KR100361829B1 - The process for preparing a ceftriaxone from reactive organic acid derivatives - Google Patents

Abstract

The present invention provides 7-ACA to a reactive thiophosphate derivative of thia (diazo) acetic acid represented by the following general formula (II) in the presence of a non-polar organic solvent, an alcohol or a mixed solvent of alcohol and water, and a base, It is characterized by the acylation reaction with a derivative, to provide a method for producing a cefem derivative of the general formula (I).

Where

R ¹ is a carboxy or protected carboxy group, which forms a salt of -COO ^- M ⁺ by an alkali metal ion (M ⁺ ), or R ² is a positively charged substituent such as pyridinium, pyrimidinium, or thiazolium If you have a COO ^- can be,

R ² represents a heterocyclic methyl or heterocyclic thiomethyl group, each of which may be substituted with a suitable substituent,

R ³ is hydrogen or an aminoprotecting group,

R ⁴ may represent a C ₁ -C ₄ alkyl group or a phenyl group, or may form a 5-6 membered heterocyclic ring together with the oxygen and the person to which they are attached,

Q is N or CH.

Description

The process for preparing a ceftriaxone from reactive organic acid derivatives}

The present invention relates to a novel process for the preparation and separation of ceftriaxone useful as antibiotics, and more particularly to reactive thiophosphates (hereinafter referred to as "reactive organic acid derivatives") of thia (dia) azole acetic acid represented by the following general formula (II). A) acylation with a 7-ACA (7-amino cephalosporinic acid) derivative, so that 2- [aminothia (dia) zolyl] -2-methoxyimine at the 7-position of the cephem nucleus. Noacetamido relates to a method for producing and isolating a cefe derivative represented by the following general formula (I) having a side branch.

Where

R ¹ is a carboxy or protected carboxy group, which forms a salt of -COO ^- M ⁺ by an alkali metal ion (M ⁺ ), or R ² is a positively charged substituent such as pyridinium, pyrimidinium, or thiazolium If you have a COO ^- can be,

R ² represents a heterocyclic methyl or heterocyclic thiomethyl group, each of which may be substituted with a suitable substituent,

R ³ is hydrogen or an aminoprotecting group,

R ⁴ may represent a C 1 -C ⁴ alkyl group or a phenyl group, or may form a 5-6 membered heterocyclic ring together with the oxygen or the person to which they are attached,

Q is N or CH.

As used herein, the terms "heterocyclic" in the terms "heterocyclic methyl" and "heterocyclic thiomethyl" mean saturated or unsaturated in the ring containing at least one hetero atom such as nitrogen, oxygen or sulfur atoms. It may be a 3 to 7-membered monocyclic ring or a polycyclic ring of two or more of these single ring, representative examples thereof include pyrrolidinyl, imidazolinyl, piperidino, pyrerazinyl, morpholinyl, thiazoli Dinil, pyrroyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, etc.), oxazolyl, Isoxazolyl, oxadiazolyl (eg, 1,2,4, -oxadiazolyl, etc.), thiazolyl, thiazolinyl, thiadiazolyl (eg, 1,2,4, -thiadiazolyl), thiethyl , Indolyl, isoindoleyl, indolzinyl, benzotriazolyl, tetrazolopyridine, quinolyl, iso Such as quinolyl, benzoxazolyl, benzothiazolyl, which also may have a positive charge in the inner ring, if possible, such as pyridinium nium, pyrimidinyl nium, thiazol sleepiness, it can be substituted with 1 to 4 suitable substituents. Preferable examples of the appropriate substituent at this time include C ₁ -C ₄ alkyl (eg, methyl, ethyl, propyl, isopropyl, t-butyl, etc.), C ₂ -C ₄ alkenyl (eg, ethenyl, 1- Propenyl, allyl, 1,3-butadienyl, etc., C ₂ -C ₄ alkynyl (e.g., ethynyl, 1- or 2-propynyl, etc.), C ₃ -C ₆ cycloalkyl (e.g., cyclo Propyl, cyclopentyl, etc.), halogen (e.g., chlorine, fluorine, iodine, etc.), substituted or unsubstituted amino (e.g., amino, methylamino, ethylamino, N, N-dimethylamino, N, N-diethylamino Etc.), hydroxy substituted or unsubstituted phenyl, and the like.

