KR100998208B1 - Method for preparing crystalline cefozopran intermediate - Google Patents

Abstract

A method for producing a high purity, high yield crystalline cytozofran intermediate in a simple process is disclosed. In the method for preparing the crystalline cellzofran intermediate, 7-amino cephalosporranic acid (7-ACA) represented by the following formula (4) is reacted with an acylating agent to protect the amine group at the 7-position represented by the following formula (2). Synthesizing and crystallizing the cephalosporan acid derivatives; The cephalosporanic acid derivative is reacted with imidazo [1,2-b] pyridazine represented by the following formula (5) to form 7beta-acylamino-3-[(imidazo [1, 2-b] synthesizing pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate; And removing the amine group protecting group at the 7-position of the 7beta-acylamino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate To synthesize 7 beta-amino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate hydrochloride represented by the following formula (1) Steps.

[Formula 1]

[Formula 2]

(3)

[Formula 4]

[Chemical Formula 5]

In the above formula, R is a benzoyl group, a phenoxyacetyl group, a para-toluoyl group, and R "is hydrogen (H), sodium (Na) or potassium (K). , Ac is an acetyl group.

7-amino cephalosporanic acid, benzoylchloride, 7beta-amino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepem-5-carboxylate , Cytozofran hydrochloride, imidazo [1,2-b] pyridazine, phosphorus pentachloride

Description

Method for preparing crystalline cellzofran intermediate {Method for preparing crystalline cefozopran intermediate}

The present invention relates to a method for preparing a crystalline cellzofran intermediate, and more particularly, a method for producing a high purity, high yield of crystalline cellzofran intermediate in a simple process and a novel compound useful for preparing the cellzofran intermediate It is about.

Cellzofran having a structure represented by the following Chemical Formula 6 has a chemical name of 7beta-[(Z) -2- (amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacet Amido] -3- (1-imidazo [1,2-b] pyridazinium) methyl-3-cepem-4-carboxylate hydrochloride, a cephalosporin-based antibiotic that is not only Gram-negative but also Gram-positive It is known to exhibit a broad antimicrobial spectrum.

[Formula 6]

An example of a method for preparing the cellzofran is disclosed in U.S. Patent No. 4,864,022, and a method using an intermediate having a structure of Formula 1 is disclosed in International Publication No. 97/39002 (WO 97/39002) and Japanese Patent Application. It is disclosed in Japanese Patent Application Laid-Open No. 10-291993.

[Formula 1]

International Publication No. 97/39002 discloses a cellzof using 7beta-amino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepem-5-carboxylate A method for preparing lan hydrochloride is disclosed, but 7beta-amino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepem-5 prepared by the above method -Carboxylate inner salt is an amorphous material, has a weak moisture resistance and poor compound stability, which is not easy to handle.

Japanese Patent Application Laid-Open No. 10-291993 discloses 7beta-amino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate hydrochloride, oxalic acid. And a method for producing cellzofran using the same. According to the above method, after 7-amino cephalosporranic acid (7-ACA) is suspended in an organic solvent such as methylene chloride, a silylation reaction is performed using hexamethyldisilazane, and iodine trimethylsilane is used. The acetoxymethyl group of 7-ACA is converted to an iodinemethyl group. The 7-ACA, wherein the 3-position is converted into a methyl group of iodine, is reacted with imidazo [1,2-b] pyridazine to react 7beta-amino-3-[(imidazo [1,2-b] pyridazinium-1. -Yl) methyl] -3-cepem-5-carboxylate dihydrochloride is prepared. However, 7beta-amino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate dihydrochloride prepared by the above method is also amorphous. Synthesized into a substance, dark reddish violet when the 7-ACA acetoxy group is substituted by the iodine methyl group by iodine trimethylsilane, and the reactant is darker by reaction with imidazo [1,2-b] pyridazine. It is colored purple. In order to discolor the colored intermediate, it is necessary to use a decolorizing agent such as activated carbon, alumina, and recrystallization several times, and to remove impurities and colors using a resin column, so that the process is complicated, and purity and yield are also reduced. There is a problem.

Accordingly, it is an object of the present invention to provide a method for preparing crystalline cytozofran intermediate having excellent color in a simple process that does not require a recrystallization process as compared to the conventional method.

Another object of the present invention is to provide a method for producing crystalline cytozofran intermediate of high purity and high yield.

Another object of the present invention is to provide a novel compound useful for the preparation of the cytozofran intermediate.

