KR20050110103A - Novel process for producing cefonicid intermediate - Google Patents

Abstract

7-Amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cef-4-carboxylic acid represented by the following Chemical Formula 1, an intermediate of cephalosidide, a cephalosporin-based antibiotic, and its A novel process for preparing salts is disclosed. The present invention provides (5-mercapto-tetrazol-1-yl) -sulfonic acid or salts thereof in the presence of an alkanesulfonic acid solvent and boron trifluoride or a complex thereof. Reacting; And crystallizing the reactant by adding water, an organic solvent or a mixture thereof, and a basic compound to the reactant. In the production method of the present invention, the high yield of the cell nisid intermediate can be prepared by a simple purification process because the reaction yield is high and there are few side reactions.

[Formula 1]

Description

Novel process for producing cefonicid intermediate

The present invention relates to a novel method for preparing a cefonicid intermediate, a cephalosporin antibiotic, and more particularly, a high purity cenisid intermediate or a salt thereof in a simple purification process due to high yield of reaction and low side reaction. It relates to a method of manufacturing.

Cephalosporin-based antibiotics are therapeutic agents for infectious diseases caused by pathogenic bacteria, and are particularly useful for treating diseases caused by bacteria that are resistant to other antibiotics such as penicillin and penicillin hypersensitivity. Meanwhile, cephalosporin antibiotics have been developed to treat diseases caused by bacteria that are resistant to conventional antibiotics or a wider range of bacteria by introducing various substituents at the 3 or 7 of the cephem ring. Examples include cephazolines, cephazedone, cepharazone, cephamandol, cephatrizin, ceftriaxone, cenisidide and the like. Since these antibiotics are used in animals and humans to treat diseases, the purity of the antibiotics should be high. However, the conventional manufacturing method has a high yield because of a large number of by-products, and even after purification, the purity of the final product is low or high. Since a number of purification steps must be performed, there is a problem that the economic efficiency is lowered.

In particular, a method of producing cenisid, which is a kind of cephalosporin-based antibiotics, is a conventionally known method, which includes 7-aminocephalosporonic acid (7-) in the presence of a neutral or weakly basic water / organic solvent mixture solution. amino cephalosporanic acid) and (5-mercapto-tetrazol-1-yl) -methanesulfonic acid (5-mercapto-tetrazol-1-yl-methane sulfonic acid) to react 3 A method of preparing an intermediate of cenisid by introducing (5-mercapto-tetrazol-1-yl) -methanesulfonic acid group instead of acetoxy group is disclosed (US Pat. No. 4,031,111,4159373). After the completion of the reaction, a large amount of 7-aminocephalosporranic acid remains unreacted, as well as a lot of impurities due to side reactions, there is a problem to undergo a complicated purification process. In addition, in order to solve the above problems, in the presence of an organic solvent such as acetonitrile, nitro methane, acetic acid, and Lewis acid such as borane trifluoride or a complex thereof. Although a method of preparing an intermediate of ceniside by reacting the reactants is disclosed (US Pat. No. 4,397,907), the yield of the reaction is still low, and there are many by-products due to side reactions, and thus high performance liquid chromatography There is a problem that the economical efficiency is lowered because it must be purified by using HPLC).

Accordingly, an object of the present invention is to provide a method for producing a high purity cenisid intermediate or salt thereof due to high reaction yield and low side reaction. Another object of the present invention relates to a method for preparing high purity cenisid intermediate or salt thereof by simple purification.

In order to achieve the above object, the present invention, in the presence of alkane sulfonic acid solvent, and boron trifluoride or a complex thereof, 7-aminocephalosporranic acid represented by the following formula (2) or salts thereof Reacting (5-mercapto-tetrazol-1-yl) -sulfonic acid or a salt thereof represented by Chemical Formula 3; And crystallizing the reactant by adding water, an organic solvent or a mixture thereof, and a basic compound to the reactant, 7-amino-3- [1-sulfomethyltetrazole-5- It provides a 7-amino-3- [1-sulfomethyltetrazol-5ylthiomethyl] -3-cephem-4-carboxylic acid) and a method for preparing the salt thereof.

In Formulas 1 to 3, R ₁ and R ₂ are each independently H, Na, K, NH ₄ , Ca, or Li.