Alkali metals in the definition of R ¹ include sodium and the like.

In general, methods for preparing β-lactam antibiotics have been reported in the prior art and prior patents, which are commonly converted to reactive derivatives using an organic acid represented by the following general formula (A) as a starting material. Then, β-lactam antibiotics are prepared by acylating the amino group of the β-lactam nucleus.

Where

R ³ and Q are the same as described above.

Reactive derivatives of the above general formula (A) compounds by these methods include acid chlorides, reactive esters, reactive amides or mixed acid anhydrides. However, when these reactive derivatives are acid chlorides or mixed acid anhydrides, they are not only prepared under difficult reaction conditions but also the resulting reactive derivatives are unstable and used in acylation reactions as they are not normally separated, which is a major cause of by-product formation. There are disadvantages. In addition, the reactive ester and the reactive amide of the compound of general formula (A) not only have a low yield at the time of preparation, but also the reactivity of these reactive derivatives is so low that the reaction time is long in the acylation reaction, and moreover, 1-hydr produced after the reaction. Hydroxy derivatives such as hydroxy benzotriazole and thiol derivatives such as 2-mercapto benzothiazole have a problem in that they are difficult to remove easily.

Accordingly, the present inventors have conducted numerous studies and experiments to solve the disadvantages of the above-mentioned known reactive derivatives, and surprisingly, have the appropriate reactivity and stability prepared from the organic acid and the chlorothiophosphate derivative of the general formula (A). By using a reactive thiophosphate derivative as a starting material, it has been found that the cefe derivative of the general formula (I), which is useful as an antibiotic, can be more economically and easily manufactured and separated, thus completing the present invention.

Therefore, the present invention provides a reactive thiophosphate derivative of thia (dia) azole acetic acid represented by the following general formula (II) to a 7-ACA derivative represented by the following general formula (III) in the presence of a mixed solvent of organic solvent and water and a base: It provides a method for the preparation and separation of cefem derivatives represented by the following general formula (I) characterized in that and acylation reaction.

Where

R ¹ , R ² , R ³ , R ⁴ and Q are the same as described above.

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

The preparation method of the compound of the general formula (I) which is the target compound of the present invention can be represented by the following reaction scheme:

Scheme

Where

R ¹ , R ² , R ³ , R ⁴ and Q are the same as described above.

The method according to the invention has the most characteristic of selecting and using the compound of general formula (II) having appropriate reactivity and stability as a reactive organic acid derivative, so that 2- [aminothia (dia) zolyl at the 7-position of the cefe nucleus ] -2-methoxyiminoacetamido groups can be widely applied to the synthesis of cephalosporin compounds known to date.

In the reaction according to the method of the present invention, the use of a slightly excess amount of the reactive organic acid derivative of the general formula (II) with respect to the compound of the general formula (III) is advantageous for the completion of the reaction, and it is usually about 1.0 to 1.5 equivalents. Although it can be used comfortably in the range, preferably 1.0 to 1.3 equivalent range is sufficient and economical to complete the reaction.

As the base that can be used in the reaction of the present invention, both an inorganic base and an organic base can be preferably used. As the inorganic base, for example, carbonates or bicarbonates of alkaline earth metals such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate and the like can be used. As the organic base, tertiary amines such as triethylamine, tri-n-butylamine, diisopropylethylamine, pyridine, N, N-dimethylaniline and the like can be used. Among these bases, sodium hydrogencarbonate, triethylamine, tri-n-butylamine and the like are most preferably used.

The amount of the base used varies depending on the kind of the substituent R ² , but is 1.5 to 3.5 equivalents, preferably 2.0 to 3.0 equivalents based on the compound of formula (III).

Organic solvents used in the present invention include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, xylene, acetonitrile, ethyl acetate, dioxane, tetrahydrofuran, acetone, N, N-dimethylformamide, N, N- Although polar or nonpolar solvents such as dimethylacetamide, methyl alcohol, ethyl alcohol, isopropyl alcohol, water and the like can be used respectively, sometimes a mixture of two or more solvents is effective to optimize reactivity and product separation.

The amount of solvent used is not critical but is usually 8 to 5 ml, preferably 10 to 30 ml per 10 mmol of starting material.

