KR860000345B1 - Process for preparing cephalosporin derivatives - Google Patents

Abstract

Cephalosporin derivative (I), used as an antibiotic agent, is prepared from cephalosporin(V) by reacting with a thio ester (IV), having formula R1-CO-S-R2, obtained from acyl chloride (II), having formula R1-CO-Cl, by reacting with thiol (III), having formula HS-R2, where: R1 = (2-amino-4-thiazolyl) [(Z)-methoxyimino! methyl gp.; R2 = 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4triazine-3-yl gp.; and M = H, Na, or a protective gp.

Description

Method for preparing cephalosporin derivative

The present invention relates to a novel process for preparing cephalosporin derivatives of general formula (I), which is particularly useful for gram-positive and gram-negative antibiotics.

In the above formula,

R 'represents a (2-amino-4-thiazolyl) [(Z) -methoxyimino] methyl group,

R ² represents a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl group,

M represents hydrogen, sodium or a protecting group.

The method of the present invention is a novel method different from the known general acylation method.

Cephalosporin derivatives of the general formula (I) have already been reported in the literature. [Reference: German Patent Application Laid-Open Patent No. 2,922,036] In the known acylation method, cephalosporin is reacted with a towel in advance at the 3 position and then acylated, which is not preferable in terms of yield, and thus economical efficiency is low.

As a result of repeated studies to solve the disadvantages of the known methods, the inventors have found a method for economically preparing cephalosporin derivatives.

The novel production method of the present invention is described in the following scheme.

Wherein R ¹ , R ² and M are as defined above.

In general, a new production method of the present invention is described by adding the thioester of the general formula (IV) obtained by reacting the acyl chloride of the general formula (II) with the thiol of the general formula (III). Reaction with palosporin affords the final product of formula (I). Solvents used for this purpose include ethyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, chloroform, methylene chloride, trichloroethane, ethyl acetate, butyl acetate, dimethylformamide, and the like, which do not inhibit the reaction. Any solvent may be used.

The reaction is usually cooled or carried out at room temperature, but may also be carried out under warming. That is, it usually reacts between -20 ° C and 35 ° C, preferably -5 ° C to + 5 ° C. Although the reaction time varies depending on the reaction temperature, the compound used in the reaction, the solvent, and the like, it is appropriately selected within several tens of minutes to several tens of hours, and usually 30 minutes to 48 hours, preferably 1 hour to 10 hours.

The present invention is a novel method for producing the cephalosporin derivative as mentioned above in a very simple manner and will be described in more detail in the following examples, which are not intended to limit the scope of the present invention.

Example 1

A) Add 18 grams of 2- (2-amino-4-thiazolyl) -2-[(Z) -methoxyimino] acetyl chloride to 200 ml of methylene chloride and stir at room temperature.

B) Add 16 grams of 2,5-dihydro-6-hydroxy-2-methyl-3-mercapto-5-oxo-1,2,4-triazine to 150 milliliters of methylene chloride for 2 hours at room temperature After stirring, the solution of a) was added over 2 hours, adjusted to pH 6.5 to pH 7.0 with trieltylamine, stirred at 20 ° C. to 25 ° C. for 5 hours, and then adjusted to pH 6.5 to pH 7.0 again using a separatory funnel. After washing twice with 100 ml of distilled water, the organic layer is separated.

C) Dissolve 27 grams of 7-amino cephalosporinic acid and 14 grams of potassium carbonate in 400 milliliters of distilled water, add 200 milliliters of methylene chloride, and stir the product at 0 ° C to 5 ° C over 1 hour. After slowly adding and stirring for 1 hour, the aqueous layer was separated, 400 ml of methylene chloride was added thereto, and the mixture was stirred, adjusted to pH 2.0 with 1N hydrochloric acid, the organic layer was separated, washed with 100 ml of distilled water, and the organic layer was separated. After concentration under reduced pressure, 100 ml of acetone is completely dissolved in the remaining yellow solid, and 600 ml of isopropanol is added to precipitate crystals. The crystals were filtered, washed with 200 milliliters of isopropanol and dried overnight at 40 ° C. to obtain 40 grams of crystals.

D) Dissolve the crystals produced in 40 g of c) in a mixed solvent of 270 ml of acetone 70 ml of n-butanol and 10 ml of distilled water, and then dissolve 10.5 grams of sodium 2-ethylhexanoate in 270 ml of n-butanol. After adding the dissolved solution to the mixture and stirring for 1 hour or more, crystals gradually precipitate. The crystals were filtered off, washed with 100 ml of acetone and dried overnight at 40 ° C. to 32 grams of 7- [2- (2-amino-4-thiazolyl) -2-[(Z) -methoxyimino] acet. Amido] -3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl) thio] methyl] -8-oxo Obtain 5-5-thia-1-azabicyclo [4.2.0] octet-2-&-2-kisan disodium salt hydrate.

Example 2

A) Add 9 grams of 2- (2-amino-4-thiazolyl) -2-[(Z) -methoxyimino] acetyl chloride to 100 ml of ethyl acetate and stir at room temperature.

B) 8 grams of 2,5-dihydro-6-hydroxy-2-methyl-3-mercapto-5-oxo-1,2,4-triazine was added to 80 ml of ethyl acetate for 2 hours at room temperature. After stirring, the solution of a) was added over 1 hour, adjusted to pH 6.5 to pH 7.0 with triethyl amine, stirred for 5 hours, then adjusted to pH 6.5 to pH 7.0, and twice with 80 ml of distilled water using a separatory funnel. Wash and separate organic layer.

C) Dissolve 13.6 grams of 7-amino cephalosporinic acid and 5.3 grams of sodium carbonate in 150 milliliters of distilled water.

150 ml of ethyl acetate was added and the product of b) was slowly added over 1 hour while maintaining 0 ° C to 5 ° C, followed by stirring for 1 hour or more, and the aqueous layer was separated. 150 ml of ethyl acetate was added to the aqueous layer and the mixture was stirred, adjusted to pH 2.0 with 1N hydrochloric acid, the organic layer was separated, washed twice with 80 ml of distilled water, the organic layer was separated, dehydrated with magnesium sulfate, filtered, and concentrated to a yellow solid. Get 29 grams This replacement is dissolved in 100 ml of acetone and 10 ml of distilled water, and a solution of 8.5 grams of sodium 2-ethylhexanoate in 100 ml of acetone is added and seeded, followed by stirring for 2 hours while maintaining 0 to 5 ° C. do.

The crystalline precipitate was filtered off, washed with 100 ml of acetone and dried overnight at 40 ° C. to yield 16 grams of 7- [2- (2-amino-4-thiazolyl) 2-[(Z) -methoxyamino] acet. Amido] -3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl) thio] methyl] -8-oxo Obtain 5-5-thia-1-azabicyclo [4.2.0] octet-2-ene-2-carboxylic acid disodium salt hydride.

Claims (1)

The reaction of acyl chloride of the following general formula (II) with thiol of the following general formula (III) and the reaction of thioester of the following general formula (IV) with cephalosporin of the following general formula (V) in a reactor To prepare a cephalosporin derivative of the following general formula (I).

In the general formula, R ¹ represents (2-amino-4-thiazolyl) [(Z) -methoxyimino] methyl group, and R ² represents 2,5-dihydro-6-hydroxy-2-methyl-5- Represents an oxo-1,2,4-triazin-3-yl group and M represents hydrogen, sodium or a protecting group.