KR100477763B1 - The Novel preparation of Intermediate of Cefatrizine Propylene gylcol - Google Patents

Abstract

The present invention reacts 7-aminocephalosporranic acid with 5-mercapto-1,2,3-triazole or an inorganic salt thereof in the presence of a methanesulfonic acid solvent and boron trifluoride or a complex thereof, thereby allowing 7-amino-3 to react. -[5- (1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid, which is prepared in the presence of an organic solvent such as acetic acid or acetonitrile. Can not be produced by-product produced in the high purity, high yield 7-amino-3- [5- (1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid In addition, Sepharidge propylene glycol useful as an antibiotic can be manufactured using the obtained compound as an intermediate.

Description

  Novel preparation of Intermediate of Cefatrizine Propylene gylcol

The present invention relates to a novel method for preparing a Sephatrizin propylene glycol intermediate, and more particularly, 7-amino-3- [5- (1,2) used as an intermediate of Sephatrizin propylene glycol, an oral antibiotic. A new process for the preparation of, 3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid in high purity, high yield and economics.

Sephazoline, Sephazedon, Ceperazone, Sephamandol, Sephatrizin, Sephatriaxone, etc. are known cephalosporins as important antibiotics, and there are many known methods for preparing intermediates useful in the preparation of such cephalosporins. have.

In particular, the Sephatrizin intermediate is often obtained from cephalosporane acid, for example in U.S. Pat.Nos. 4,012,382 and 4,376,200 and Japanese Patent Publication No. 60-22718, the 3-positions of 7-aminocephalosporranic acid. A method of introducing a 5-mercapto-1,2,3-triazole group at a 3-position by reacting an acetoxy group with 5-mercapto-1,2,3-triazole or salts thereof is disclosed.

US patents in the prior art are generally reacted in an aqueous solution containing an aqueous solution or an organic solvent under a neutral or about a base. However, the product obtained in such a method contains a large amount of impurities, and contains a starting material 7-aminocephalosporranic acid as well as a very low yield of 30-50%.

Meanwhile, in the presence of an organic solvent such as acetonitrile, 7-aminocephalosporranic acid and 5-mercapto-1,2,3-triazole or salts thereof are reacted using Lewis acid such as boron trifluoride or a complex thereof. A method of obtaining 7-amino-3- [5- (1,2,3-triazole) thiomethyl] -Δ3-cefe-4-carboxylic acid is known. For example, Japanese Patent Application Laid-open No. 60-22718 discloses a reaction of boron trifluoride or a complex thereof with 7-aminocephalosporranic acid and 5-mercapto-1,2,3-triazine in acetic acid solvent, thereby producing cepatrizine propylene. A method for preparing glycol intermediates is disclosed. However, when 5-mercapto-1,2,3-triazine sodium and 7-aminocephalosporranic acid which are easy to purchase and stable during storage are reacted according to such a method, a low yield and an impure product are produced. However, there is a problem that complicated operation is required for purification of the product.

Accordingly, the present inventors have carried out high purity and high purity of 7-amino-3- [5- (1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid from 7-aminocephalosporanic acid. While research efforts have been made to produce in yield, 5-mercapto-1,2,3-triazole or its inorganic salts from 7-aminocephalosporanic acid are present in the presence of a methanesulfonic acid solvent and boron trifluoride or a complex thereof. As a result of the reaction, it was found that the cefatrizine propylene glycol intermediate can be obtained in high purity and high yield without the side product, thereby completing the present invention.

Accordingly, it is an object of the present invention to provide a process for the preparation of cepatrizine propylene glycol intermediates useful as antibiotics from 7-aminocephalosporranic acid in high purity, high yield.

In order to achieve the above object, the method for preparing the Sephatrizin propylene glycol intermediate of the present invention is 7-aminocephalosporranic acid represented by the following Chemical Formula 2 and the following Chemical Formula 3 (wherein R is hydrogen, sodium or potassium). 5-mercapto-1,2,3-triazole or an inorganic salt thereof represented by the reaction is reacted in the presence of a methanesulfonic acid solvent and boron trifluoride or a complex thereof to form 7-amino-3- [5 It is characterized by the preparation of-(1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid.

