KR0129567B1 - The process for preparation of cephalosporins - Google Patents

Abstract

A cepham derivative of general formula(1) can be produced by acylating a reactive thiophosphate derivative of thiazole acetic acid of general formula(2) with 7-ACA derivative of general formula(III) in an alcohol or mixed solvent of alcohol and water under basic condition. The produced cepham derivative can be easily synthesized as a B-antibiotics. In the above formula, R1 is carboxyl or the protected carboxyl group, R2 is hydrogen, acylocmethyl or like. R3 is hydrogen or the protected amino group and R3 is alkyl or phenyl group of C1-C4. Q is nitrogen atom or hydrocarbon.

Description

Method for preparing cephalosporin compound from reactive organic acid derivative

The present invention relates to a novel method for preparing a cephalosporin compound useful as an antibiotic, and more specifically to a reactive thiophosphate (hereinafter referred to as a reactive organic acid derivative) of thia (dia) azole acetic acid represented by the following general formula (II): Characterized by acylation with 7-ACA (7-aminocephalosporinic acid) derivative, 2- [aminothia (dia) zolyl] -2-methoxyiminoacetamido at the 7-position of the cefe nucleus It relates to a method for producing a cefem derivative represented by the following general formula (I) having:

In the above formula,

R ¹ is a carboxy or protected carboxy group, which forms a salt of -COO-M ⁺ by an alkali metal ion (M ⁺ ) such as sodium, or R ² is positively charged such as pyridinium, pyrimidinium or thiazolium. May be -COO ^- if it has a substituent,

R ² represents a hydrogen, acyloxymethyl, 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 represents a C ₁ -C ₄ alkyl group or a phenyl group, or they may be bonded together to form a 5-6 membered heterocyclic ring with oxygen or a person;

Q is N or CH.

As used herein, the meaning of acyl in the term acyloxymethyl includes all acyl groups commonly known in the field of β-lactams, including carbamonyl, aliphatic acyl groups, and acyl groups containing aromatic or heterocycles, but preferred Examples are C ₁ -C ₄ alkanoyls, such as formyl, acetyl, propionyl, butyryl and the like, particularly preferably C ₁ -C ₂ alkanoyls.

Heterocyclic in the terms heterocyclicmityl and heterocyclicthiomethyl means a saturated or unsaturated 3-7 membered monocyclic ring containing at least one hetero atom such as nitrogen, oxygen or sulfur atom in the ring or A single ring may be a multi-ring fused two or more, representative examples thereof include pyrrolidinyl, imidazolinyl, piperidino, pyrerazinyl, morpholinyl, thiazolidinyl, pyrroyl, pyrrolinyl, Dazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, etc.), oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, and the like), thiazolyl, thiazolinyl, thiadizolyl (eg, 1,2,4-thiadiazolyl), thiethyl, indolyl, isoyldolyl, indolzinyl, benzo Triazolyl, tetrazolopyridyl, quinolyl, isoquinolyl, benzoxazolyl, benzothio As one and the like, which also, if possible, such as flutes Stadium, pyrimidinyl nium, thiazol sleepiness may have a positive charge in the inner ring, it may be substituted with 1 to 4 suitable substituents. Preferred examples of suitable substituents here include C ₁ -C ₄ alkyl (eg methyl, ethyl, propyl, isopropyl, t-butyl, etc.), C ₂ -C ₄ alkenyl (eg ethenyl, 1-pro Penyl, allyl, 1,3-butadienyl, and the like), C ₂ -C ₄ alkynyl (eg, ethynyl, 1- or 2-phoropinyl, etc.), C ₃ -C ₆ cycloalkyl (eg, cyclopropyl , Cyclopentyl and the like), 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.

In general, methods for preparing β-lactam antibiotics have been reported in the prior art and patents, which are commonly used as starting materials of organic acids represented by the following general formula (A) and converting the reactive derivatives. Next, β-lactam antibiotics are prepared by acylating the amino group of β-lactam ham.

In the above formula

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, if these reactive derivatives are acid chlorides or mixed acid anhydrides, they are not only prepared under difficult reaction conditions, but also the reactive derivatives produced are unstable and are usually used in acylation reactions without being separated, thereby being a major cause of by-product formation. There are disadvantages. In addition, the reactive ester and the reactive amide of the compound of the general formula (A) not only have a low yield at the time of preparation, but also the reaction time of the acylation reaction is long because the reactivity of these reactive derivatives is too low, and moreover, the 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.

