KR19980077157A - Method for preparing intermediate for manufacturing cefem derivatives - Google Patents

Abstract

In the concentrated hydrochloric acid solution, the compound of formula 1 was stirred at a temperature of 50-80 ° C. and the temperature was cooled to room temperature to dissolve the compound of formula 2 in a dimethylformamide solution, followed by addition of phosphorus oxychloride. After the compound is prepared, methylene chloride is added and the compound of Formula 4 is added to prepare a compound of Formula 5 that can be used as an intermediate in the preparation of cefem derivatives.

Description

Method for preparing intermediate for manufacturing cefem derivatives

[Industrial use]

The present invention relates to a cefem derivative, and more particularly to a new method for preparing intermediates used in the production of cefem derivatives.

[Prior art]

Cephalosporins (CEP), like penicillins, are antibiotics that exhibit bactericidal activity by inhibiting the cell wall formation of pathogens. Cephalosporin has a basic structure of 7-ACA (7-aminocephalosporanic acid), but sephamycin (cephamycin) with a methoxy group (-OCH ₃ ) attached to carbon 7 has been developed, and the cephamycin and cephalosporin are collectively known as the cefemine system. It is called an antibiotic.

The cefem antibiotics are classified into first generation, second generation, and third generation mainly on in vivo metabolism. Among them, the third generation cefe type antibiotics have high safety against gram-lactamase caused by gram-negative bacteria and have a broad antimicrobial spectrum, which is effective for almost all gram-negative bacillus. In addition, the third generation cefem antibiotics have a strong bactericidal activity against Pseudomonas aeruginosa , and is injected into the muscle or vein because of poor absorption in the stomach. Commonly applied symptoms include urinary tract infections in patients with reduced defense function, lower respiratory tract infections in hospitals, sepsis, meningitis in hospitals, sepsis and meningitis in newborns, surgical prophylaxis, and severe infections before the causative organism is identified. have. Antibiotics belonging to it include cefoaxime, ceftizoxime, cefoperazone, ceftazidime, ceftriaxone and the like.

In general, the production method of the intermediate used in the manufacture of cetactac, ceftriaxone and the like is as follows.

Scheme 1

The reaction uses triphenylpospine (TPP) as a reaction raw material, which is expensive and uses about 1.2 equivalents, which requires a large amount.

In addition, triphenylphosphine is a poisonous substance, which is highly toxic to aquatic environment organisms, and thus has problems in use, and triphenylphosphine oxide (TPPO), which is a form recovered after use, should be discarded because it has no other purpose. The toxicity to aquatic organisms is strong, there is a problem that must go through another process when disposed.

The present invention has been made to solve the above-mentioned problems of the prior art, an object of the present invention in the conventional method for producing an intermediate used in the production of cefem derivatives, generated by using a toxic substance triphenylphosphine An object of the present invention is to provide a method for preparing an intermediate for preparing a new cefem derivative.

[Means for solving the problem]

The present invention has the following configuration to achieve the above object of the present invention.

The present invention prepares the compound of formula 2 by stirring the compound of formula 1 below in a concentrated hydrochloric acid solution at a temperature of 50 ~ 80 ℃ and cooling the temperature to room temperature and the compound of formula 2 is dimethylformamide : Dissolved in a polar organic solvent or a halogenated organic solvent such as DMF), and then phosphorus oxychloride is added to prepare a compound of Formula 3 below, and a halogenated organic solvent is added to the compound of Formula 3, and a compound of Formula 4 It provides a method for producing an intermediate for the preparation of cefem derivatives comprising the step of preparing a compound of formula (5) by adding a.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

In the present invention, the phosphorus oxychloride is preferably selected from the group consisting of PCl ₃ , POCl ₃ , PCl ₅ and SOCl ₂ .

In the present invention, the compound of Formula 1 is 195 to 205 parts by weight, the compound of Formula 2 is 230 to 240 parts by weight, the compound of Formula 3 is 260 to 270 parts by weight, and the compound of Formula 4 is 185 to 195 By weight, the compound of Formula 5 is preferably 340 to 350 parts by weight.

The new production method of the intermediate used for the production of cefem derivatives according to the present invention will be described in detail as follows.