In order to achieve the above object, the present invention, by reacting the 7-amino cephalosporranic acid (7-ACA) represented by the following formula (4) with an acylating agent, the amine group of the 7 position represented by the following formula (2) Synthesizing and crystallizing cephalosporan acid derivatives; The cephalosporanic acid derivative is reacted with imidazo [1,2-b] pyridazine represented by the following formula (5) to form 7beta-acylamino-3-[(imidazo [1, 2-b] synthesizing pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate; And removing the amine group protecting group at the 7-position of the 7beta-acylamino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate To synthesize 7 beta-amino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate hydrochloride represented by the following formula (1) It provides a method for producing a crystalline cellzofran intermediate comprising the step.

[Formula 1]

[Formula 2]

(3)

[Formula 4]

[Chemical Formula 5]

In the above formula, R is a benzoyl group, a phenoxyacetyl group, a para-toluoyl group, and R "is hydrogen (H), sodium (Na) or potassium (K). , Ac is an acetyl group.

The present invention further provides 7beta-acylamino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepem-5-carboxyl represented by Chemical Formula 3 above. Provide rate.

According to the present invention, a method for preparing a crystalline cellzofran intermediate according to the present invention can be prepared through a simple process, which is excellent in color and has crystallinity, without requiring recrystallization with high purity and high yield. Cellzofran useful as an antibiotic can be prepared in high purity and high yield.

Hereinafter, the present invention will be described in detail.

According to the present invention, in order to prepare a crystalline cytozofran intermediate, first, by reacting a 7-amino cephalosporranic acid (7-ACA) represented by the following formula (4) with an acylating agent, 7 A cephalosporan acid derivative in which the amine group in position is protected with an acyl group is synthesized and crystallized.

[Formula 2]

[Formula 4]

In the above formula, R is a benzoyl group, a phenoxyacetyl group, a para-toluoyl group, and R "is hydrogen (H), sodium (Na) or potassium (K). , Ac is an acetyl group (please let me know if there are more examples of R, R ").

As the acylating agent, benzoyl chloride, benzoyl bromide, peoxyacetyl chloride, peoxyacetyl bromide, para-toluoyl chloride, para-toluoyl bromide, mixtures thereof, and the like may be used, and more preferably, Benzoyl chloride. The amount of the acylating agent added is 0.9 to 2.0 equivalents, preferably 1.0 to 1.2 equivalents, relative to 7-aminocephalosporanic acid (7-ACA). If the amount of the added acylating agent is more than 2.0 equivalents, the amount of added acylating agents may be present in an excessive amount, and impurities may be generated. If the amount is less than 0.9 equivalents, unreacted starting materials remain, resulting in a decrease in purity. .

Methylene chloride, acetonitrile, chloroform, water, alcohols, mixtures thereof, and the like may be used as a reaction solvent for synthesizing cephalosporanic acid derivatives. Preferably, an organic solvent such as methylene chloride may be used alone, or A mixed solvent of an organic solvent, water and alcohols can be used. The reaction time is 1 to 5 hours, preferably 1 hour to 2 hours. If the reaction time is shorter than 1 hour, the reaction does not occur completely, and even if the reaction time is longer than 5 hours, there is no particular advantage. The reaction temperature is -30 to 20 ° C, preferably -20 to 10 ° C. If the reaction temperature is lower than -30 ℃ the reaction time is long, if the reaction temperature is higher than 20 ℃ there is a problem that the side reaction is generated and colored.

Crystallization of the cephalosporanic acid derivative, after completion of the acylation reaction, the reaction solution is cooled to 0 ~ 5 ℃, water or alcohol, preferably methanol is added dropwise, and then the pH is adjusted using hydrochloric acid or the like. After acidification by maintaining at 1 to 2, the mixture is extracted with an organic solvent such as ethyl acetate, methylene chloride, chloroform, toluene, preferably ethyl acetate or methylene chloride. The extracted organic layer is washed with saturated brine, and a base such as sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, and preferably anhydrous sodium acetate is added to crystallize the cephalosporanic acid derivative represented by [Formula 2]. . The amount of the base used here is 0.8 to 3.0 equivalents, preferably 1.0 to 1.2 equivalents, relative to 7-ACA. If the amount of the base is less than 0.8 equivalent, the yield is lowered. If the amount of the base is more than 3.0 equivalent, there is a problem that the color is colored yellow.

