KR0174431B1 - Process for preparing cefdinir - Google Patents

Abstract

The present invention relates to a process for the preparation of ceftinir of formula (I) characterized by removing the trityl oxime protecting group of ceftinir intermediate of formula (II) in the presence of an acid.

Description

How to prepare Cefdinir

The present invention relates to a novel process for preparing ceftinir represented by the following structural formula (I) as a cephalosporin antibiotic.

Cefdinir of the above formula (I) has a chemical name of 7β- [2- (2-aminothiazol-4-yl) -2 (Z)-(hydroxyimino) acetamido] -3-vinyl-3- A third generation oral cephalosporin-based antibiotic that is cefem-4-carboxylic acid, which shows a broader antimicrobial spectrum across Gram-positive bacteria and Gram-negative bacteria compared to other oral antibiotics, in particular Staphylococci and Streptococci It is known to have excellent antimicrobial activity against strains.

A method for preparing cefdinir is known from US Pat. No. 4,559,334 and Korean Patent Publication No. 91-3118, which method is shown briefly in Scheme 1 below.

That is, in the conventional method, 7-amino-3-vinyl-3-cepem-4-carboxylic acid ester (A) is reacted with a reactive carboxylic acid derivative to prepare 7-amido compound (B), and this is nitro. N-oxime compound (C) is prepared by treating with a nitrosating agent. Subsequently, the compound (C) is cyclized with thiourea to prepare an aminothiazole compound (D), and finally, carboxy protecting group is removed to prepare ceftinir of formula (I).

However, when the ceftinir is prepared according to the above method, there is a process difficulty of reacting at a low temperature and anhydrous state of −20 ° C. or lower in the step of preparing the 7-amido compound (B), and the N-oxime compound ( In the step of preparing C), the solvent is distilled under reduced pressure after the reaction to obtain a product as a syrup-like or foam-like solid, which has a disadvantage of causing many problems in obtaining such a product during in situ separation. In addition, in the step of preparing the aminothiazole compound (D), the production yield is low, the product purity is low, and a very poor color of brown color is obtained, which is a detrimental effect on the purity and color of the final product, ceftinir. There is a problem that gives. In addition, the manufacturing method is a total reaction because the cefdinir is synthesized through a multi-step reaction consisting of four steps using a fairly expensive 7-amino-3-vinyl-3-cepem-4-carboxylic acid derivative as a starting material The production cost of Cefdinir is increasing due to rising production cost due to lower yield.

Thus, the present inventors have conducted extensive research to develop a new method for producing a high-purity ceftinir in a simpler but higher yield than the preparation method, as a result of the novel ceftinir intermediate of the formula (II) The present invention was completed by discovering that using this as a starting material can achieve this object.

Wherein Φ represents phenyl,

p-TsOH stands for paratoluenesulfonic acid,

DMAC stands for N, N-dimethylacetamide.

Hereinafter, the configuration of the present invention will be described in detail.

The present invention relates to a process for producing ceftini of formula (I), characterized in that the trityl oxime protecting group of ceftinir intermediate of formula (II) is removed in the presence of an acid, as shown in Scheme 2 below.

The method for preparing cefdinir according to the present invention is characterized by the use of the novel cefdinir intermediate of the above formula (II) as a starting material which is very excellent in yield and purity.

Cefdinir intermediates of formula (II) used as starting materials are described in detail in the specification filed on the same date as this patent application under the name of the invention: Novel crystalline Cefdinir intermediates and methods for their preparation. This intermediate is a crystalline compound that is a complex with a salt and a solvate, reacting the reactive ester of formula (III) with the 3-cefem derivative of formula (IV) in the presence or absence of a base in a solvent, as shown in Scheme 3 below. It can then be easily prepared by adding paratoluenesulfonic acid.

In which Z is or Wherein R ′ represents C ₁ -C ₄ alkyl or phenyl or may form a 5-6 membered heterocycle with the oxygen and phosphorus atoms to which they are attached.

On the other hand, acids that can be used in the method for producing ceftinir according to the present invention include inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, Lewis acid; Organic acids such as acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid; Or an acidic hydrogen ion exchange resin, wherein examples of Lewis acid include boron trifluoride, boron trifluoride ethyl etherate, aluminum trichloride, antimony pentachloride, ferric chloride, tin chloride, tetrachloride Titanium, zinc chloride, etc. are mentioned. When using an organic acid or a Lewis acid such as trifluoroacetic acid or p-toluenesulfonic acid, it is preferable to carry out the reaction in the presence of anisole which is a cationic trapping agent. The preferred amount of acid is 1 to 20 equivalent times based on starting material (II).

