JP2599105B2 - Dioxane adduct - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the following chemical formula (2):

Embedded image An intermediate used in a method for industrially producing a compound represented by the formula (syn isomer) or a salt thereof with high yield and high purity, that is, the following chemical formula (1)

Embedded image And a dioxane adduct (syn isomer) represented by the formula:

[0002]

2. Description of the Related Art A compound (syn isomer) represented by the chemical formula (2) useful as an antibacterial agent having an excellent antibacterial spectrum and exhibiting an excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, a salt thereof, and salts thereof. The production method is described in
No. 99592.

[0003]

However, in order to implement this industrially, a more excellent manufacturing method has been required.

[0004]

Means for Solving the Problems The inventors of the present invention have made intensive studies to solve the above-mentioned problems, and as a result, the general formula (3)

Embedded image [Wherein, X represents a halogen atom. (Syn isomer) or a salt thereof, and a compound represented by the chemical formula (4):

Embedded image After reacting with a compound represented by or a salt thereof or a reactive derivative thereof, subjected to a dehydration reaction,
The compound (syn isomer) represented by the chemical formula (1) is isolated by treating with dioxane, and then the dioxane is removed therefrom to obtain the compound (syn isomer) represented by the chemical formula (2) or a salt thereof. Was obtained in high yield and high purity, that is, the compound (syn isomer) represented by the chemical formula (1) was useful as an intermediate in the above production method, and the present invention was completed. .

Hereinafter, the present invention will be described in detail. Examples of the salt of the compound represented by the formula (2), (3), (4) or (5) include a salt in a basic group or an acidic group which is well known in the field of penicillin and cephalosporin compounds. Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid and sulfuric acid; and organic acids such as oxalic acid, succinic acid, formic acid, trichloroacetic acid and trifluoroacetic acid. Salts with carboxylic acids; methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-
Salts with sulfonic acids, such as sulfonic acid and mesitylenesulfonic acid (2,4,6-trimethylbenzenesulfonic acid), and salts of acidic groups, for example, salts with alkali metals such as sodium and potassium; Salts with alkaline earth metals such as calcium and magnesium; ammonium salts; salts with nitrogen-containing organic bases such as triethylamine, trimethylamine, aniline, N, N-dimethylaniline, pyridine and dicyclohexylamine.

Next, an embodiment of the present invention will be described. The production method of the compound of the present invention is as follows. In the formula, X represents a halogen atom.

Embedded image

(1) Acylation The compound represented by the chemical formula (5) (syn isomer) or a salt thereof is represented by the compound represented by the general formula (3) (syn isomer) or a salt thereof represented by the chemical formula (4). Compound or a salt thereof in a solvent, in the presence or absence of a base,
It can be obtained by reacting. The solvent used in this reaction may be any solvent as long as it does not adversely affect the reaction. For example, water, acetone, dioxane, acetonitrile, chloroform, methylene chloride,
Ethylene chloride, tetrahydrofuran, methyl acetate, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, ethylene glycol monomethyl ether
Examples thereof include solvents such as ter, ethylene glycol dimethyl ether, dimethyl sulfoxide, and sulfolane, or a mixture of two or more of these solvents. As the base used in this reaction, an inorganic base such as an alkali metal hydroxide, hydrogen carbonate or carbonate or a trimethylamine, triethylamine, tributylamine, pyridine, methylpyridine, N-methylmorpholine, lutidine, collidine or the like can be used. Tertiary amines may be mentioned. The compound represented by the chemical formula (4) has an amino group and / or
Alternatively, it can be used as a reactive derivative at a carboxyl group. Examples of the reactive derivative include a compound represented by the chemical formula (4) and a silyl compound such as bis (trimethylsilyl) acetamide, trimethylsilylacetamide, and trimethylsilyl chloride; Rin,

Embedded image A silyl derivative, a phosphorus derivative, a tin derivative, or the like generated by a reaction with a phosphorus compound such as (CH ₃ CH ₂ O) ₂ PCl or (CH ₃ CH ₂ ) ₂ PCl or a tin compound such as (C ₄ H ₉ ) ₂ SnCl. Those commonly used in acylation in the art can be mentioned. The amount of the compound represented by the general formula (3) (syn isomer) or a salt thereof is about 1.0 to 1.5 moles per mol of the compound represented by the chemical formula (4) or a salt thereof or a reactive derivative thereof. . This reaction may be carried out usually at -35 ° C to 25 ° C for several minutes to several hours.