Thus, the present inventors continue to research to solve the disadvantages of the above-mentioned known reactive derivatives, surprisingly new reactive derivatives having appropriate reactivity and stability from the organic acid and chlorotophosphate derivative of the general formula (A) It has been successfully manufactured in high yield and high purity by a fairly simple method (see Patent Application No. 93-6008 of Lucky Co., Ltd., filed April 10, 1993), and this reactive organic acid is used as an antibiotic as a starting material. The present invention has been accomplished by finding out that it is possible to make economically more useful cefem derivatives of the above-mentioned ordinary stone (I).

That is, the present invention relates to a reactive thiophosphate derivative of thia (diazo) acetic acid represented by the following general formula (II) according to the following reaction formula and a 7-ACA derivative represented by the following general formula (III) in the presence of a solvent and a base. It provides a method for producing a cefem derivative represented by the following general formula (I) characterized by acylation reaction.

In the above formula,

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 method according to the invention has the greatest feature of using the compound of the 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 ] Can be widely applied to the synthesis of cephalosporin compounds known to date having a 2-methoxyiminoacetamido group.

The amount of the reactive organic acid derivative of the general formula (II) in the reaction according to the method of the present invention is advantageously used for the completion of the reaction in a slight excess of the compound of the general formula (III), and usually 1.0 to 1.5 equivalents Although it can be used comfortably in the range of degree, preferably 1.0 to 1.2 equivalent range is sufficient to complete the reaction and economical.

As the base that can be used in the reaction of the present invention, both inorganic base and 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 type of substituent R ² , but is 1,5 to 3.5 equivalents based on the compound of formula (III).

The solvent used in the present invention is 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 and water can be used respectively, sometimes it is effective to mix two or more solvents to optimize reactivity and product separation.

The amount of solvent used is not critical, but is usually 8 to 50 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, but in most cases, the reaction may be carried out within 2 to 6 hours even at a temperature in the range of 0 to 30 ° C., especially at room temperature of 20 to 25 ° C. It can be completed to easily obtain the desired compound.

On the other hand, when R ³ is an amino protecting group in the above reaction scheme, the compound of the general formula (I), which is the target compound, is removed by deprotection from the acyl compound produced after the reaction.

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 aforementioned Korean Patent Application No. 93-6008. This compound (II) has unique physical and chemical properties, so it has very good solubility in polar or non-polar 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 dissolved in the aqueous layer 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 in the process for producing the above general formula (I) compound provides a great advantage that it is easy to synthesize high purity and high yield of the final β-lactam antibiotics.

Representative compounds that can be prepared according to the method of the present invention are listed as follows.