The reaction is preferably carried out at a low temperature of -30 to 5 ℃, but when using 1 to 2 equivalents of acid with respect to Cefdinir intermediate of formula (II) can be carried out at a temperature of 40 to 70 ℃. .

The reaction solvent may be at least one selected from water, ethanol, methanol, propanol, t-butanol, tetrahydrofuran, dioxane, N, N-dimethylformanide, N, N-dimethylacetamide, methylene chloride, and chloroform. In some cases, the reaction may be performed using an organic acid or an inorganic acid itself as a reaction solvent.

Cefdinir of formula (I) prepared according to the method described above shows superior results in color, yield and purity than that prepared by conventional methods, which results in the Cefdinir intermediate of formula (II). It is due to use as starting material. That is, this intermediate is a pale yellow crystalline compound, which has good color and maintains high purity of 98% or more, so that this quality affects the next step, and as a result, cefdinir of excellent quality can be produced. In addition, as described above, in the present invention, compared to the manufacturing of cefdinir through a three-step process from the expensive 3-sefe derivative (A) in the present invention is a relatively inexpensive reactive ester of formula (III) and formula (IV) Since the final product is obtained through a two-step reaction from the cefe derivatives of), the total yield is prevented from being reduced due to the multi-step reaction and the manufacturing cost is reduced. Therefore, it can be seen that the present invention is an excellent method of producing and supplying products at low prices and consequently retaining product competitiveness.

Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited to these examples.

[Production Example 1]

7β- [2- (2-aminothiazol-4-yl) -2 (Z)-(trityloxyimino) acetamido] -3-vinyl-3-cepem-4-carboxylic acid p-toluene Preparation of sulfonic acid, 2N, N-dimethylacetamide

8.0 g (35.4 mmol) of 7-amino-3-vinyl-3-cepem-4-carboxylic acid and (Z)-(2-aminothiazol-4-yl) -2-trityloxyiminoacetic acid 2-benzo 21.5 g (37.1 mmol) of thiazolyl thioester was suspended in 80 mL of N, N-dimethylacetamide, 16.8 mL (70.0 mmol) of tri-n-butylamine was added thereto, and then maintained at a temperature of 15 to 20 DEG C for 1 hour. Stirred. 240 mL diethyl ether was added and stirred for 30 minutes and then filtered over celite. 20.2 g (0.11 mmol) of p-toluenesulfonic acid monohydrate dissolved in 40 ml of methanol was added to the filtrate, followed by stirring at room temperature for 2 hours. Further 160 ml of diethyl ether was added and stirred at room temperature for 1 hour, then cooled to 0 to 5 ° C, stirred for 1 hour and filtered. The obtained crystals were washed successively with 50 ml of N, N-dimethylacetamide-diethyl ether (1: 5, v / v) and 50 ml of diethyl ether and dried to give 32.3 g of a slightly yellow crystalline title compound (yield). : 93%) was obtained.

HPLC purity: 99.2%

Melting Point (℃): 164-165

IR (KBr, cm ^-1 ): 3061, 1780, 1622, 1192

¹ H-NMR (MeOH-d ₄ ) δ: 2.0 (s, 6H), 2.3 (s, 3H), 2.9 (s, 6H), 3.0 (s, 6H), 3.7 (s, 2H), 5.0- 6.0 (m, 4H), 6.9-7.5 (m, 17H), 7.7 (d, 2H, J = 8Hz)

Example 1

7β- [2- (2-aminothiazol-4-yl) -2 (Z)-(trityloxyimino) acetamido] -3-vinyl-3-cepem-4-carboxylic acid p-toluene 15.0 g (15.2 mmol) of sulfonic acid 2N, N-dimethylacetamide was dissolved in 90 mL of methanol, 0.51 mL (15.2 mmol) of 99% formic acid was added, and the mixture was stirred under reflux for 5 hours. Methanol was removed under reduced pressure, 50 ml of water, 30 ml of tetrahydrofuran and 60 ml of ethyl acetate were added to the residue, and then adjusted to 6.5 to 7.5 of the aqueous layer with a small amount of sodium bicarbonate. The aqueous layer was separated, washed with 30 ml of tetrahydrofuran and 60 ml of ethyl acetate, and then the pH was adjusted to 2.4 to 2.8 with 2N-HCl. The precipitated crystals were stirred for 1 hour in an ice bath, filtered, washed with 30 ml of water and dried to give 7β- [2- (2-aminothiazol-4-yl) -2 (Z)-(tri 5.5. G (yield: 92%) of butyloxyimino) acetamido] -3-vinyl-3-cepem-4-carboxylic acid was obtained.