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

In order to prepare 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cefe-4-carboxylic acid and salts thereof represented by Chemical Formula 1 according to the present invention, As shown in Scheme 1, in the presence of an alkanesulfonic acid solvent and boron trifluoride or a complex thereof, 7-aminocephalosporranic acid represented by Formula 2 or a salt thereof and a compound represented by Formula 3 above (5- Mercapto-tetrazol-1-yl) -sulfonic acid or salt thereof is reacted.

7-Aminocephalosporranic acid represented by the formula (2) or a salt thereof according to the present invention is the 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cefe-4- As a starting material for preparing a carboxylic acid, the amino group, the seventh group of the cefe ring, is reacted with an acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and methanesulfonic acid. Salts produced.

(5-mercapto-tetrazol-1-yl) -sulfonic acid or its salt represented by the above formula (3) is 7-aminocephalosporranic acid represented by the above formula (2) or the 3rd group of the cefem ring of the salt thereof as reactant to be introduced into said three-Devonian the substitution reaction of methoxy groups, R ₁ of tetra jolhwan 1 Devonian methyl sulfonic groups (-SO ₃ R ₁₎ and 5 Devonian a thiol group (-R ₂ S) in (tetrazole ring) And R ₂ may each independently be hydrogen or a Group 1 or Group 2 metal such as sodium, potassium, calcium, lithium, or ammonium (NH ₄ ).

The alkanesulfonic acid solvent, which serves as a reaction solvent of the reaction, may be used without limitation to lower carbon alkanesulfonic acid having 1 to 2 carbon atoms, preferably methanesulfonic acid may be used. When the alkanesulfonic acid is used as the solvent, the yield of the reaction is increased and the side reactions are lowered compared to using water, a mixture of water / organic solvent, or acetonitrile, nitromethane, acetic acid, or a mixture thereof as a reaction solvent. Purity of the product can be improved.

The boron trifluoride or a complex thereof acts as a Lewis acid in the reaction to further improve the yield of the reaction, and can be used without limitation, boron trifluoride or a complex that is commonly used, without limitation Complex salts with dialkyl ethers, salts with amines, salts with aliphatic acids such as acetic acid, salts with nitriles, and salts with carboxyl esters. And boron trifluoride diethyl ether, which is preferably a complex salt with a dialkyl ether, can be used.

The content of (5-mercapto-tetrazol-1-yl) -sulfonic acid or salt thereof represented by Formula 3 is 1 mol relative to 1 mol of 7-aminocephalosporranic acid or salt thereof represented by Formula 2 above. It is preferable that it is 1-3 mol, More preferably, 1-1.5 mol can be used. If the amount is less than 1 mole, the reaction is not completed. If the amount is more than 3 mole, a large amount of by-products are generated due to side reactions of the unreacted substances due to the excessive input, which may lower the yield and purity of the product. The content of the alkanesulfonic acid is preferably 5 to 20 moles with respect to 1 mole of 7-aminocephalosporanic acid or salts thereof. If less than 5 moles, the reactivity may be lowered. If more than 20 moles, after completion of the reaction, the purity of the reactants may be lowered due to an increase in the amount of basic compounds such as ammonia water used in the neutralization reaction for purifying the reactants. There is. It is preferable that the content of boron trifluoride or its complex is 5-10 mol with respect to 1 mol of 7-amino cephalosporranic acid or its salt. If the amount is less than 5 moles, the reaction rate is slow, and the process time is long, and the by-products from the side reactions increase, and the yield of the reactants is reduced. There is a problem in that the purity of the reactants is lowered due to the increase in the amount of.

The 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cef-4-carboxylic acid or salt thereof represented by Chemical Formula 1 produced by the reaction is the 7th group of the cefem ring. Amino groups may include salts produced by reaction with acids such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, and the like.

The reaction may be performed at a temperature of −20 to 80 ° C. and atmospheric pressure for 20 minutes to 5 hours. If the reaction temperature is lower than -20 ° C or higher than 80 ° C, the yield of the reactants decreases due to an increase in byproducts due to side reactions. If the reaction time is less than 20 minutes, the reaction is not completed, if it exceeds 5 hours, only the process time is long, there is no particular advantage.

