1
2Hz), 5.13 (1H, d, J = 4.5Hz), 5.62 (1H, dd, J = 4.5,8.5Hz), 6.
92 (2H, d, J = 8.5Hz), 7.17 ~ 7.38 (7H, m), 9.11 (1H, d, J = 8.5H
z)

IR ^KBr ν _max (cm ^-1 ); 3263,3046,296
2,1780,1702,1659,1615,1539,1518,1455,1395,1360,128
8,1250,1231,1174,1119,1033

Example 10 (b) Hydrochloride of 7β-amino-3- (2-butynyl) thio-3-cephem-4-carboxylic acid paramethoxybenzyl ester NMR (DMSO-d ₆ ) δ (ppm); 1.80 (3H, t, J =
2.5Hz), 3.75 (3H, S), 3.76 ~ 3.87 (2H, m), 3.82 and 3.94 (2
H, ABq, J = 16.5Hz), 5.07 (1H, d, J = 4.5Hz), 5.16 (2H, S), 5.24
(1H, d, J = 4.5Hz), 6.92 (2H, d, J = 8.5Hz), 7.34 (2H, d, J = 8.5H
z), 9.15 (3H, bS)

IR ^KBr ν _max (cm ⁻¹ ); 3436,2915,223
1,1780,1699,1613,1515,1464,1396,1294,1249,1213,117
6,11241032

Example 10 (c) 7β- {2- (2-Tritylaminothiazol-4-yl) -2-[(Z) -trityloxyimino] acetamido} -3- (2-butynyl) thio-3 -Cephem-4-
Carboxylic acid paramethoxybenzyl ester NMR (DMSO-d ₆ ) δ (ppm) 1.77 (3H, t, J = 2.5Hz), 3.68 to 3.79 (2H, m), 3.81 (2H, bS), 5.
18 (2H, bS), 5.24 (1H, d, J = 4.5Hz), 5.75 (1H, dd, J = 4.5,8H
z), 6.67 (1H, S), 6.93 (2H, d, J = 8.5Hz), 7.06 ~ 7.73 (32H,
m), 8.76 (1H, bS) 9.84 (1H, d, J = 8Hz)

IR ^KBr ν _max (cm ^-1 ); 3382,3057,295
7,1786,1731,1688,1613,1516,1493,1448,1360,1249,121
8,1175,1116,1085,1034

Example 10 (d) 7β- {2- (2-aminothiazol-4-yl) -2
-[(Z) -Hydroxyimino] acetamide} -3-
Sodium salt of (2-butynyl) thio-3-cephem-4-carboxylic acid NMR (DMSO-d ₆ ) δ (ppm); 1.78 (3H, t, J =
2.5Hz), 3.43 (1H, dq, J = 16,2.5Hz), 3.51 and 3.66 (2H, AB
q, J = 17Hz), 3.56 (1H, dq, J = 16,2.5Hz), 4.99 (1H, d, J = 4.5H
z), 5.59 (1H, dd, J = 4.5,8Hz), 6.65 (1H, S), 7.12 (2H, bS), 9.
39 (1H, d, J = 8Hz), 11.40 (1H, S)

IR ^KBr ν _max (cm ^-1 ); 3412,1762,166
2,1607,1533,1393,1353,1183,1129,1046

Example 11 7β- {2- (2-aminothiazol-4-yl) -2
-[(Z) -Hydroxyimino] acetamide} -3-
(2-Butynyl) thio-3-cephem-4-carboxylic acid pivaloyl oxymethyl ester NMR (DMSO-d ₆ ) δ (ppm); 1.16 (9H, S), 1.
80 (3H, t, J = 2.5Hz), 3.74 (1H, dq, J = 2.5,16Hz), 3.83 (1H, d
q, J = 2.5,16Hz), 3.84 and 3.88 (2H, ABq, J = 17Hz), 5.21 (1
H, d, J = 4.5Hz), 5.74 (1H, dd, J = 4.5,8Hz), 5.77 and 5.90 (2
H, ABq, J = 6Hz), 7.12 (2H, bS), 9.46 (1H, d, J = 8Hz)

IR ^KBr ν _max (cm ^-1 ); 3436,2975,178
0,1757,1674,1615,1531,1481,1456,1372,1282,1217,115
8,1110,1029 Example 12 (a) 7β-phenylacetamido-3- (2-propynyl) thio-3-cephem-4-obtained in Example 1 (a)
20 g of carboxylic acid paramethoxybenzyl ester was dissolved in 60 ml of dichloromethane, and 6 ml of anisole under ice cooling.
And 30 ml of trifluoroacetic acid were added and stirred for 1.5 hours.

