JPH07116200B2 - Cephalosporin manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention has the following chemical formula: The present invention relates to a method for industrially producing a compound (syn isomer) or a salt thereof with high yield and high purity.

[Prior Art] A compound (syn isomer) represented by the chemical formula [IV] having an excellent antibacterial spectrum and useful as an antibacterial agent showing excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, salts thereof, and salts thereof The manufacturing method is disclosed in JP-A-57-99592.

[Problems to be Solved by the Invention] However, in order to carry out this industrially, a further excellent manufacturing method was required.

[Means for Solving the Problem] As a result of earnest studies to solve the above problems, the present inventors have found that the general formula [In the formula, X represents a halogen atom. ] The compound (syn isomer) represented by or its salt and chemical formula After reacting with a compound represented by or a salt thereof or a reactive derivative thereof, dehydration reaction is carried out, and then,
The compound represented by the chemical formula [III] (syn isomer) is isolated by treating with dioxane, and then the dioxane is eliminated from the compound, whereby the compound represented by the chemical formula [IV] (syn isomer) or a salt thereof. Can be obtained in high yield and high purity, and further has the chemical formula [III] The inventors have found that the dioxane addition compound (syn compound) represented by is useful as an intermediate in the above-mentioned production method, and completed the present invention.

Hereinafter, the present invention will be described in detail.

Examples of the salt of the compound represented by the formula [I], [II], [IV] or [V] include salts in a basic group or an acidic group well known in the art 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; 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-
Examples thereof include salts with sulfonic acids such as sulfonic acid, mesitylene sulfonic acid, and (2,4,6-trimethylbenzenesulfonic acid). Examples of salts in the acidic group include salts with alkali metals such as sodium and potassium. Salts with alkaline earth metals such as calcium and magnesium; ammonium salts; triethylamine, trimethylamine,
Examples thereof include salts with a nitrogen-containing organic base such as aniline, N, N-dimethylaniline, pyridine and dicyclohexylamine.

Next, an embodiment of the method of the present invention will be described. The manufacturing method of the present invention is as follows.

In the formula, X represents a halogen atom.

(1) Acylation A compound represented by the chemical formula [V] (syn isomer) or a salt thereof is a compound represented by the general formula [I] (syn isomer) or a salt thereof and a compound represented by the chemical formula [II] or The salt and the 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, and examples thereof include 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 ethylene glycol dimethyl ether, dimethyl sulfoxide, and sulfolane, or a mixture of two or more kinds of these solvents. Examples of the base used in this reaction include alkali metal hydroxides, inorganic bases such as hydrogen carbonate and carbonate, or trimethylamine, triethylamine, tributylamine, pyridine,
Examples include tertiary amines such as methylpyridine, N-methylmorpholine, lutidine and collidine. The compound represented by the chemical formula [II] can also be used as a reactive derivative at the amino group and / or the carboxyl group. Examples of the reactive derivative include the compound represented by the chemical formula [II] and bis (trimethylsilyl). ) Acetamide, trimethylsilylacetamide, silyl compounds such as trimethylsilyl chloride, phosphorus trichloride, (CH ₃ CH _{2) 2} silyl derivative formed by the reaction of a phosphorus compound or a (C ₄ H ₉₎ tin compounds such as ₂ S _n Cl such as PCl, frequently used in the acylation in the art such as phosphorus derivatives or tin derivatives The things that are done are listed. General formula [I]
The compound (syn isomer) or a salt thereof is used in an amount of about 1.0 to 1.5 times the molar amount of the compound represented by the chemical formula [II] 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 Next, the compound (syn isomer) represented by the chemical formula [V] or a salt thereof obtained by acylation is subjected to a dehydration reaction in the presence or absence of an acid to give the chemical formula [I
A compound represented by V] (syn isomer) or a salt thereof can be obtained. This reaction is preferably carried out in a solvent, and any solvent may be used as long as it does not adversely influence the reaction, and examples thereof include methanol, ethanol, acetone, acetonitrile, nitromethane, methyl acetate, ethyl acetate, chloroform and chloride. Solvents such as methylene, tetrahydrofuran, N, N-dimethylformamide and N, N-dimethylacetamide, a mixture of two or more of these solvents, or a mixture of water and two or more of these solvents can be mentioned. Examples of the acid used in this reaction include protic acids such as hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid and mesitylenesulfonic acid; Lewis acids such as boron trifluoride, aluminum chloride and zinc chloride; trifluoride. Examples thereof include complex compounds of Lewis acids such as boron and diethyl ether. When the solvent used is a non-aqueous solvent, a suitable dehydrating agent such as anhydrous magnesium sulfate or molecular sieve may be added to the reaction system. This reaction may be carried out at 0 ° C to 30 ° C for several minutes to several hours.