Next, the cephalosporranic acid derivative is reacted with imidazo [1,2-b] pyridazine represented by the following formula (5) to form 7beta-acylamino-3-[(imidazo) represented by the following formula (3). Synthesize [1,2-b] pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate.

(3)

[Chemical Formula 5]

In the above formula, R is a benzoyl group, a peoxyacetyl group or a para-toluoyl group.

The solvent of the 7beta-acylamino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate synthesis reaction is acetonitrile, tetrahydro Furan, nitromethane, N, N-dimethylformamide, water, alcohols, mixtures thereof and the like can be used, preferably an organic solvent such as acetonitrile is used alone, or the organic solvent, water and alcohols A mixed solvent of can be used. The reaction is preferably carried out in the presence of a catalyst, the catalyst may be used potassium iodide, sodium iodide and the like, the reaction time is 1 to 7 hours, preferably 3 to 5 hours. If the reaction time is shorter than 3 hours, the reaction does not occur completely, and even if the reaction time is longer than 5 hours, there is no particular advantage. Reaction temperature is 30-80 degreeC, Preferably it is 50-70 degreeC. If the reaction temperature is lower than 50 ℃, the reaction time is long, if the reaction temperature is higher than 70 ℃ there is a problem that the impurities are generated and the purity is lowered as well as colored brown. 7beta-acylamino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepem-5-carboxylate represented by Formula 3 is a novel compound, It is useful for the preparation of the crystalline cytozofran intermediate of the present invention.

Next, the amine group protecting group at the 7-position of the above 7beta-acylamino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate To 7beta-amino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepem-5-carboxylate hydrochloride represented by the following Chemical Formula 1 Synthesize and crystallize.

[Formula 1]

The deprotection reaction is carried out at the C4 position of 7beta-acylamino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate. It is preferable to protect and carry out the carboxyl group with a silyl group, and the silylating agent for protecting the carboxyl group at the C4 position may be trimethylsilyl chloride, dichlorodimethylsilane, N, O-bis-trimethylsilylamide, hexamethyldisilazane Etc. may be used, preferably trimethylsilylchloride. The amount of the silylating agent may be used in an amount of 1 to 5 equivalents based on the molar ratio of the compound represented by Formula 3, and preferably 1 to 3 equivalents. If the amount of the silylating agent is less than 1 equivalent, the silylation does not occur completely. If the amount of the silylating agent is more than 5 equivalents, there is a concern that by-products due to the excess silylating agent are generated. Acetonitrile, chloroform, dichloroethane, toluene, methylene chloride, and the like may be used as the reaction solvent of the silylation reaction, and methylene chloride may be preferably used. Reaction temperature is 5-40 degreeC, Preferably it is 15-20 degreeC. If the reaction temperature is lower than 5 ℃ the reactivity is lowered, if the reaction temperature is higher than 40 ℃ there is a problem that the side reaction material is generated. The reaction time is 30 minutes to 4 hours, preferably 2 hours. If the reaction time is less than 30 minutes, the reaction does not occur completely, even if the reaction time is longer than 4 hours there is no particular advantage.

In order to remove the amine group protecting group in the 7 position, the amide group is modified to aminochloride with phosphorus pentachloride in the presence of a base. As the base, pyridine, N, N-dimethylaniline, or the like may be used. The amount of the base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, based on the molar ratio of the compound represented by Chemical Formula 3. If the amount of the base is less than 1 equivalent, there is a problem that the purity is lowered due to the unreacted material, and if the amount of the base is more than 5 equivalents, the quality may be degraded due to by-products. The amount of phosphorus pentachloride may be used in an amount of 1 to 4 equivalents based on the molar ratio of the compound represented by Formula 3, and preferably 1 to 1.5 equivalents. If the amount of phosphorus contaminants is less than 1 equivalent, the generation of unreacted substances increases, and if the amount of phosphorus contaminants is more than 1.5 equivalents, there is a problem that the purity decreases due to side reactions. Reaction temperature is -60-30 degreeC, Preferably it is -30-0 degreeC. If the reaction temperature is lower than -60 ℃ the reaction time is long, if the reaction temperature is higher than 30 ℃ there is a problem that the purity is lowered due to the secondary reaction material. The reaction time is 30 minutes to 3 hours, preferably 1 hour. If the reaction time is shorter than 30 minutes, the reaction does not occur completely, even if the reaction time is longer than 3 hours there is no particular advantage.