The reaction solution was added dropwise to 1 liter of diisopropyl ether, and the precipitated crystals were collected by filtration to give 7β-phenylacetamide-3- (2-propynyl) thio-3-cephem-4.
14.5 g of carboxylic acid were obtained.

NMR (DMSO-d ₆ ) δ (ppm);
3.28 (1H, t, J = 2.5Hz), 3.50 and 3.58 (2H, ABq, J = 14Hz), 3.
71 (1H, dd, J = 2.5,17Hz), 3.79 (1H, dd, J = 2.5,17Hz), 3.84 (2
H, bS), 5.11 (1H, d, J = 4.5Hz), 5.61 (1H, dd, J = 4.5,8.5Hz),
7.17 ~ 7.38 (5H, m), 9.11 (1H, d, J = 8.5Hz), 13.42 (1H, bS)

IR ^KBr ν _max (cm ⁻¹ ); 3273,3047,178
5,1702,1670,1538,1452,1405,1346,1274,1238,1173,110
6

(B) 2.0 g (5.2 mM) of 7β-phenylacetamido-3- (2-propynyl) thio-3-cephem-4-carboxylic acid obtained in (a) above was added to N, N-. It was dissolved in 20 ml of dimethylformamide, 386 mg (3.6 mM) of sodium carbonate was added at room temperature and the mixture was stirred for 20 minutes.

Then, 1.63 g (6.8 mM) of pivaloyloxymethyl iodide was added under ice cooling and the mixture was stirred for 30 minutes.

After the reaction, 40 ml of 0.1N hydrochloric acid was added and extracted with 100 ml of ethyl acetate, and 50 ml of saturated saline solution × 2
After washing with, it was dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: n-hexane = 2: 1) to give 7β-phenylacetamide-3-.
2.4 g of (2-propynyl) thio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester was obtained.

NMR (DMSO-d ₆ ) δ (ppm);
1.16 (1H, S), 3.30 (1H, t, J = 2.5Hz), 3.49 and 3.58 (2H, AB
q, J = 14Hz), 3.79 (1H, dd, J = 2.5,16Hz), 3.87 (1H, dd, J = 2.5,
16Hz), 3.86 and 3.94 (2H, ABq, J = 17Hz), 5.23 (1H, d, J = 4.5
Hz), 5.64 (1H, dd, J = 4.5,8Hz), 5.79 and 5.89 (2H, ABq, J = 6
Hz), 7.21 to 7.33 (5H, m), 9.12 (1H, d, J = 8Hz)

IR ^KBr ν _max (cm ⁻¹ ); 3288,2976,178
6,1758,1707,1515,1482,1455,1375,1288,1236,1157,111
0,1029

(C) 7β-Phenylacetamido-3- (2-propynyl) thio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester obtained in (b) above.
0 g (4.0 mM) was dissolved in 20 ml of anhydrous dichloromethane, 0.63 g (8.0 mM) of pyridine and 1.24 g (6.0 mM) of phosphorus pentachloride were added under ice cooling, and at room temperature, 1
Stir for hours.

Then, under ice cooling, 1.77 g (24 mM) of isobutyl alcohol was added and stirred for 1 hour, then 6.5 ml of water was further added and stirred for 30 minutes. After the reaction, the precipitated crystals were collected by filtration to obtain 1.42 g of 7β-amino-3- (2-propynyl) thio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester hydrochloride.

