KR930007419B1 - Process for preparing cephalosporin derivatives - Google Patents

Abstract

Cephalosporin derivatives of formula (II). (where M= hydrogen or natrium) and their pharmaceutically acceptable salt were prepd. by the reaction of 7-aminocephalosporanic acid and 1H- tetrazol-5-thiol in acetonitrile at anhydrous condition. In this reaction, catalyst is trifluoroboric ethylether (BF3OEt2).

Description

Method for preparing cephalosporin derivative

The present invention relates to a method for preparing cephalosporin acid and salts thereof of the following formula (I).

Wherein M represents hydrogen or sodium.

The compound and its salts are known compounds known as cefamandole nafate and exhibit a wide range of antimicrobial activities against gram positive or gram negative groups.

The present invention is characterized by providing an economical and more advanced method with a simpler manufacturing process than the existing manufacturing method.

Existing methods for preparing compounds of formula (I) include 7-amino-3 as described in US Pat. Nos. 3,641,021, 3,928,592 (Korean Patent Publication No. 80-604), 4,006,138. -(1-Methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid (7-TACA) is silylated with excess monotrimethylsilylacetamide (MSA) followed by 0-formylman Reaction with deloyl chloride (FMC) at 20-30 ° C prepared the target. The monotrimethylsilyl acetamide (MSA) used at this time was silylated by using at least 5 equivalents as an expensive reagent, so even though the yield was 80%, it was not economical and was not recoverable.

In order to solve the above-mentioned deficiencies, 7-TACA hydrochloride is dissolved in a tertiary amide polar solvent (1-methyl-2-pyrrolidinone) without going through the silylation process, and 0.2 to 0.5 equivalents of water remover (trimethylchlorosilane Or hexamethyldisilazane) and reacted with FMC at 10-30 ° C for 1-3 hours to produce Sephamandol Naphate in 85% yield, which is known as Korean Patent Publication No. 87-2003. It was not complicated and economical.

In addition, U.S. Patent No. 3,928,334 acylates in the presence of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, but has a disadvantage of poor yield (71%). In particular, the main acylation reactions of these processes are carried out under difficult anhydrous conditions.

The present invention provides a new method for economically preparing the desired product by acylation reaction under a mixed solvent of organic solvent and water without going through the silylation process by a simpler method than the foregoing method.

That is, the following structural formula (II) compound is suspended in water, and then an inorganic or organic basic compound is added to adjust pH to 8-9.5 to dissolve the liquid, and then dissolved in an organic solvent that is miscible with water, that is, tetrahydrofuran, acetonitrile, In particular, acetonitrile in dimethylformamide or dimethylacetamide is added, followed by acylation with a compound of the following structural formula (III) to produce a target product in high yield (about 87%).

The present invention will be described in more detail, when dissolving the structural formula (II) compound suspended in water to adjust the liquidity, the amount of base is preferably used 1.5-4 equivalents to the structural formula (II) compound, wherein the inorganic base is sodium bicarbonate Inorganic bases such as sodium carbonate, sodium hydroxide, potassium hydroxide, potassium bicarbonate or potassium carbonate may be used, but sodium bicarbonate is most preferred, and organic amines such as tertiary amine organic base such as thiriethylamine and idiisopropylethylamine may be used. Acetonitrile may be used but is most preferred. The acylation reaction should be such that the initial pH is between 8-9.5 and the reaction temperature should be reacted at 20-30 ° C. within 30 minutes. This is because the formyl group can be prevented from being broken during acylation and the reaction of the structural formula (III) compound with the carboxylic acid of the structural formula (I) compound can be prevented.

Another object of the present invention is to provide a novel method for preparing the compound of formula II.