(2) Dehydration reaction Then, the compound (syn isomer) represented by the chemical formula (5) obtained by the acylation or a salt thereof is subjected to a dehydration reaction in the presence or absence of an acid to obtain a compound represented by the chemical formula (5). The compound (syn isomer) represented by (2) or a salt thereof can be obtained. This reaction is preferably performed in a solvent, and any solvent may be used as long as it does not adversely affect the reaction. Examples thereof include methanol, ethanol, acetone, acetonitrile, nitromethane, methyl acetate, and ethyl acetate. , Chloroform, methylene chloride, tetrahydrofuran, N, N-dimethylformamide,
Examples thereof include a solvent such as N, N-dimethylacetamide, a mixture of two or more of these solvents, and a mixture of two or more of these solvents with water. Examples of the acid used in this reaction include protonic acids such as hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid and mesitylenesulfonic acid; Lewis acids such as boron trifluoride, aluminum chloride and zinc chloride; Examples include Lewis acid complex compounds such as boron and diethyl ether. When the solvent used is a non-aqueous solvent, a suitable dehydrating agent in the reaction system, for example,
Anhydrous magnesium sulfate or molecular sieve may be added. This reaction may be performed at 0 ° C. to 30 ° C. for several minutes to several hours.

(3) Formation of dioxane adduct The compound (syn isomer) represented by the chemical formula (2) or a salt thereof is treated with dioxane in the presence or absence of a solvent to give the compound represented by the chemical formula (1). (Syn isomer) can be obtained. Although it does not specifically limit as a solvent, For example, the mixed solvent of water and hydrophilic organic solvents, such as acetonitrile, is mentioned. The amount of dioxane used here is 1 to 10 times the molar amount of the compound (syn isomer) represented by the chemical formula (2) or a salt thereof. This treatment is preferably carried out under acidic conditions, and optimally has a pH of 2.5 to 3.0. In addition, this treatment is 15 ℃ ~ 30 ℃
Then, it may be carried out for 10 minutes to 10 hours.

Next, a method for producing a compound of formula (3) (syn isomer) or a salt thereof used as a raw material will be described. These compounds can be easily produced, for example, by the following production method. More specifically, it can be produced by the method described in JP-A-60-199894. In the formula, X represents a halogen atom.

[0011]

Embedded image Next, the compound represented by the chemical formula (2) can be easily produced by the following production method using the compound of the present invention.

[0012]

Embedded image Examples of a method for removing dioxane from the compound (syn isomer) represented by the chemical formula (1) include a method using an acid / base treatment, a solvent treatment, or the like, alone or in combination. Specifically, (i) ) The compound represented by the formula (1) (syn isomer) is converted into a salt by a conventional method using a base, and then dioxane is extracted and removed with an organic solvent such as chloroform, methylene chloride, and ethyl acetate. Acetone is added at 3.0 to obtain an acetone adduct, which is then treated with methanol. (Ii) The compound (syn isomer) represented by the chemical formula (1) is converted to an acid (for example, hydrochloric acid, etc.)
After treatment with an organic solvent system to form an acid addition salt (for example, hydrochloride), this is dissolved or suspended in an alcohol or hydrous alcohol, and then a deoxidizing agent such as triethylamine, pyridine, There are a method of reacting with propylene oxide and a method of (iii) acid / base treatment.

As the base used in (i),
Inorganic bases such as hydroxides, carbonates or bicarbonates of alkali metals, and organic bases such as triethylamine and pyridine are exemplified. The organic solvent used in (ii) may be any solvent as long as it does not adversely affect the reaction, and examples thereof include acetone, acetonitrile, and ethanol. Examples of the acid used in (iii) include hydrochloric acid, sulfuric acid, and the like.
The same inorganic or organic base as in (i) can be mentioned.

[0014]

Thus, by using the compound of the present invention, the compound represented by the chemical formula (2) (syn isomer) or a salt thereof can be obtained industrially with high yield and high purity.

EXAMPLES Next, the present invention will be described with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Example 1 7β-amino-3-[(5-methyl-2H-tetrazo-
2-yl) methyl] - [delta ³ - was suspended cephem-4-carboxylic acid 10.00g of anhydrous methylene chloride 100 ml, 0 to
At 5 ° C., 9.16 g of trimethylsilyl chloride is added, and 8.53 g of triethylamine is added dropwise at the same temperature over 30 minutes, and the mixture is reacted at the same temperature for 1 hour. The reaction solution was cooled to −30 ° C., and 12.87 g of hydrobromide of 2- (2-amino-4-hydroxy-2-thiazolin-4-yl) -2- (syn) -methoxyiminoacetic chloride was added to the reaction mixture. After adding at 30 to -20 ° C for 10 minutes, the reaction is carried out at 0 to 5 ° C for 1.5 hours. Then, after adding 50 ml of water and separating the aqueous layer, acetonitrile was added.
Add 50 ml. After adjusting the pH to 2.7 with sodium carbonate and filtering off insolubles, dioxane (16 ml) was added to the filtrate, and the mixture was added at 23 to 27.
Stir for 1 hour at 18 ° C and further for 1 hour at 18-22 ° C. The resulting crystals are collected by filtration and show a melting point of 183-185 ° C (decomposition).
β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(5
-Methyl-2H-tetrazol-2-yl) methyl]-
Delta ³ - dioxane adduct 15 cephem-4-carboxylic acid.
15 g (79.2% yield) are obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1770, 1675-1610 NMR (d ₆ -DMSO) δ value; 2.47 (3H, s, -CH ₃ ), 3.46 (2H, bs, C _2-
H), 3.58 (8H, s , di- oxane), 3.86 (3H, s, -OCH 3), 5.15 (1H, d, J =
_{5Hz, C 6 -H), 5.64} (2H, bs, C 3 -CH 2), 5.83 (1H, dd, J = 5Hz, 8H
z, C ₇ -H), 6.74 (1H, s, thiazole C ₅ -H), 7.15 (3H, bs, -N
H ₃ ⁺ ), 9.59 (1H, d, J = 8Hz, -CONH-)