Next, after completion of the reaction, water, an organic solvent or a mixture thereof is added to the reactants, a basic compound is added to the reactant to which the solvent is added, and the reactants represented by Chemical Formula 1 are aged for 30 minutes to 3 hours. Phosphorus 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cefe-4-carboxylic acid or salt thereof is crystallized.

 As the organic solvent, organic solvents such as alcohol-based compounds that are commonly used may be used without limitation, and non-limiting examples include methanol, ethanol, isopropanol, propanol, n-butanol, 2-butanol, isobutanol, t-butanol , Acetone, tetrahydrofuran, 1,4-dioxane and mixtures thereof may be exemplified. Preferably, water and alcohols are removed to remove the by-products such as inorganic salts, thereby reducing the content and purity of the reactants. A mixed solution of a system compound can be used. The content of the organic solvent is preferably a volume / weight ratio (ml / g) of 1 to 50 ml with respect to 1 g of 7-amino cephalosporranic acid or a salt thereof, and more preferably 10 to 20 times the volume / weight ratio. If it is less than 1 volume / weight ratio, there is a concern that the purity of the reactant is lowered, and if it exceeds 50 volume / weight ratio, the crystallization rate is slow and only the process time is long, there is no particular advantage. It is preferable that the other solvent is in the range of 1-50 volume ratio with respect to any solvent, and, as for the mixing ratio of a water / alcohol type compound, it is more preferable if it is 1-10 volume ratio. Outside the above range, the effect of mixing is insignificant, in particular, there is a fear that the yield and purity of the reactants are lowered.

The basic compound serves to control the hydrogen ion concentration (pH) of the reactants, and the basic compound can be used without limitation, conventionally used, without limitation, amine, ammonia, diethylamine, triethyl Amines and mixtures thereof can be exemplified, preferably ammonia. The content of the basic compound depends on crystallization conditions such as the crystallization rate of the 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cef-4-carboxylic acid or salts thereof, Preferably the pH of the reactants can be used to be 0 to 7, more preferably 1 to 4. If the pH of the reactants is out of the above range there is a fear that the yield of the reaction is lowered.

The crystallization step may be carried out under the usual crystallization process conditions of the cenisid intermediate, for example, at a temperature of 0 ℃, can be carried out for 2 hours.

Further, if necessary, the reaction product containing the crystallized 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cef-4-carboxylic acid or salts thereof is filtered and then water , 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cef-4-, a compound represented by Chemical Formula 1, washed with an organic solvent or a mixture thereof and dried to obtain high purity. Carboxylic acids or salts thereof may be prepared, and the final product may be purified using liquid chromatography or the like to further increase the purity of the final target product. The washing of the reactant is preferably an organic solvent that can be used in the crystallization step, preferably methanol and acetone. For example, the reactant may be sequentially washed with water, methanol and acetone.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited by the following examples.

Example 1 Preparation of 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cefe-4-carboxylic acid and salts thereof

 400 ml of methanesulfonic acid and 320 ml of boron trifluoride diethyl ether were added to the reactor, and the temperature of the reactant was cooled to 0 ° C., and then 100 g of 7-aminocephalosporanic acid represented by the formula (2) and (5 The reaction was carried out for 4 hours by adding 84.4 g of -mercapto-tetrazol-1-yl) -methanesulfonic acid. After the reaction was completed, 1500 ml of purified water and 1500 ml of methanol were slowly added dropwise to the reaction, and at 0 ° C., ammonia water was added to the added reaction to crystallize the reactant for 2 hours at pH 2.0 of the reactant, and the crystallized reactant was filtered. The filtered reaction was washed sequentially with water, methanol and acetone, and then dried to give the product 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cefe-4-car 148 g of acid was obtained (yield: 98.6%), and high-purity 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cepem-4-carboxyl was obtained using high performance liquid chromatography. Acid was prepared (purity: 99% or more).