A new method for preparing the compound of formula (II), which uses acid as a catalyst, which uses a mixed acid of concentrated sulfuric acid and methanesulfonic acid as a catalyst, or uses boron trifluoride ethyl ether complex (BF ₃ O Et ₂ ) as a catalyst. 1-methyl-1H-tetrazol-5-thiol nucleophilic substitution reaction of acetoxy group of 7-amino cephalosporanic acid (7-ACA) under anhydrous conditions in an organic solvent to obtain a high yield in a relatively simple process. Way.

Acetonitrile is the best solvent.

Compared to the prior art of the present invention,

First, since water is used as the solvent in the acylation reaction, no expensive silylating agent such as monotrimethylsilyl acetamide is required,

Secondly, there is no need to use expensive tertiary amide polar solvent (1-methyl-2-pyrrolidinone) and water remover.

Third, it is an economical way to obtain the target product in high yield because there is almost no side reaction even though it is not silylated by adjusting the liquidity of the reaction.

The following examples are intended to illustrate the invention in more detail.

Example 1

Synthesis of 7-amino-3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid.

2.72 g (0.01 mol) of 7-aminocephalos-foranic acid and 1.33 g (0.011 mol) of 1-methyl-1H-tetrazol-5-thiol are suspended in 30 ml of acetonitrile, and 10 g of concentrated sulfuric acid and 2 g of After adding methanesulfonic acid at 0 ° C or below, gradually raising the temperature and reacting at 30 ° C for 3 hours, adjusting the pH of the reaction solution to 3.8 with ammonia water, stirring at the same temperature for 4 hours, filtering and drying under reduced pressure, 2.79 g (84.8) %)

Example 2

Instead of sulfuric acid and methanesulfonic acid used as catalysts in Example 1, 7.0 g of boron trifluoride ethyl ether complex (BF ₃ OEt ₂ ) was used to react at 50 ° C. for 3 hours to give the desired compound 7-amino-3- (1-methyl 3.03 g (92%) of 1-tetrazol-5-ylthiomethyl) -3-cepm-4-carboxylic acid are obtained.

Example 3

3.28 g (0.01 mol) of 7-amino-3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid was suspended in 60 ml of water, and then 1.51 g of sodium bicarbonate was added thereto. After stirring for an hour, 30 ml of acetonitrile was added to adjust the pH to 8-9.5. 2.11 g (0.011 mol) of 0-formylmandeloyl chloride was added dropwise to the solution at 20-30 ° C. at room temperature, followed by reaction for 30 minutes. The pH was adjusted to 2 with 6N-HC1 and extracted with ethyl acetate solvent. To dryness and concentrated to give 7- (2-formyloxy-2-phenylacetamide) -3- (1-methyl-1H-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid .

30 ml of acetone was added to the solvent, and a solution of 1.7 g of sodium-2-ethylhexanoate in 30 ml of acetone was added dropwise to the solution over 30 minutes at room temperature, and then reacted for 8 hours. 4.45 g of white 7- (2-formyloxy-2-phenylacetamido) -3- (1-methyl-1-tetrazol-5-ylthiomethyl) -3-cepem-4- when dried under reduced pressure at 占 폚. Sodium carboxylate salt is obtained.

Yield 87%

Example 4

When dimethylformamide is used as the solvent in the acylation process of Example 3, the desired compound 7- (2-formyloxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5 4.2 g of sodium thiomethyl) -3-cefe-4-carboxylic acid is obtained. Yield 82%

Example 5

When triethylamine was used instead of sodium bicarbonate in Example 3, the desired compound 7- (2-formyloxy-2-phenylacetamido) -3- (1-methyl-1H-tetrazol-5-ylthio 3.8 g of methyl) -3-cefe-4-carboxylic acid sodium salt are obtained. Yield 74%

Claims (1)

In preparing the compound of formula II, boron trifluoride ether ether complex (BF ₃ OEt ₂ ) with 7-aminocephalosporanic acid gutyl-1H-tetrazol-5-thiol under anhydrous conditions in an acetonitrile organic solvent Process for producing a compound of formula (II) characterized in that the reaction with a catalyst.