Hereinafter, the present invention will be described in more detail.

The intermediate of the sephatrizin propylene glycol to be obtained in the present invention is 7-amino-3- [5- (1,2,3-triazole) thiomethyl] -Δ3-cepem-4-car represented by Chemical Formula 1 Acid. In the present invention schematically showing a method for obtaining such an intermediate of the Sephatrijin propylene glycol is shown in the following Scheme 1.

As shown in Scheme 1, in the present invention, 7-aminocephalosporranic acid represented by the general formula (2) used in the preparation of a conventional cepatrizine propylene glycol intermediate is used as a starting material. Such 7-aminocephalosporranic acid and 5-mercapto-1,2,3-triazole represented by the formula (3) or inorganic salts thereof (for example, sodium salt and potassium salt) are converted into 7-aminocephalo React with sporanic acid.

However, conventionally, boron trifluoride or a complex thereof was used as a Lewis acid for inducing such a substitution reaction, and acetonitrile, nitromethane, acetic acid, or the like has been used as an organic solvent. However, in the presence of such a solvent, a large amount of side products such as those obtained by substituting unsubstituted nitrogen atoms of 5-mercapto-1,2,3-triazole at 3-position of 7-aminocephalosporanic acid are generated. Or unreacted 7-aminocephalosporranic acid containing a large amount of unreacted to reduce the purity as well as the yield was uneconomical.

In order to overcome such drawbacks, the present invention uses boron trifluoride or a complex thereof under acidic conditions of methanesulfonic acid to form 7-aminocephalosporanic acid and 5-mercapto-1,2,3-triazole or an inorganic thereof. The salt is reacted.

At this time, it is preferable that the addition amount of methanesulfonic acid is 5-20 mole ratio with respect to 7-amino cephalosporranic acid which is a starting material. If the amount of methanesulfonic acid added is less than 5 molar ratio with respect to the starting material, the reactivity is lowered. If the amount of methanesulfonic acid exceeds 20 molar ratio, the amount of the basic product such as ammonia water used for neutralization is increased, thereby decreasing the content of the final product.

In addition, the addition amount of boron trifluoride or a complex thereof (for example, boron trifluoride diethyl ether) added to Lewis acid is preferably 5 to 10 molar ratio with respect to starting material 7-aminocephalosporanic acid. If the amount of fluorine trifluoride or its complex is less than 5 molar ratio, the reaction time is longer, so the side reactions increase, and if the amount is more than 10 molar ratio, the yield decreases because the product is less than 10 molar ratio. .

On the other hand, the reaction temperature is -20 ~ 80 ℃, the reaction time is preferably 20 minutes to 5 hours. If the reaction temperature is out of the above range, there is a problem in that yield is low and impure products are obtained. If the reaction time is out of the above range, there is a concern that a side reaction is increased to decrease the yield.

As described above, when 7-aminocephalosporranic acid and 5-mercapto-1,2,3-triazole or its inorganic salts are reacted in the acidic condition of methanesulfonic acid and in the presence of boron trifluoride or a complex thereof, the reaction is It proceeds quickly and no side products are obtained by using conventional organic solvents.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by the Examples.

Example 1

150 ml of methanesulfonic acid was added to a 500 ml reactor, and after cooling to 10 ° C., 50 g of 7-aminocephalosporanic acid and 25 g of 5-mercapto-1,2,3-triazole were added and 85 g of boron trifluoride was added. It heated up at 30 degreeC after that. After reacting for 3 hours at the same temperature, the resulting reaction solution was cooled to 5 ° C, and 100 ml of acetone and 100 ml of distilled water were slowly added dropwise. The solution was kept at a pH of 3.8 using 28% ammonia water under cooling, and the resulting crystals were filtered, washed sequentially with 100 ml of distilled water and 100 ml of acetone, and dried to obtain 7-amino-3- [5- ( 48 g of 1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid were obtained. The obtained 7-amino-3- [5- (1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid was identified by IR and quantified by HPLC. Yields and purity are shown in Table 1 below.