3-Acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyino] acetamido-3-cefe-4-carboxylic acid (Cetrataxime: Cefotaxime): 7- [[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3-[(2,5-dihydro-6-hydroxy-2-methyl- 5-oxo-1,2,4-triazin-3-yl) thiomethyl] -3-cepem-4-carboxylic acid (ceftriaxone 0: Ceftriaxone): 7-[[α- (2-amino- 4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3-[(methyl-1H-tetrazol-5-yl) thiomethyl] cepem-4-carboxylic acid (sefmenoxime : Ceftriaxone): 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-cepem-4-carboxylic acid Ceftizoxime): 7-[[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido] -3- (2,3-dicyclopentenopyridiniummethyl ) -3-cepem-4-carboxylate (Cepirome): 7-[[2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1 Methylpi Lolidiummethyl) -3-cepem-4-carboxylate (cepepime): 7-[[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acet Amido] -3- (4,6-diamino-1,1-methylpyrimidinium-2-yl) thiomethyl-3-cepem-4-carboxylate: 7-[[(Z) -2- (2-amino-1,2,4-thiazol-3-yl) -2-methoxyimino] acetamido] -3- (4,6-diamino-1-methylpyrimidin-2-yl ) Thiomethyl-3-cepem-4-carboxylate: 7-[[(Z) -2- (2-amino-1,2,4-thiazol-3-yl) -2-methoxyimino] acet Amido] -3- (4,6-diamino-1-epipyrimidinium-2-yl) thiomethyl-3-cepem-4-carboxylate: 7-[[(Z) -2- (2 -Amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1,4,6-triaminopyrimidin-2-yl) thiomethyl-3-cepem-4-carboxyl Rate: 7-[[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (4,6-diamino-1,5-dimethylpyri Midinium-2-yl) thiomethyl-3-cepem-4-carboxylate: 7-[[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (2,6-diamino-3-ethylpyrimidin-4 -Yl) thiomethyl-3-cepem-4-carboxylate: methyl-3-cepem-4-carboxylate: 7-[[(Z) -2- (2-amino-4-thiazolyl)- 2-methoxyimino] acetamido] -3- (2,6-diamino-3-ethylpyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate: 7-[[( Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3-(2,6-diamino-3-methylpyrimidin-4-yl) thiomethyl -3-cefe-4-carboxylate: 7-[[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (4,5, 6-triamino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate: 7-[[(Z) -2- (2-amino-4-thiazolyl)- 2-methoxyimino] acetamido] -3- (4-amino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate: 7-[[(Z)- 2- (2-amino-4-thiazolyl) -2-meth Cyimino] acetamido] -3- (4-amino-1-methylpyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate: 7-[[(Z) -2- ( 2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (4-amino-1-aminopyrimidin-2-yl) thiomethyl-3-cepem-4-carboxyl Rate: 7-[[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1,4,5-triaminopyridium-2- Yl) thiomethyl-3-cepem-4-carboxylate: 7-[[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- ( 4-amino-1-methyl-6- (N, N-dimethyl) aminopyrimidinium-2-yl) thiomethyl-3-cepem-4-carboxylate: 7-[[(Z) -2- ( 2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1,4,5,6-tetraaminopyrimidin-2-yl) thiomethyl-3-cepem-4 -Carboxylate: 7-[[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] acetamido-3- (1,4-diamino- 5-methyl Limidinium-2-yl) thiomethyl-3-cepem-4-carboxylate: 7-[[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetami Fig.]-3- (1,4, -Diamino-5-ethylpyrimidium-2-yl) thiomethyl-3-cepem-4-carboxylate: 7-[[(Z) -2- (2- Amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1,4-diamino-6- (N-methyl) aminopyrimidin-2-yl) thiomethyl-3- Cefem-4-carboxylate: 7-[[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1,4, -diamino -5-methyl-6- (N-methyl) aminopyrimidin-2-yl) thiomethyl-3-cepem-4-carboxylate: 7-[[(Z) -2- (2-amino-4 -Thiazolyl) -2-methoxyimino] acetamido] -3- (3,4-diamino-3,5,6,7-tetrahydrocyclopentapyrimidin-2-yl) thiomethyl-3 -Cefe-4-carboxylate: 7-[[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (2-amino-1- Methyl-1,5,6,7-tetrahydrocy Lofentapyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate: 7-[[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] Acetamido] -3- (1,2-diamino-1,5,6,7-tetrahydrocyclopentapyrimidin-4-yl) thiomethyl-3-cepem-4-carboxylate: 7- [[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (7-amino-1-methyl [1,2,4] -triazolo [1,5-c] pyrimidinium-5-yl) thiomethyl-3-cepem-4-carboxylate: or 7-[[(Z) -2- (2-amino-4-thiazolyl)- 2-methoxyimino] acetamido] -3- (1-methyl [1,3] -imidazo [1,2-c] pyrimidin-5-yl) thiomethyl-3-cepem-4-car Carboxylate.

Hereinafter, the preparation method of the present invention will be described in more detail with reference to Examples. However, as described above, the biggest feature of the present invention is that the reactive organic acid derivative of Formula (II) is used to prepare the target compound. The technical scope of the present invention is not limited by the following examples unless the 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) Suspended in anhydrous dichloromethane (220 ml) and then diethylchlorothiophosphate (24.52 g) was added dropwise for 20 minutes while the solution was cooled to 0 ° C to 5 ° C under nitrogen atmosphere and further stirred for 2 hours.

After completion of the reaction, distilled water (300ml) 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 (300ml) and saturated brine (300ml), dried over magnesium sulfate, filtered, and then under reduced pressure. Concentrate. 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

MNR (δ, CDCl₃): 1.38 (t, 6H), 4.05 (s, 3H), 4.31 (m, 4H), 5.49 (bs, 2H), 6.87 (s, 1H)

Example 1

Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido-3-cefe-4-carboxylic acid (Cefotaxime)

7% aminocephalosporinic acid (54.46 g), diethylthiophosphoryl- (Z)-(2-aminothiazol-4-yl) Toxyiminoacetate (77.74 g) was added sequentially. Triethylimine (40.48 g) was added to the reaction mixture, and the mixture was stirred for 3 hours at 20 to 25 ° C., followed by addition of concentrated hydrochloric acid (31.25 g) to 95% ethyl alcohol (200 ml). The mixture was stirred vigorously for about 1 hour to sufficiently precipitate the crystals, and then filtered, washed with water, and dried to yield 83.8 g (yield: 92%) of the white solid title compound.