The temperature of the reaction according to the present invention does not need to be particularly limited so long as it does not adversely affect the reaction. However, in most cases, the reaction may be performed within 1 to 3 hours even in the range of silver in the range of 0 to 30 ° C., especially in the room temperature range of 20 to 25 ° C. It can be completed to easily obtain the desired compound.

Obtaining the target compound has the advantage that it can be selectively separated by adjusting the pH with an acid or a base without any additional process, solidifying the desired form, that is, the acid form or the inorganic salt form of the target compound, and filtering in the reaction solution without an extraction step. .

As the solidifying acid, acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and formic acid are used in 1.0 to 8.0 equivalents, preferably 1.5 to 3.0 equivalents, based on the compound of formula (III).

As the base to be solidified, bases such as sodium hydrogen carbonate, sodium carbonate, sodium acetate and sodium 2-ethylhexanoate are used in 1.0 to 5.0 equivalents, preferably 1.5 to 3.0 equivalents, based on the compound of formula (III). .

On the other hand, when R ³ is an amino protecting group in the reaction scheme, the protecting group is removed through a deprotection reaction from the acyl compound produced after the reaction to obtain the compound of formula (I) as the target compound.

The reactive organic acid derivatives of the general formula (II) used as starting materials in the present invention can be easily synthesized according to the method described in the above-mentioned Korean Patent Application No. 93-6008 filed April 10, 1993 by the applicant. . This compound (II) has unique physical and chemical properties, so it has very good solubility in polar or nonpolar organic solvents, and does not decompose into organic acids even when washed with acidic, basic or neutral water in the state dissolved in such solvents. On the other hand, in the amino group acylation reaction of β-lactam nucleus, the reaction proceeds easily even under mild conditions, and the thiophosphate derivative produced after the reaction remains in a solvent and is easily removed.

In addition, if necessary in the reaction according to the method of the present invention, the acylation reaction may proceed after introduction of an amino protecting group to R ³ of the general formula (II) compound, but since the acylation reaction can be carried out without any restriction without a protecting group. The application of the method of the present invention to a process for the production of the above general formula (I) compounds provides a great advantage that it is easy to synthesize and separate high purity and high yield of the final β-lactam antibiotics. .

Hereinafter, the preparation method of the present invention will be described in more detail with reference to Examples, but as described above, the greatest feature of the present invention is the use of a reactive organic acid derivative of formula (II) and an acid or Since the pH is adjusted with a base to easily separate the target compound of the desired form by solidification, the technical scope of the present invention is not limited by the following examples unless such a key configuration is changed.

Preparation Example Synthesis of Diethylthiophosphoryl (Z)-(2-aminothiazol-4-yl) methoxyiminoacetate

(Z)-(2-aminothiazol-4-yl) methoxyiminoacetic acid (20.1 g), tri-n-butylamine (24.10 g) and 1,4-diazabicyclo [2.2.2] octane (0.11 g) was suspended in anhydrous dichloromethane (200 mL) and then diethyl chlorothiophosphate (24.52 g) was added dropwise for 20 minutes while stirring the solution at 0 ° C. to 5 ° C. under nitrogen atmosphere and stirred for a further 2 hours. After completion of the reaction, distilled water (300 mL) was added to the reaction solution, the mixture was stirred for 5 minutes, the organic layer was separated, washed sequentially with 5% aqueous sodium bicarbonate solution (300 mL) and saturated brine (300 mL), dried over magnesium sulfate, and filtered. Then concentrated under reduced pressure. Normal hexane (400 mL) was added to the concentrated solution, solidified, filtered, washed with normal hexane (100 mL), and dried to obtain 33.2 g (yield 94.0%) of the title compound as a slightly yellow solid.

Melting point: 87-88 ° C

NMR (δ, CDCl ₃ ): 1.38 (t, 6H), 4.05 (s, 3H), 4.31 (m, 4H), 5.49 (bs, 2H), 6.87 (s, 1H)

Example 1. 7-[[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamide] -3-[(2,5-dihydro-6-hydroxy Synthesis of -2-methyl-5-oxo-1,2,4-triazin-3-yl) thiomethyl] -3-cepem-4-carboxylic acid (Cefotaxime)

Dichloromethane (30 mL), ethanol (120 mL) and water (80 mL) were added to a 1 L-round flask and stirred with 7-amino-3-[(2,5-dihydro-6-hydroxy-2-methyl -5-oxo-1,2,3-triazin-3-yl) thiomethyl] -3-cepem-4-carboxylic acid (37.14 g), diethylthiophosphoryl (Z) -2- (2-amino Thiazol-4-yl) methoxyiminoacetate (35.34 g) is added. Tri n-butylamine (46.34 g) is added to the reaction. The reaction solution is stirred at room temperature for 2 hours, and then hydrochloric acid (31.25 g) is added. The precipitate was sufficiently precipitated, filtered, washed with water and dried to give 51.6 g (yield: 93%) of the title compound as white.