The crystallization of the above 7beta-amino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate hydrochloride is completed after the reaction Is cooled to -30 ~ -20 ℃, alcohols are added dropwise. By the reaction with the alcohol, the silyl group is desilylated, and the aminochloride becomes an amine. Here, 1,3-propanediol, isobutanol, methanol, isopropanol, a mixture thereof, and the like are used as the alcohols, and preferably 1,3-propanediol and isobutanol are used. The reaction temperature is -60 ~ 40 ℃, preferably -20 ~ 10 ℃. If the reaction temperature is lower than -60 ℃, the reaction time is long, if the reaction temperature is higher than 40 ℃ there is a problem that the reactant is colored. The alcohol is added to the reaction mixture, and the resulting crystals are filtered and dried. The reaction time is 7 to 12 hours, preferably 8 to 10 hours. If the reaction time is shorter than 7 hours, the crystallization does not occur completely, the yield is reduced, even if the reaction time is longer than 12 hours there is no particular advantage.

According to the present invention, the compound represented by the formula (1) can be obtained in high purity and high yield, and when the cell zofran is prepared using the crystalline cytozofran intermediate thus obtained, it is possible to produce high purity and high yield of cytozofran. In addition, since the manufacturing process is simple, an effect of saving time and costs can be obtained.

Schematic representation of the method for producing a crystalline cytozoran intermediate according to the present invention is shown in Scheme 1 below.

Scheme 1

In the above formula, R is a benzoyl group, a phenoxyacetyl group, a para-toluoyl group, and R "is hydrogen (H), sodium (Na) or potassium (K). , Ac is an acetyl group.

Hereinafter, preferred examples for aiding in understanding the present invention are presented. The following examples are intended to illustrate the invention and are not intended to limit the invention.

Example 1 Preparation of a Compound Represented by Chemical Formula 2

40 g of 7-amino cephalosuroranic acid (7-ACA), a mixed solvent of 60 ml of water and 240 ml of methanol were added to the reactor, and the mixture was cooled to −10 ° C., followed by 50 ml of triethylamine. 22 ml of benzoyl chloride is added dropwise at -10 to 15 DEG C for 30 minutes and stirred for 90 minutes. After the reaction was completed, 280 ml of water and 600 ml of ethyl acetate were added thereto, the pH was maintained at 1.5 with dilute hydrochloric acid, and the organic layer was separated. The organic layer was washed with saturated brine, a solution of 12 g of anhydrous sodium acetate dissolved in 140 ml of methanol was added dropwise, and the crystals were filtered and washed to obtain 42 g of 7-benzoylamino sodium cephalosporanate represented by [Formula 3]. . Yield: 83%, purity (HPLC): 98.7%, ¹ HNMR (DMSO-d ₆ ): δ 2.00 (s, 3H), δ 3.45 (q, 2H, J = 15 Hz), δ 4.85 (q, 1H, J = 20 Hz), δ 5.10 (d, 1H, J = 1 Hz), δ 5.77 (q, 1H, J = 1 Hz), δ 7.44 to 7.91 (m, 5H), δ 9.37 (d, 1H, J = 2 Hz)

Example 2 Preparation of a Compound Represented by Chemical Formula 3

9 g of imidazo [1,2-b] pyridazine, 7.5 ml of water, 23 ml of acetonitrile, and 28.2 g of sodium iodide were added to the reactor, heated to 65 ° C., and the 7-benzoylamino obtained in [Example 1] was added. Add 15 g of sodium cephalosporanate and react for 3 hours and 30 minutes. After the reaction was completed, 40 ml of water and 70 ml of ethyl acetate were added thereto, stirred for 30 minutes, and the aqueous layer was separated. 60 ml of tetrahydrofuran was added to the aqueous layer, the pH was adjusted to 1.0 with 6N hydrochloric acid, 50 ml of ethyl acetate was added thereto, followed by stirring. 100 ml of tetrahydrofuran was added to the separated aqueous layer, followed by adding 20 g of salt, stirring for 10 minutes, and then separating the organic layer. The separated organic layer was washed four times with 40 ml of saturated brine, 1 g of activated carbon and 5 g of anhydrous magnesium sulfate were added to the organic layer, stirred for 30 minutes, and filtered to remove carbon and magnesium sulfate. The organic solvent was concentrated under reduced pressure, 200 ml of isopropanol was added thereto, stirred for 2 hours, filtered and washed to obtain 7beta-benzoylamino-3-[(imidazo [1,2-b] pyridazin-1-yl). 12.62 g of methyl] -3-cepem-5-carboxylate hydrochloride were obtained. Yield: 71% ¹ HNMR (DMSO-d ₆ ): δ 3.43 (d, 1H, J = 4 Hz), δ 3.63 (d, 1H, J = 4 Hz), δ 5.332 (q, 2H, J = 10 Hz), δ 5.55 (q. 2H, J = 10Hz), δ 5.92 (q, 2H, J = 1Hz), δ 7.42 ~ 7.88 (m, 5H), δ 8.03 ~ 9.47 (m, 5H)