REFERENCE EXAMPLE 1 (1) To 330 ml of water, 38.0 g of sodium nitrite and 66.1 g of 3-oxothiobutyric acid-S-methyl ester were added.
With stirring at 8 ° C., 210 ml of 4N sulfuric acid is added dropwise over a period of 30 minutes. After completion of the dropwise addition, the mixture is reacted at the same temperature for 30 minutes, and then the reaction solution is introduced into 500 ml of ethyl acetate. Separate the organic layer and add water 5
After washing with 00 ml, drying over anhydrous magnesium sulfate,
The solvent is distilled off under reduced pressure. After dissolving the obtained residue in 650 ml of an aqueous solution containing 106 g of sodium carbonate, methanol was added.
150 ml. To this solution, add 75.7 g of dimethyl sulfate
After the dropwise addition at 20 ° C., the reaction is carried out at the same temperature for 2 hours. Then, the reaction solution is introduced into 1 liter of ethyl acetate, the organic layer is separated, washed with 300 ml of water, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is distilled under reduced pressure to give 2-methoxyimino-3-oxothiobutyric acid-S-methyl ester having a boiling point of 80 to 86 ° C./2 mmHg (a mixture of syn and anti forms). ) 60.4 g (yield 68.9)
%).

(2) Dissolve 10.0 g of 2-methoxyimino-3-oxothiobutyric acid-S-methyl ester (a mixture of syn and anti forms) in 150 ml of 1,4-dioxane,
Pyridinium hydrobromide perbromide 20.1
g and react for 4 hours at room temperature. Then, the solvent is distilled off under reduced pressure, and 100 ml of ethyl acetate and 100 ml of water are added to the obtained residue. The organic layer was separated, and 100 ml of a 5% aqueous sodium bisulfite solution, 100 ml of water, and 10
After successively washing with 0 ml, it is dried over anhydrous magnesium sulfate. When the solvent was distilled off under reduced pressure, 11.6 g of 4-bromo-2-methoxyimino-3-oxothiobutyric acid-S-methyl ester (a mixture of syn and anti forms) was obtained (yield: 80.0 g).
%).

(3) (i) 50.0 g of 4-bromo-2-methoxyimino-3-oxothiobutyric acid-S-methyl ester (a mixture of syn and anti) was dissolved in 250 ml of acetone,
At −25 to −20 ° C., 7.5 g of thiourea are added over 1 hour.
The mixture was reacted at the same temperature for 2 hours, and the precipitated crystals were collected by filtration and washed with 50 ml of acetone to give 2- (2-amino-4-hydroxy-2-thiazolin-4-yl) -2- (syn) -methoxy. Hydrobromic acid of iminothioacetic acid-S-methyl ester
30.9 g (47.5% yield) are obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1650 (ii) The filtrate obtained in (i) above is concentrated under reduced pressure, and the obtained residue is dissolved in 200 ml of ethyl acetate. Then water 2
After washing with 00 ml, it is dried over anhydrous magnesium sulfate.
After introducing 2.0 g of dry hydrogen chloride at 0 to 5 ° C and reacting at room temperature for 5 hours, the mixture is washed twice with 100 ml of water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, the obtained residue is dissolved in 120 ml of acetone, and 3.0 g of thiourea is added over 1 hour at -25 to -20 ° C. The reaction was allowed to proceed at the same temperature for 2 hours, and the precipitated crystals were collected by filtration and washed with 20 ml of acetone.
(2-amino-4-hydroxy-2-thiazoline-4-
Yl) -2- (syn) -methoxyiminothioacetic acid-S-
10.1 g (15.5% yield) of the hydrobromide of the methyl ester are obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1650