(3) Formation of dioxane adduct A compound represented by the chemical formula [III] (syn isomer) or a salt thereof is treated with dioxane in the presence or absence of a solvent to obtain a compound represented by the chemical formula [III] ( Syn isomer) can be obtained. The solvent is not particularly limited, and examples thereof include a mixed solvent of water and a hydrophilic organic solvent such as acetonitrile. The amount of dioxane used here is 1 to 10 moles per mol of the compound represented by the chemical formula [IV] (syn isomer) or a salt thereof. This treatment is preferably carried out under acidic conditions, optimally pH 2.5-3.0. In addition, this treatment is 15 ℃ ~ 30 ℃
Then, it may be carried out for 10 minutes to 10 hours.

(4) Desorption of dioxane Examples of the method of removing dioxane of the compound (syn isomer) represented by the chemical formula [III] include a method of using acid / base treatment, a solvent treatment and the like, alone or in combination, Specifically, (i) a compound represented by the chemical formula [III] (syn isomer) is converted into a salt by a conventional method using a base, and then dioxane is extracted with an organic solvent such as chloroform, methylene chloride or ethyl acetate. Acetone adduct is obtained by adding acetone at pH 2.5 to 3.0, and then treating the product with methanol. (Ii) The compound represented by the chemical formula [III] (syn isomer) is treated with an acid (for example, hydrochloric acid). Etc.)-Treated with an organic solvent system, acid addition salt (for example,
(Hydrochloride, etc.), and then dissolving or suspending this in alcohol or hydrous alcohol, and then reacting with a deoxidizing agent such as triethylamine, pyridine, propylene oxide, (iii) acid / base treatment There are ways to do it.

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

Next, a method for producing the compound of formula [I] (syn isomer) or a salt thereof used as a raw material will be described.

These compounds can be easily produced, for example, by the production method shown below. Furthermore, specifically,
It can be produced by the method described in JP-A-60-199894.

In the formula, X represents a halogen atom.

[Effects of the Invention] Thus, by carrying out the method of the present invention, the compound (syn isomer) represented by the chemical formula [IV] or a salt thereof can be industrially obtained in 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.

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 to give 5 to 8
210 ml of 4N-sulfuric acid was added dropwise over 30 minutes with stirring at ℃.
After the dropping is completed, the reaction is carried out 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 500 ml of water.
After washing with, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue obtained is sodium carbonate
After dissolving in 650 ml of an aqueous solution containing 106 g, methanol 150
Add ml. To this solution, add 75.7g of dimethylsulfate to 15 ~ 20 ℃.
Then, the mixture is reacted at the same temperature for 2 hours. Then, the reaction solution is introduced into ethyl acetate 1, the organic layer is separated, washed with 300 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was distilled under reduced pressure to give 2-methoxyimino-3-oxothiobutyric acid-S-methyl ester (a mixture of syn and anti forms) having a boiling point of 80 to 86 ° C / 2 mmHg. ) 60.4 g (yield 68.9%) are obtained.

(2) 2-methoxyimino-3-oxothiobutyric acid-S-
Methyl ester (mixture of syn and anti forms) 10.0g
Is dissolved in 150 ml of 1,4-dioxane, 20.1 g of pyridinium hydrobromide perbromide is added, and the mixture is reacted at room temperature for 4 hours. Then, the solvent was distilled off under reduced pressure,
100 ml of ethyl acetate and 100 ml of water are added to the residue obtained. The organic layer is separated and a 5% aqueous solution of sodium hydrogen sulfite is added.
The extract is washed successively with 100 ml, 100 ml of water and 100 ml of saturated saline, and then dried over anhydrous magnesium sulfate. If the solvent is distilled off under reduced pressure, 4-bromo-2-methoxyimino-3-
11.6 g (yield 80.0%) of oxothiobutyric acid-S-methyl ester (mixture of syn and anti forms) is obtained.