HPLC purity: 98.6%

Example 2

Synthesis of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] -acetamido-3-cefe-4-carboxylic acid (Cefotaxime)

Distilled water (100 ml) and isopropyl alcohol (400 ml) were used instead of ethyl alcohol in Example 1 and the process was carried out in a similar manner to obtain 82.0 g (yield: 90%) of the title compound.

HPLC purity: 98.4%

Example 3

7-[[2- (2-amino-4-thiozolyl) -2- (Z) -methoxyimino] acetamido] -3- [2,5-dihydro-6-hydroxy-2-methyl Synthesis of -5-oxo-1,2,4-triazin-3-yl) thiomethyl] -3-cepem-4-carboxylic acid (Ceftriaxone)

Add 95% ethyl alcohol (400 ml) to the 1 L-round flask and stir with 7-amino-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4- Triazin-3-yl) thiomethyl] -3-cef-4-carboxylic acid (37.1 g), diethylthiophosphoryl- (Z)-(2-aminothiazol-4-yl) methoxyiminoacetate (38.8 g) and triethylamine (30.36 g) are added sequentially. The reaction solution was stirred at 20 to 25 ° C. for 3 hours, and concentrated hydrochloric acid (26.04 g) was added to 95% ethyl alcohol (200 ml). The precipitate formed solution was sufficiently stirred in an ice cold bath for 1 hour, and then filtered, washed with water and dried to obtain 50.7 g (yield: 91.5%) of the title compound.

HPLC purity: 99.3%

Example 4

7-[[2- (2-amino-4-thiozolyl) -2- (Z) -methoxyimino] acetamido] -3-[(1-methyl-1H-tetrazol-5-yl) thio Synthesis of Methyl] -3-cepem-4-carboxylic Acid (Cefmenoxime)

Add 95% ethyl alcohol (400 ml) to a 1 L-round flask and stir with 7-amino-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem-4-carboxylic acid (32.8 g), diethylthiophosphoryl- (Z)-(2-aminothiazol-4-yl) methoxyimino acetate (38.8 g), and triethylamine (20.24 g) were added sequentially, at 20 to 25 ° C. Stir for 5 hours. Dilute hydrochloric acid (15.63 g) was added to the reaction solution, diluted with 95% ethyl alcohol (200 ml), and stirred for 1 hour in an ice-cold bath. The resulting precipitate was filtered, washed, and dried to obtain 46.3 g of the title compound (yield: 90.6%).

HPLC purity: 99.4%

Example 5

Synthesis of 7-[[2-methoxyinino-2 (2-amino-1,3-thiazol-4-yl)] acetamido] -3-cepem-4-carboxylic acid (Ceftizoxime)

Add 95% ethyl alcohol (400 ml) to a 1 L-round flask and stir with 7-amino-3-cepem-4-carboxylic acid (20 g), diethylthiophosphoryl- (Z) -2- (2-aminothia Zol-4-yl) methoxyimino acetate (38.8 g) and triethylamine (20.24 g) were added sequentially and stirred at 20-25 ° C. for 5 hours. To this reaction was added diluted hydrochloric acid (15.63 g) in 95% ethyl alcohol (200 ml) and stirred for 1 hour in ice cold water. The resulting precipitate was filtered, washed and dried to give 35.8 g of the title compound (yield: 93.4%).

HPLC purity: 98.4%

Example 6

7-[[2- (2-amino-4-thiozolyl) -2- (Z) -methoxyimino] acetamido] -3- [2,3-cyclopentenopyridinium mityl) -3- Synthesis of Cefem-4-carboxylate (Cefpirome Sulfate)

Add 95% ethyl alcohol (400 ml) to a 1 L-round flask and stir with 7-amino-3- (2,3-cyclopentenopyridiniummethyl) -3-cepm-4-carboxylate hydroiodine salt (45.9 g), diethylthiophosphoryl- (Z)-(2-aminothiazol-4-yl) methoxyimino acetate (38.8 g) and triethylamine (20.2 g) are added sequentially. The reaction solution was stirred at 20 to 25 ° C. for 3 hours, and then concentrated sulfuric acid (12.25 g) was added to 95% ethyl alcohol (300 ml) and stirred for 1 hour while maintaining the temperature at 0 to 5 ° C .. The resulting precipitate was filtered, washed with water and dried to give 47.1 g (yield: 76.9%) of the title compound.