(4) 20.0 g of hydrobromide of 2- (2-amino-4-hydroxy-2-thiazolin-4-yl) -2- (syn) -methoxyiminothioacetic acid-S-methyl ester Suspended in 100 ml of anhydrous methylene chloride, 0-5 ° C
Then, 100 ml of an anhydrous methylene chloride solution containing 8.6 g of chlorine is added dropwise over 10 minutes. Then, after reacting at the same temperature for 30 minutes, the precipitated crystals are collected by filtration and washed twice with 20 ml of anhydrous methylene chloride to give 2- (2-amino-4-) having a melting point of 120 to 122 ° C (decomposition). Hydroxy-2-thiazolin-4-yl) -2
14.6 g (75.7% yield) of hydrobromide salt of-(syn) -methoxyiminoacetic chloride are obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1780

Reference Example 2 (1) 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3
- [(5-methyl -2H- tetrazole - 2-yl) methyl] - [delta ³ - dioxane adduct 10.00g cephem-4-carboxylic acid was suspended in water 25 ml, bicarbonate at 18 to 22 ° C. 1.48 g of sodium are added and dissolved over 10 minutes.
Then, after adding 50 ml of methylene chloride and stirring for 10 minutes,
Separate the aqueous layer. After adding 50 ml of methylene chloride again and stirring for 10 minutes, the aqueous layer is separated. Then, 38 ml of acetone is added, the pH is adjusted to 5.0 with 2N hydrochloric acid, 500 mg of activated carbon is added, the mixture is stirred for 10 minutes, and then filtered through celite. The cake was washed with a mixed solvent of acetone (7 ml) and water (5 ml), and the filtrate was washed with a mixture of 23-27.
After adjusting the pH to 2.7 with 2N hydrochloric acid at ℃, 30 minutes at the same temperature,
Stir for an additional 30 minutes at 18-22 ° C. The obtained crystals are filtered, washed successively twice with 5 ml of 50% acetone and 15 ml of water, and then dried to give 7β showing a melting point of 149 to 153 ° C (decomposition).
-[(Z) -2- (2-aminothiazol-4-yl)
-2-methoxyiminoacetamido] -3-[(5-methyl-2H-tetrazol-2-yl) methyl]-[Delta] ³
-1/4 acetone adduct of cephem-4-carboxylic acid 6.
86 g (78.9% yield) are obtained. IR (KBr) cm ^-1 ; ν _{C = O} 1770, 1690-1610 NMR (d ₆ -DMSO) δ value; 2.09 (1.5 H, s, 1/4 acetone), 2.47 (3
H, s, -CH ₃ ), 3.46 (2H, bs, C ₂ -H), 3.85 (3H, s, -OCH ₃ ), 5.15
(1H, d, J = 5Hz, C ₆ -H), 5.41 (3H, bs, -NH ₃ ⁺ ), 5.64 (2H, bs, C _{3-
CH 2), 5.81 (1H,} dd, J = 5Hz, 8Hz, C 7 -H), 6.71 (1H, s, thiazole -
Le _{C 5 -H), 9.64 (1H} , d, J = 8Hz, -CONH-)

(2) 7β-[(Z) obtained in (1)
-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-[(5-methyl-2H
- tetrazole - 2-yl) methyl] - [delta ³ - 1/4 acetone adduct 5.00g cephem-4-carboxylic acid methano - are suspended in Le 10 ml, stirred for 1 hour at 18 to 22 ° C.. The obtained crystals were collected by filtration, washed with 3.8 ml of methanol, and dried to give 7β-[(Z) -2- (2-aminothiazo-
Ru-4-yl) -2-methoxyiminoacetamide]-
3-[(5-methyl-2H-tetrazol-2-yl)
Methyl] -Δ ³ -cephem-4-carboxylic acid 4.00 g (yield
82.3%). NMR (d ₆ -DMSO) δ value; 2.57 (3H, s, -CH ₃ ), 3.47 (2H, bs, C _2-
H), 3.86 (3H, s , -OCH 3), 5.15 (1H, d, J = 5Hz, C 6 -H), 5.65 (2H,
bs, C ₃ -CH ₂ ), 5.81 (1H, dd, J = 5Hz, 8Hz, C ₇ -H), 6.73 (1H, s, thiazole C ₅ -H), 6.92 (3H, bs, -NH ₃ ⁺ ), 9.61 (1H, d, J = 8Hz,-
CONH-)

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Isamu Isakawa 7-52 Oizuminakacho, Toyama City, Toyama Prefecture Examiner Megumi Saito (56) References JP-A-57-99592 (JP, A) JP-A-56-61388 (JP, A) JP-A-52-83574 (JP, A)

Claims (1)

(57) [Claims] [Claim 1] A dioxane adduct (syn isomer).