NMR (DMSO-d ₆ ) δ (ppm);
1.15 (9H, S), 3.36 (1H, t, J = 2.5Hz), 3.85 and 4.01 (2H, AB
q, J = 16.5Hz), 3.94 (2H, d, J = 2.5Hz), 5.09 (1H, d, J = 4.5Hz),
5.26 (1H, d, J = 4.5Hz), 5.76 and 5.91 (2H, ABq, J = 6Hz), 9.1
9 (2H, bS)

IR ^KBr ν _max (cm ⁻¹ ); 3436,3267,297
6,2897,2648,2586,1771,1742,1718,1588,1541,1471,144
7,1400,1278,1210,1161,1126,1110,1034,1011

(D) 1.0 g of the hydrochloride obtained above (2.
6 mM) to which 30 ml of 1% aqueous sodium hydrogen carbonate was added to add ethyl acetate 30
Extracted with ml.

The organic layer was washed with 20 ml of saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off to give 7β-amino-3- (2-propynyl) thio-3-cephem-4.
-Carboxylic acid pivaloyloxymethyl ester 905m
g was obtained.

This ester was converted into tetrahydrofuran 15
1 ml of 2- (2-aminothiazol-4-yl) -2-[(Z) -trityloxyimino] acetic acid dissolved in ml.
-Oxybenzotriazole ester 1.4 g (2.6
(mM) was added at room temperature and stirred for 15 hours.

30 ml of water was added to the reaction solution to obtain ethyl acetate 4
Extract with 0 ml, 15 ml of sodium hydrogen carbonate solution 15 ml, saturated saline solution 30
After washing with ml successively, it was dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: n-hexane = 1: 1) to give 7β- {2- (2-aminothiazol-4-yl)-. 2-[(Z) -Trityloxyimino] acetamide} -3- (2-propynyl) thio-3-
Cefem-4-carboxylic acid piovaloyloxymethyl ester 1.7 g was obtained.

NMR (DMSO-d ₆ ) δ (ppm);
1.17 (9H, S), 3.30 (1H, t, J = 2.5Hz), 3.83 3.93 (2H, ABq, J = 1
7Hz), 3.86 (2H, d, J = 2.5Hz), 5.30 (1H, d, J = 4.5Hz), 5.80 an
d 5.92 (2H, ABq, J = 6Hz), 5.86 (1H, dd, J = 4.5,8.5Hz), 6.67
(1H, S), 7.17 ~ 7.37 (17H, m), 9.86 (1H, d, J = 8.5Hz)

IR ^KBr ν _max (cm ⁻¹ ); 3442,3283,308
9,2976,1790,1753,1683,1619,1538,1492,1448,1371,127
9,1217,1158,1108,1030

(E) 90% of 1.0 g (1.3 mM) of the piovaloyloxymethyl ester compound obtained in (d) above
It was dissolved in 3 ml of formic acid and stirred at room temperature for 1 hour.

The precipitated crystals were filtered off and the filtrate was washed with water 5
0 ml was added and extracted with 100 ml of ethyl acetate, water 50
After washing with ml × 8, it was dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the residue was subjected to Toyopearl column chromatography (eluting solvent; dichloromethane: acetone = 1: 1) to give 7β- {2- (2-aminothiazol-4-yl) -2- [(Z) -Hydroxyimino]
Acetamide} -3- (2-propynyl) thio-3-cephem-4-carboxylic acid pivaloyloxymethyl ester 0.5 g was obtained.

This product had the same NMR and IR spectra as those of the pivaloyloxymethyl ester product obtained in Example 2 (Production Method I).

Example 13 (a) 7β-Phenylacetamido-3- (2-propynyl) thio-3-cephem-4-obtained in Example 1 (a)
2.0 g (5.2 mM) of carboxylic acid was dissolved in 20 ml of N, N-dimethylformamide, and 386 mg (3.6 mM) of sodium carbonate was added at room temperature and stirred for 20 minutes.

Then, the mixture was cooled to -8 ° C., 1.7 g (6.7 mM) of 1-iodoethylisopropyl carbonate was added, and the mixture was stirred for 1 hour.

After the reaction, 70 ml of water was added and ethyl acetate 1 was added.
After extracting with 00 ml and washing with 70 ml of saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off, 11 ml of methanol was added to the residue, and the mixture was left for 1 hour.