HPLC purity: 98.1%

Example 7

7-[[2- (2-amino-4-thiozolyl) -2-methoxyimino] acetamido] -3- (1-methylpyrrolidiummethyl) -3-cepm-4-carboxylate (Cefepime Synthesis of Sulfate

Add 95% ethyl alcohol (400 ml) to a 1 L-round flask and stir with 7-amino-3- (1-methylpyrrolidiummethyl) -3-cepem-4-carboxylate hydroiodide salt (43.4 g), diethyl Thiophosphoryl- (Z) -2- (2-aminothiazol-4-yl) methoxyimino isate (38.8 g) and triethylamine (20.2 g) are added in turn. The reaction solution was stirred at 20 to 25 ° C. for 4 hours, then activated carbon (5 g) was added, stirred for 3 minutes and filtered. The filtrate is added by diluting concentrated sulfuric acid (12.25 g) in 95% ethyl alcohol (400 ml) and stirring for 1 hour while maintaining the cooling to 0 to 5 ℃. The resulting precipitate was filtered, washed with water and dried to give 45.1 g (yield: 75%) of the title compound.

HPLC purity: 97.1%

Claims (10)

Acylation reaction of the reactive thiophosphate derivative of thia (diazo) acetic acid represented by the following general formula (II) with 7-ACA derivative represented by the following general formula (III) in the presence of alcohol or a mixed solvent of alcohol and water and a base Process for the preparation of cefem derivatives of the general formula (I) In the above formula, R ¹ is a carboxy or protected carboxy group, and forms a salt of -COO-M ⁺ by an alkali metal ion (M ⁺ ) such as sodium, or R ² is pyridinium, pyrimidinium, or thiazolium. If, as with the belt is a positively charged substituent include -COO ^- it can be and, R ² is hydrogen, a cyclic acyloxy methyl, heterocyclic methyl or heterocyclic o represents a methyl group, each of which may be suitable substituted, R ³ is hydrogen or an aminoprotecting group, R ⁴ represents a C ₁ -C ₄ alkyl or phenyl group or they are bonded to form a 5-6 membered heterocyclic ring with oxygen or a person and Q is N Or CH. The method of claim 1, wherein the cefem derivative of formula (I) is 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyimino] acetamido-3-cef 4-carboxylic acid: 7-[[2- (2-amino-4-thiazolyl) -2- (Z) -methoxyimino] acetamido-3-[(2,5-dihydro-6 -Hydroxy-2-mitene-5-oxo-1,2,4-triazin-3-yl) thiomethyl] -3-cepem-4-carboxylic acid: 7-[[α- (2-amino- 4-thiazolyl) -2- (Z) -methoxyimino] acetamino] -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] cepem-4-carboxylic acid: 7- [2-methoxyimino-2- (2-amino-1, 3-thiazol-4-yl) acetamido] -3-carboxylic acid: 7-[[2- (2 amino-4-thiazolyl ) -2- (Z) -methoxyimino] acetamino] -3- (2,3-dicyclopentenopyridiniummethyl) -3-cepem-4-carboxylate or 7-[[2- ( 2-amino-4-thiazolyl) -2-methoxyimino] acetamido] -3- (1-methylpyrrolidinium methyl) -3-cefe-4-carboxylate. The method of claim 1, wherein the alcohol is methyl alcohol or isopropyl alcohol. The method according to claim 1, wherein the base is selected from carbonates, bicarbonates or tertiary amines of alkaline earth metals. 5. The process of claim 4 wherein the base is sodium bicarbonate, triethylamine or tri-n-butyl amine. The method according to claim 4, wherein the amount of base used is 1.5 to 3.5 equivalents based on the compound of formula (III). 7. The process according to claim 6, wherein the amount of base used is 2.0 to 3.0 equivalents based on the compound of formula (III). The method according to any one of claims 1 to 7, characterized in that the reaction temperature is 0 to 30 ° C. The method of claim 8, wherein the reaction temperature is 20 to 25 ℃. The method according to any one of claims 1 to 7, characterized in that the amount of the reactive derivative of formula (II) is 1.0 to 1.2 equivalents.