Example 3 Preparation of Compound Represented by Formula 1

10 g of 7beta-benzoylamino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cef-5-carboxylate hydrochloride obtained in Example 2 was added to the reactor. It is suspended in 100 ml of dichloromethane, and 46.6 g of N, N-dimethylaniline and 34.7 g of trimethylsilyl chloride are added at 15 to 20 ° C., and the mixture is stirred at the same temperature for 2 hours. The reaction solution was cooled to -30 ° C and 13.1 g of phosphorus pentachloride was added and stirred for 1 hour. At the same temperature, 24.4 g of 1,3-propanediol and 23.8 g of isobutyl alcohol are slowly added dropwise for 30 minutes and stirred at room temperature for one day. The resulting crystals were filtered off, washed with isopropanol and dried to obtain 7beta-amino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepem-5-carboxyl 5.8 g of acrylate hydrochloride were obtained. Yield: 84% ¹ HNMR (DMSO-d ₆ ): δ 3.28 (d, 1H, J = 18 Hz), δ 3.50 (d, 1H, J = 18 Hz), δ 4.86 (d, 1H, J = 5 Hz), δ 5.00 (d, 1H, J = 5 Hz), δ 5.41 (AB, 2H), δ 8.00 (m, 1H), δ 8.30 (1H), δ 8.82 (1H), δ 8.87 (1H), δ 9.10 (1H)

Claims (6)

A 7-amino cephalosporranic acid (7-ACA) represented by the following formula (4) is reacted with an acylating agent to synthesize and crystallize the cephalosporanic acid derivative protected by the amine group at the 7 position represented by the following formula (2). step; The cephalosporanic acid derivative is reacted with imidazo [1,2-b] pyridazine represented by the following formula (5) to form 7beta-acylamino-3-[(imidazo [1, 2-b] synthesizing pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate; And The amine group protecting group at the 7-position of the 7beta-acylamino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepm-5-carboxylate was removed Synthesis of 7beta-amino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepem-5-carboxylate hydrochloride represented by the following Chemical Formula 1 Method for producing a crystalline cellzofran intermediate comprising a. [Formula 1]

[Formula 2]

(3)

[Formula 4]

[Chemical Formula 5]

In the above formula, R is a benzoyl group, a phenoxyacetyl group or a para-toluoyl group, and R "is hydrogen (H), sodium (Na) or potassium (K). , Ac is an acetyl group. The crystal of claim 1, wherein the acylating agent is selected from the group consisting of benzoyl chloride, benzoyl bromide, phenoxyacetyl chloride, phenoxyacetyl bromide, para-toluoyl chloride, para-toluoyl bromide, and mixtures thereof. Method for the preparation of sex cellzofran intermediate. The reaction solvent of claim 1, wherein the 7beta-acylamino-3-[(imidazo [1,2-b] pyridazinium-l-yl) methyl] -3-cepm-5-carboxylate synthesis solvent Is selected from the group consisting of acetonitrile, tetrahydrofuran, nitromethane, N, N-dimethylformamide, water, alcohols, mixtures thereof, and synthesized in the presence of a catalyst selected from the group consisting of potassium iodide and sodium iodide. Method for producing a crystalline cytozofran intermediate. The method of claim 1, wherein the removing of the amine group protecting group at the 7 position is 7beta-acylamino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl]- A method for preparing a crystalline cytozofran intermediate, which is carried out after protecting the carboxyl group at the C4 position of 3-cefem-5-carboxylate with a silyl group. The method of claim 1, wherein removing the amine group protecting group at the 7 position is using phosphorus pentachloride. 7beta-acylamino-3-[(imidazo [1,2-b] pyridazinium-1-yl) methyl] -3-cepem-5-carboxylate represented by the following formula (3). (3)

In the above formula, R is a benzoyl group, a phenoxyacetyl group or a para-toluoyl group.