(3) (i) 4-bromo-2-methoxyimino-3-oxothiobutyric acid-S-methyl ester (syn and anti-mixture) (50.0 g) was dissolved in acetone (250 ml) to give -25 to -20.
Add 7.5 g of thiourea over 1 hour at 0 ° C. 2 at the same temperature
After reacting for a period of time, 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) -methoxyiminothioacetic acid- 30.9 g (yield 47.5%) of hydrobromic acid of S-methyl ester is obtained.

IR (KBr) cm ^-1 ; ν _{C = O} 1650 (ii) The filtrate obtained in (i) above is concentrated under reduced pressure and the residue obtained is dissolved in 200 ml of ethyl acetate. Then, it is washed with 200 ml of water and dried over anhydrous magnesium sulfate. 2.0 g of dry hydrogen chloride was introduced at 0 to 5 ° C., reacted at room temperature for 5 hours, washed twice with 100 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was dissolved in 120 ml of acetone, and the temperature was -25 to -20 ° C.
Then, 3.0 g of thiourea is added over 1 hour. After reacting for 2 hours at the same temperature, the precipitated crystals were collected by filtration and washed with 20 ml of acetone to give 2- (2-amino-4-hydroxy-2-thiazolin-4-yl) -2- (syn) -methoxyimino. 10.1 g of hydrobromide of thioacetic acid-S-methyl ester (yield 15.
5%).

IR (KBr) cm ^-1 ; ν _{C = O} 1650 (4) 2- (2-amino-4-hydroxy-2-thiazolin-4-yl) -2- (syn) -methoxyiminothioacetic acid-S-methyl 20.0 g of the ester hydrobromide is suspended in 100 ml of anhydrous methylene chloride and 100 ml of an anhydrous methylene chloride solution containing 8.6 g of chlorine is added dropwise at 0-5 ° C. over 10 minutes. Then, after reacting for 30 minutes at the same temperature, the precipitated crystals are collected by filtration and washed twice with 20 ml of anhydrous methylene chloride to give a melting point of 12
1-4.6 g (yield of 2- (2-amino-4-hydroxy-2-thiazolin-4-yl) -2- (syn) -methoxyiminoacetic acid chloride hydrobromide showing 0-122 ° C (decomposition) 7
5.7%).

IR (KBr) cm ⁻¹ ; ν _C═O 1780 Example 1 7β-Amino-3-[(5-methyl-2H-tetrazol-2-yl) methyl] -Δ ³ -cephem-4-carboxylic acid 10.00 g Suspended in 100 ml of anhydrous methylene chloride, 0-5
9.16 g of trimethylsilyl chloride was added at ℃,
At the same temperature, 8.53 g of triethylamine was added dropwise over 30 minutes, and the reaction was carried out at the same temperature for 1 hour. The reaction solution was cooled to −30 ° C., and 12.87 g of 2- (2-amino-4-hydroxy-2-thiazolin-4-yl) -2- (syn) -methoxyiminoacetic acid chloride hydrobromide was added. After adding at 30 to -20 ° C over 10 minutes, the mixture is reacted at 0 to 5 ° C for 1.5 hours. Then, 50 ml of water was added to separate the aqueous layer, and then acetonitrile was used.
Add 50 ml. The pH was adjusted to 2.7 with sodium carbonate, the insoluble matter was filtered off, 16 ml of dioxane was added to the filtrate, and 23 to 27
Stir at 1 ° C for 1 hour, then at 18-22 ° C for 1 hour. The crystals obtained have a melting point of 183 to 185 ° C. (decomposition) when filtered.
β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(5
-Methyl-2H-tetrazol-2-yl) methyl] -Δ
Dioxane adduct of ³ -cephem-4-carboxylic acid 15.15
g (yield 79.2%) is obtained.