A compound of formula 1 is dissolved in a concentrated hydrochloric acid solution to form a compound of formula 2 in amine hydrochloride form as shown in Scheme 2 below. Then, as shown in Scheme 3 below, the compound of Formula 2 is again prepared as a compound of Formula 3 in acyl chloride form using PCl ₃ , POCl ₃ , PCl _5, or SOCl ₂ . The resulting material is reacted with compound Na-MBT of formula 4 to obtain a compound of formula 5, which is the desired intermediate, which is shown in Scheme 4 below.

Scheme 2

Scheme 3

Scheme 4

When water is added to the compound of formula 5 and neutralized with caustic soda to remove salt, a compound of formula 5 having a yield of 99% and a purity of 99.7% or more is obtained.

This reaction seems to be somewhat more complicated than the existing method, but it is improved significantly in the conventional method in terms of reaction yield, production cost, and stability of by-product treatment after production.

The following presents a preferred embodiment to aid the understanding of the present invention. However, the following examples are merely provided to more easily understand the present invention, and the present invention is not limited to the following examples.

EXAMPLE

Representative Example

In a concentrated hydrochloric acid solution, the compound of formula 1 was stirred at a temperature of 50 to 80 ° C. to obtain a clear solution, and then cooled to room temperature to precipitate the compound of formula 2 and a polar organic solvent or halogenated compound such as dimethylformamide. After dissolving in an organic solvent, phosphorus oxychloride is injected to prepare a compound of formula 3 in the form of white crystals. Then, the compound of formula 3 is separated, put into a halogenated organic solvent, and the compound of formula 4 is added to form a compound of formula 5, and then water is added, followed by neutralization with caustic soda to remove salt to prepare a compound of formula 5 of high purity. .

Example

In a concentrated hydrochloric acid solution, 202 g of the compound of Formula 1 was stirred at a temperature of 50 to 80 ° C. to obtain a clear solution, and then cooled to room temperature to precipitate 233 g of the compound of Formula 2. At this time, the reaction yield was 98%. Then, 200 g of the compound of Formula 2 was dissolved in 1000 ml of dimethylformamide solution, and then 180 g of phosphorus oxychloride was injected to prepare 211 g of the compound of Formula 3 in the form of white crystals. The reaction yield was 98%. 200 g of the compound of Formula 3 was separated and put into 1000 ml of methylene chloride, and 0.8 equivalent of the compound of Formula 4 was added to form a compound of Formula 5, and neutralized with caustic soda after removing water to yield 99% of purity and purity of 99.7. More than% compound of formula 5 was prepared.

Comparative example

As in Scheme 1, 202 g of the compound of formula 1 and 332 g of 2,2'-di-benzothiazyl disulfide (DBBS) were mixed with 314 g of triphenylphosphine, 10 g of TBAB, and a solvent. By reacting together, a compound of Formula 5 was prepared.

The reaction method is significantly improved than the conventional method in terms of reaction yield, production cost, and stability of by-product treatment after production.

Claims (3)

The compound of formula 2 is prepared by stirring the compound of formula 1 below in a concentrated hydrochloric acid solution at a temperature of 50-80 ° C. and cooling the temperature to room temperature; Dissolving the compound of Formula 2 in a halogenated organic solvent and then adding phosphorus oxychloride to prepare a compound of Formula 3; Preparing a compound of Chemical Formula 5 by adding a halogenated organic solvent to the compound of Chemical Formula 3 and adding a compound of Chemical Formula 4; Method for producing an intermediate for the preparation of cefem derivatives comprising the step. [Formula 1] [Formula 2] [Formula 3] [Formula 4] [Formula 5] The method of claim 1, wherein the phosphorus oxychloride is selected from the group consisting of PCl ₃ , POCl ₃ , PCl _5, and SOCl ₂ . According to claim 1, wherein the compound of Formula 1 is 195 to 205 parts by weight, the compound of Formula 2 is 230 to 240 parts by weight, the compound of Formula 3 is 260 to 270 parts by weight, the compound of Formula 4 is 185 to 195 parts by weight, the compound of Formula 5 is 340 to 350 parts by weight of the method for producing an intermediate for the preparation of cefem derivatives.