The precipitated crystals were collected by filtration, and the obtained crystals were recrystallized from 10 ml of methanol to give 7β-phenylacetamide-3-, a single diastereomeric isomer.
811 mg of (2-propynyl) thio-3-cephem-4-carboxylic acid 1- (isopropyloxycarbonyloxy) ethyl ester was obtained.

NMR (DMSO-d ₆ ) δ (ppm);
1.29 (3H, d, J = 6Hz), 1.30 (3H, d, J = 6Hz), 1.55 (3H, d, J = 5.5H
z), 2.33 (1H, t, J = 2.5Hz), 3.42 (1H, dd, J = 2.5,18Hz), 3.58
(1H, dd, J = 2.5,18Hz), 3.64 (2H, S), 3.66 and 3.72 (2H, AB
q, J = 17Hz), 4.91 (1H, m), 4.97 (1H, d, J = 5Hz), 5.73 (1H, dd, J
= 5,9Hz), 6.21 (1H, d, J = 9Hz), 6.96 (1H, q, J = 5.5Hz), 7.20〜
7.42 (5H, m),

IR ^KBr ν _max (cm ^-1 ); 3339,3291,298
8,1781,1757,1694,1529,1454,1379,1290,1269,1222,116
4,1100,1075,1044,1001

In accordance with the operation and reaction conditions disclosed in Examples 12 (c) to (e), the following Examples 13 (b) to
The compound of (d) was obtained.

Example 13 (b) 7β-Amino-3- (2-propynyl) thio-3-cephem-4-carboxylic acid 1- (isopropyloxycarbonyloxy) ethyl ester hydrochloride NMR (DMSO-d ₆ ). δ (ppm); 1.22 (3H, d, J = 6
Hz), 1.24 (3H, d, J = 6Hz), 1.47 (3H, d, J = 5.5Hz), 3.37 (1H, t,
J = 2.5Hz), 3.82 and 4.01 (2H, ABq, J = 16Hz), 3.92 (2H, d, J =
2.5Hz), 4.81 (1H, m), 5.05 (1H, d, J = 5Hz), 5.24 (1H, d, J = 5H
z), 6.75 (1H, q, J = 5.5Hz), 9.08 (2H, bS)

IR ^KBr ν _max (cm ^-1 ); 3436,3284,298
7,2893,1776,1755,1724,1589,1543,1470,1397,1295,127
0,1209,1191,1162,1136,1114,1082,1037

Example 13 (c) 7β- {2- (2-aminothiazol-4-yl) -2
-[(Z) -Trityloxyimino] acetamide} -3
- (2-propynyl) thio-3-cephem-4-carboxylic acid 1- (isopropyloxycarbonyloxy) ethyl ester _{NMR (DMSO-d 6) δ} (ppm); 1.21 (3H, d, J = 6
Hz), 1.23 (3H, d, J = 6Hz), 1.50 (3H, d, J = 5.5Hz), 3.32t, J = 2.
5Hz), 3.83and 3.94 (2H, ABq, J = 17Hz), 3.88 (2H, d, J = 2.5H
z), 4.79 (1H, m), 5.29 (1H, d, J = 5Hz), 5.86 (1H, dd, J = 5,8.5H
z), 6.69 (1H, S), 6.82 (1H, q, J = 5.5Hz), 7.20 ~ 7.42 (17H,
m), 9.85 (1H, d, J = 8.5Hz)

IR ^KBr ν _max (cm ^-1 ); 3442,3285,308
9,2984,2936,1790,1762,1683,1619,1538,1493,1448,137
6,1268,1218,1161,1102,1074,1043

Example 13 (d) 7β- {2- (2-aminothiazol-4-yl) -2
-[(Z) -Hydroxyimino] acetamide} -3-
(2-propynyl) thio-3-cephem-4-carboxylic acid 1- (isopropyloxycarbonyloxy) ethyl ester This compound was obtained from the ester compound obtained in Example 5, NMR and I.
The R spectra were in agreement.

Front Page Continuation (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] Claims: (In the formula ¹ , R ¹ and R ³ represent a hydrogen atom or a lower alkyl group, and R ² represents a hydrogen atom or a group that is hydrolyzable in vivo.) Toxic salt.