IR (KBr) cm^-1; Ν_{C = O}1770, 1675 to 1610 NMR (d₆-DMSO) δ value; 2.47 (3H, s, -CH₃), 3.46 (2H, bs, C₂-H), 3.58 (8H,
s,), 3.86 (3H, s, −OCH₃), 5.15 (1H, d, J = 5Hz, C₆-H),
5.64 (2H, bs, C₃-CH₂), 5.83 (1H, dd, J = 5Hz, 8Hz, C₇−
H), 6.74 (1H, s, thiazole C_Five-H), 7.15 (3H, bs, -N
H₃ ), 9.59 (1H, d, J = 8Hz, -CONH-) Example 2 (1) 7β-[(Z) -2- (2-aminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
[(5-Methyl-2H-tetrazol-2-yl) meth
] -Δ³-Cephem-4-carboxylic acid with dioxane
Suspend 10.00 g of the added body in 25 ml of water and add sodium bicarbonate at 18-22 ° C.
Add 1.48 g of thorium over 10 minutes to dissolve. One
Then, add 50 ml of methylene chloride and stir for 10 minutes.
Separate layers. Add 50 ml of methylene chloride again and stir for 10 minutes.
After stirring, the aqueous layer is separated. Then add 38 ml of acetone.
Adjust the pH to 5.0 with 2N-hydrochloric acid and add 500 mg of activated carbon.
After stirring for 10 minutes, it is filtered through Celite. Acetone from the filter cake
Wash with a mixed solvent of 7 ml and 5 ml of water, and filter the filtrate at 23-27 ° C.
After adjusting the pH to 2.7 with 2N-hydrochloric acid, add 30 minutes at the same temperature.
Stir for 30 minutes at 18-22 ° C. The obtained crystals are filtered,
Washed sequentially with 5% 50% acetone and 15 ml water twice each
If dried afterwards, 7β- showing a melting point of 149-153 ° C (decomposition)
[(Z) -2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3-[(5-methyl
L-2H-tetrazol-2-yl) methyl] -Δ³-C
6.86 g of 1/4 acetone adduct of fem-4-carboxylic acid
Rate 78.9%).

IR (KBr) cm^-1; Ν_{C = O}1770, 1690-1610 NMR (d₆-DMSO) δ value; 2.09 (1.5H, s, 1/4 acetone), 2.47 (3H, s, -CH₃), 3.46
(2H, bs, C₂-H), 3.85 (3H, s, -OCH₃), 5.15 (1H, d, J
= 5Hz, C₆-H), 5.41 (3H, bs, -NH₃ ), 5.64 (2H, bs, C
₃-CH₂), 5.81 (1H, dd, J = 5Hz, 8Hz, C₇-H), 6.71 (1H,
s, thiazole C_Five-H), 9.64 (1H, d, J = 8Hz, -CONH-) (2) 7β-[(Z) -2- (2-a
Minothiazol-4-yl) -2-methoxyiminoacetate
Toamido] -3-[(5-methyl-2H-tetrazole-
2-yl) methyl] -Δ³-Cephem-4-carboxylic acid
1/4 acetone adduct of 5.00 g was suspended in 10 ml of methanol.
And stir at 18-22 ° C for 1 hour. The crystals obtained are collected by filtration
Then, if it is washed with 3.8 ml of methanol and then dried, 7β-
[(Z) -2- (2-aminothiazol-4-yl)-
2-Methoxyiminoacetamide] -3-[(5-methyl
L-2H-tetrazol-2-yl) methyl] -Δ³-C
4.00 g (82.3% yield) of fem-4-carboxylic acid is obtained.