Comparative Example 1 Preparation of 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cefe-4-carboxylic acid and salts thereof

500 ml of purified water and 21.0 g of sodium bicarbonate were added to the reactor, and a mixed solution of 27.2 g of 7-aminocephalosporanic acid represented by the formula (2), 500 ml of purified water, and 250 ml of acetone was added thereto, and the temperature of the reactant was 45 ° C. 29.3 g of (5-mercapto-tetrazol-1-yl) -methanesulfonic acid and 1000 ml of acetone were slowly added dropwise while maintaining the temperature at 45 ° C., and the reaction was maintained at 7.4 to 7.6 for 2 hours. The reaction was carried out at reflux. After the reaction was completed, the reaction was cooled to 0 ° C., diluted hydrochloric acid was added to the cooled reaction to bring the pH of the reaction to 4.0, and the reaction was crystallized. The crystallized reactant was filtered off, the filtered reactant was washed with acetone and dried to yield the product 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cepem-4-carboxyl. 28.5 g of acid were obtained (yield: 70%), and high-purity 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cef-4-carboxyl was obtained using high performance liquid chromatography. Acid was prepared (purity: 95%).

Comparative Example 2 Preparation of 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cefe-4-carboxylic acid and salts thereof

 140 ml of acetonitrile in the reactor, 27.2 g of 7-aminocephalosporanic acid represented by the formula (2), 29.3 g of (5-mercapto-tetrazol-1-yl) -methanesulfonic acid and 42.6 of boron trifluoride diethyl ether g was added sequentially and the temperature of the reaction was raised to 50 ° C., followed by stirring for 2 hours. After the reaction was completed, the reaction was cooled to 0 ° C., and 140 ml of purified water was added to the cooled reaction, and the reaction was crystallized for 2 hours while the pH of the reaction was adjusted to 4.0 by adding ammonia water. The crystallized reaction was filtered, washed with acetone and dried to give 33 g of 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cefe-4-carboxylic acid (yield: 81%), using high performance liquid chromatography to prepare high purity 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cepem-4-carboxylic acid (purity: 92 %).

The method for producing a cell nisid intermediate or a salt thereof according to the present invention has the advantage of producing a high purity cell nisid intermediate or a salt thereof with high yield of reaction and less side reactions, and also a high purity cell nitrile by a simple purification process. There is an advantage that the seed intermediate or salt thereof can be economically prepared.

Claims (6)

In the presence of an alkanesulfonic acid solvent and boron trifluoride or a complex thereof, 7-aminocephalosporane acid represented by the following formula (2) or its salt and (5-mercapto-tetrazol-1- represented by the following formula (3): Reacting the 1) -sulfonic acid or salt thereof; And 7-amino-3- [1-sulfomethyltetrazol-5-ylthio represented by the following Chemical Formula 1, which comprises crystallizing the reactant by adding water, an organic solvent or a mixture thereof, and a basic compound to the reactant. Methyl] -3-cepem-4-carboxylic acid and its salt. [Formula 1] [Formula 2] [Formula 3] In Formulas 1 to 3, R ₁ and R ₂ are each independently H, Na, K, NH ₄ , Ca, Li. The compound according to claim 1, wherein 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cef-4-carboxylic acid or a salt thereof is represented by Formula 1, and Formula 2 above. 7-Aminocephalosporanic acid or a salt thereof is 7-amino-3, wherein an amino group of the cefme ring is a salt produced by reacting with an acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and methanesulfonic acid. -[1-Sulfomethyltetrazol-5-ylthiomethyl] -3-cefe-4-carboxylic acid or a salt thereof. According to claim 1, wherein the temperature of the reaction step is -20 to 80 ℃, the reaction time is 20 minutes to 5 hours 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cefem-4-carboxylic acid and its salt. The method of claim 1, wherein the alkanesulfonic acid is methanesulfonic acid, and the content of methanesulfonic acid is 5 to 20 mol based on 1 mol of the 7-aminocephalosporonic acid or salts thereof. 1-Sulfomethyltetrazol-5-ylthiomethyl] -3-cefe-4-carboxylic acid and a salt thereof. The method of claim 1, wherein the boron trifluoride or a complex thereof is boron trifluoride diethyl ether, and the content of the boron trifluoride diethyl ether is 5 to 1 mole of the 7-aminocephalosporranic acid or salt thereof. A method for producing 7-amino-3- [1-sulfomethyltetrazol-5-ylthiomethyl] -3-cefe-4-carboxylic acid and salts thereof having 10 moles. The 7-amino-3- [1-sulfomethyltetrazol-5-yl according to claim 1, wherein the solvent used in the crystallization step is selected from the group consisting of water, methanol, ethanol and mixtures thereof. Thiomethyl] -3-cepem-4-carboxylic acid and its salt.