HPLC purity: 99.2%

IR (KBr, cm ^-1 ): 3300, 1780, 1665, 1180, 1130

¹ H-NMR (DMSO-d ₆ ) δ: 3.5, 3.80 (2H, ABq, J = 18 Hz), 5.2 (1H, d, J = 5 Hz), 5.3 (1H, d, J = 10 Hz), 5.6 ( 1H, d, J = 17Hz, 5.8 (1H, dd, J = 8Hz, 5Hz), 6.7 (1H, s), 6.9,1H, dd, J = 17Hz, 10Hz, 7.1 (2H, brs), 9.4 (1H, d, J = 8 Hz), 11.3 (1H, brs)

Example 2

7β- [2- (2-aminothiazol-4-yl) -2 (Z)-(trityloxyimino) acetamido] -3-vinyl-3-cepem-4-carboxylic acid p-toluene 10.0 g (10.2 mmol) of sulfonic acid, 2N, N-dimethylacetamide was dissolved in 20 ml of methanol, and 20 ml (0.26 mol) of trifluoroacetic acid and 10 ml (92 mmol) of anisole were added thereto. Stir at temperature for 5 hours. Methanol was removed under reduced pressure, and the residue was dispersed in 200 ml of ethyl acetate, stirred for 30 minutes and filtered. The pale yellow solid obtained was dried and dissolved in 60 ml of water, 30 ml of tetrahydrofuran and 60 ml of ethyl acetate, and then the pH of the aqueous layer was adjusted to 5.5 to 6.5 with small amounts of sodium bicarbonate. The aqueous layer was separated, washed with 30 ml of tetrahydrofuran and 60 ml of ethyl acetate, and then the pH was adjusted to 2.4 to 2.8 with 2N-HCl. The precipitated crystals were stirred for 1 hour in an ice bath, filtered, washed with 30 ml of water and dried to give 7β- [2- (2-aminothiazol-4-yl) -2 (Z)-(tri 3.6 g (yield: 90%) of butyloxyimino) acetamido] -3-vinyl-3-cefe-4-carboxylic acid were obtained. HPLC analysis showed a purity of 99.4% and IR and ¹ H-NMR data were the same as in Example 1.

Example 3

7β- [2- (2-aminothiazol-4-yl) -2 (Z)-(trityloxyimino) acetamido] -3-vinyl-3-cepem-4-carboxylic acid p-toluene 15 ml of 85% formic acid was added to 5.0 g (5.1 mmol) of sulfonic acid · 2N, N-dimethylacetamide, followed by stirring at room temperature for 2 hours. The precipitated tritylcarbinol was removed by filtration and the filtrate was concentrated under reduced pressure. 30 ml of water, 10 ml of tetrahydrofuran and 20 ml of ethyl acetate were added to the residue, and the pH of the aqueous layer was adjusted to 6.5 with small amounts of sodium bicarbonate. The aqueous layer was separated, washed with 10 ml of tetrahydrofuran and 20 ml of ethyl acetate, and then the pH was adjusted to 2.4 to 2.8 with 2N-HCl. The precipitated crystals were stirred in an ice bath for 1 hour, filtered, washed with 10 ml of water, and dried to dry 7β- [2- (2-aminothiazol-4-yl) -2 (Z)-(tri 1.9 g (yield: 93%) of methyloxyimino) acetamido] -3-vinyl-3-cepem-4-carboxylic acid were obtained. HPLC analysis showed a purity of 99.1% and IR and ¹ H-NMR data were the same as in Example 1.

Claims (8)

A process for preparing ceftinir of the following formula (I) characterized by removing the trityl oxime protecting group of the following formula (II) in the presence of an acid. The method according to claim 1, wherein the acid is one selected from inorganic acids, organic acids and acidic hydrogen ion exchange resins. The method of claim 2, wherein the inorganic acid is one selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and Lewis acid. The method according to claim 3, wherein the Lewis acid is one selected from boron trifluoride, boron trifluoride ethyl etherate, aluminum trichloride, antimony pentachloride, ferric chloride, tin chloride, titanium tetrachloride, and zinc chloride. The method according to claim 2, wherein the organic acid is one selected from acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. The process of claim 2 wherein the reaction is carried out in the presence of a cation scavenger when using Lewis or organic acids. The method of claim 6 wherein the cation scavenger is anisole. The process according to claim 1, wherein the acid is used in 1 to 20 equivalent times with respect to the compound of formula (II).