NMR (d₆-DMSO) δ value; 2.57 (3H, s, -CH₃), 3.47 (2H, bs, C₂-H), 3.86 (3H,
s, −OCH₃), 5.15 (1H, d, J = 5Hz, C₆-H), 5.65 (2H, bs,
C₃-CH₂), 5.81 (1H, dd, J = 5Hz, 8Hz, C₇-H), 6.73 (1
H, s, thiazole C_Five-H), 6.92 (3H, bs, -NH₃ ), 9.61
(1H, d, J = 8Hz, -CONH-) Example 3 (1) 7β-[(Z) -2- (2-aminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
[(5-Methyl-2H-tetrazol-2-yl) meth
] -Δ³-Cephem-4-carboxylic acid with dioxane
Suspend 10.00g of added body in 30ml of 90% ethanol, 23-27 ℃
Then add 2.1 ml of concentrated hydrochloric acid to dissolve and add 1.00 g of activated carbon.
Stir for 10 minutes. Then, it is filtered through Celite and the filter cake is 90%
After washing with 15 ml of ethanol, add 2.1 ml of concentrated hydrochloric acid to the filtrate.
Stir at 23-27 ° C for 5 hours. The crystals obtained are collected by filtration
Then, wash with 5 ml of 90% ethanol and dry. Melting point 156-
7β-[(Z) -2- (2-ami) showing 158 ° C (decomposition)
Nothiazol-4-yl) -2-methoxyiminoaceto
Amido] -3-[(5-methyl-2H-tetrazole-2
-Yl) methyl] -Δ³-Of cephem-4-carboxylic acid
6.84 g (75.2% yield) of hydrochloric acid hydrochloride is obtained.

IR (KBr) cm^-1; Ν_{C = O}1770, 1720, 1680-1620 NMR (d₆-DMSO) δ value; 2.48 (3H, s, -CH₃), 3.61 (2H, bs, C₂-H), 3.99 (3H,
s, −OCH₃), 5.20 (1H, d, J = 5Hz, C₆-H), 5.68 (2H, bs,
C₃-CH₂), 5.81 (1H, dd, J = 5Hz, 8Hz, C₇-H), 6.41 (3
H, bs, −NH₃ ), 6.97 (1H, s, thiazole C_Five-H), 9.95
(1H, d, J = 8Hz, -CONH-) (2) 7β-[(Z) -2- (2-aminothiazole-
4-yl) -2-methoxyiminoacetamide] -3-
[(5-Methyl-2H-tetrazol-2-yl) meth
] -Δ³-5.20 g of cephem-4-carboxylic acid hydrochloride
Dissolve it in 11 ml of methanol and propylene oxide at 25 ℃.
After adding 1.17 g of id, stir at 23-27 ° C for 1.5 hours.
The crystals obtained are collected by filtration, washed twice with 3 ml of methanol and dried.
If dried, 7β-[(Z) -2- (2-aminothiazo
L-4-yl) -2-methoxyiminoacetamide]-
3-[(5-methyl-2H-tetrazol-2-yl) me
Chill] -Δ³-Cephem-4-carboxylic acid 3.61 g (yield 7
4.7%).

The physical properties (NMR) of this compound were the same as those obtained in Example 2 (2).

Example 4 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-[(5
-Methyl-2H-tetrazol-2-yl) methyl] -Δ
3.50 g of dioxane adduct of ³ -cephem-4-carboxylic acid
Is suspended in 21 ml of water, and sodium hydrogen carbonate 52
Add 0 mg over 10 minutes to dissolve. Then, the pH is adjusted to 2.7 with 2N hydrochloric acid, and the mixture is stirred at the same temperature for 10 minutes. The crystals obtained were collected by filtration, washed twice with 5 ml of water and dried to give 7β.
-[(Z) -2- (2-aminothiazol-4-yl)
2-Methoxyiminoacetamido] -3-[(5-methyl-2H-tetrazol-2-yl) methyl] -Δ ³ −
2.35 g (yield 79.4%) of cephem-4-carboxylic acid are obtained.

The physical properties (NMR) of this compound were the same as those obtained in Example 2 (2).

 ─────────────────────────────────────────────────── ─── Continuation of front page Examiner Kenji Hiromi (56) References JP-A-57-99592 (JP, A) JP-A-56-61388 (JP, A) JP-A-52-83574 (JP, A)

Claims (1)

[Claims] 1. A general formula [In the formula, X represents a halogen atom. ] The compound (syn isomer) represented by After reacting with a compound represented by or a salt thereof or a reactive derivative thereof, it is subjected to dehydration reaction and then treated with dioxane to obtain a compound represented by the chemical formula: A dioxane addition compound (syn isomer) represented by is isolated, and dioxane is eliminated from this compound. A method for producing a compound represented by (syn isomer) or a salt thereof.