Example 2

In the same manner as in Example 1, 7-amino-3- [5- (1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid was prepared, but instead of boron trifluoride. 150 ml of boron fluoride diethyl ether was used. Yields and purity are shown in Table 1 below.

Comparative Example 1

In the same manner as in Example 1, 7-amino-3- [5- (1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid was prepared, but methanesulfur was used as a reaction solvent. 150 ml of phonic acid and 150 ml of acetonitrile were used. Yields and purity are shown in Table 1 below.

Comparative Example 2

In the same manner as in Example 1, 7-amino-3- [5- (1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid was prepared, but methanesulfur was used as a reaction solvent. 500 ml of acetic acid was used instead of 150 ml of phonic acid. Yields and purity are shown in Table 1 below.

Comparative Example 3

In the same manner as in Example 1, 7-amino-3- [5- (1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid was prepared, but methanesulfur was used as a reaction solvent. 150 ml of trifluoroacetic acid was used instead of 150 ml of phonic acid. Yields and purity are shown in Table 1 below.

[Comparative Example 4]

In the same manner as in Example 1, 7-amino-3- [5- (1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid was prepared, but methanesulfur was used as a reaction solvent. 150 ml of phonic acid and 250 ml of ethyl acetate were used. Yields and purity are shown in Table 1 below.

[Comparative Example 5]

Prepare 7-amino-3- [5- (1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid, except using 150 ml of methanesulfonic acid and 250 ml of nitromethane as reaction solvents. It was. Yields and purity are shown in Table 1 below.

Example Comparative example One 2 One 2 3 4 5 yield(%) 83 82 13 25 72 75 78 water(%) 99.4 99.2 22 59.7 92.7 91.6 96.5

   From the results in Table 1, 7-aminocephalosporranic acid and 5-mercapto-1,2,3-triazole or inorganic salts thereof are reacted in the presence of a methanesulfonic acid solvent and boron trifluoride according to the present invention. As a result, it can be seen that 7-amino-3- [5- (1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid can be prepared in high yield without formation of byproducts. have.

However, when acetonitrile or acetic acid is used as the organic solvent, the reaction is very slow, and the product contains a large amount of the side product and starting material, 7-aminocephalosporranic acid, and the yield is very low. Ethyl acetate or nitromethane In the case of using as an organic solvent, a large amount of the by-products in which the unsubstituted nitrogen atom of 5-mercapto-1,2,3-triazole is substituted in 3-position of 7-aminocephalosporanic acid is obtained, resulting in lower purity and yield. It can also be seen that low.

As described in detail above, according to the present invention, boron trifluoride or a complex thereof is used as 7-aminocephalosporranic acid and 5-mercapto-1,2,3-triazole or an inorganic salt thereof, and methane sulfide is used. When the reaction is performed in the presence of an acid solvent of phonic acid, no side product is generated when the reaction is performed in the presence of an organic solvent such as ethyl acetate, nitromethane, acetic acid or acetonitrile. Thus, 7-amino-3- [ 5- (1,2,3-triazole) thiomethyl] -Δ3-cepem-4-carboxylic acid can be prepared, and the obtained compound can be used as an intermediate to prepare cepatrizine useful as an antibiotic.

Claims (4)

5-mercapto-1,2,3-triazole represented by the following formula (3) (wherein R is hydrogen, sodium or potassium) or an inorganic salt thereof In a solution consisting of 5 to 20 molar ratios of methanesulfonic acid solvent with respect to the 7-aminocephalosporanic acid and 5 to 10 molar ratios of boron trifluoride or a complex thereof with respect to the 7-aminocephalosporanic acid To prepare 7-amino-3- [5- (1,2,3-triazole) thiomethyl] -Δ-3-cepem-4-carboxylic acid represented by the formula (1). Method for preparing lysine propylene glycol intermediate. [Formula 1] [Formula 2] [Formula 3] The method of claim 1, wherein the reaction temperature is -20 ~ 80 ℃, the reaction time is 20 minutes to 5 hours the method for producing a propylene glycol intermediate. delete delete