HPLC purity: 99.9%

Example 2. 7-[[2- (2-amino-4-thiazolyl) -2- (Z) -3-methoxyimino] acetamido] -3-[(2,5-dihydro-6 Synthesis of -hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl) thiomethyl] -3-cepem-4-carboxylate sodium salt

Proceed in a similar manner to Example 1, add sodium acetate (24.61 g) instead of concentrated hydrochloric acid, and then sufficiently precipitate the crystals, followed by filtration, washing and drying to give 55.78 g of a white solid title compound (yield: 93.2% )

HPLC purity: 99.9%

Example 3. 7-[[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3-[(2,5-dihydro-6-hydro Synthesis of Roxy-2-methyl-5-oxo-1,2,4-triazin-3-yl) thiomethyl] -3-cepem-4-carboxylate sodium salt

In a similar manner to Example 1, 54.77 g (yield: 91.5%) of the title compound was obtained using acetone (200 mL) and water (40 mL) instead of ethanol.

HPLC purity: 99.8%

Claims (17)

Acylation reaction of the reactive thiophosphate derivative of thia (dia) azole acetic acid represented by the following general formula (II) with the 7-ACA derivative represented by the following general formula (III) in the presence of a mixed solvent of organic solvent and water and a base: Method for producing a cefem derivative of the general formula (I) Where R ¹ is a carboxy or protected carboxy group which forms a salt of -COO ^- M ⁺ by an alkali metal ion (M ⁺ ), or R ² is a positively charged substituent such as pyridinium, pyrimidinium or thiazolium. If you are having -COO ^- it may be, R ² represents a heterocyclic methyl or heterocyclic thiomethyl group, each of which may be substituted with a suitable substituent, R ³ is hydrogen or an aminoprotecting group, R ⁴ may represent a C ₁ -C ₄ alkyl group or a phenyl group, or may form a 5-6 membered heterocyclic ring together with the oxygen or the person to which they are attached, Q is N or CH. The process according to claim 1, characterized in that the cefem derivative of formula (I) is separated by solidification with an acid or a base in the reaction mixture. The process according to claim 2, wherein the acid to be solidified is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or formic acid. 4. The process according to claim 3, wherein the amount of acid used is 1.0 to 8.0 equivalents based on the compound of formula (III). The method according to claim 4, wherein the amount of acid used is 1.5 to 3.0 equivalents based on the compound of formula (III). The process according to claim 2, wherein the base to be solidified is sodium hydrogen carbonate, sodium carbonate, sodium acetate or 2-ethylhexanoate sodium salt. 7. The process according to claim 6, wherein the amount of base used is 1.0 to 5.0 equivalents based on the compound of formula (III). 8. Process according to claim 7, characterized in that the amount of base used is 1.5 to 3.0 equivalents. The method of claim 1, wherein the organic solvent is dichloromethane, acetone, tetrahydrofuran, carbon tetrachloride, methyl alcohol, ethyl alcohol or isopropyl alcohol. 10. The method of claim 9, wherein the solvent is a single solvent or a mixture of two or more solvents. The method according to claim 1, wherein the base is at least one selected from carbonates, bicarbonates and tertiary amines of alkaline earth metals. 12. The process according to claim 11, wherein the base is sodium hydrogen carbonate, triethylamine or tri-n-butylamine. The method according to claim 11, wherein the amount of base used is 1.5 to 3.5 large amount based on the compound of formula (III). 14. A process according to claim 13 wherein the amount of base used is from 2.0 to 3.0 equivalents based on the compound of formula (III). The method of claim 1, wherein the reaction temperature is 0 to 30 ℃. The method of claim 15, wherein the reaction temperature is 20 to 25 ℃. The method according to claim 1, wherein the amount of the reactive derivative of formula (II) is 1.0 to 1.3 equivalents.