KR100485364B1 - Halogenation of cephalosporin - Google Patents

Abstract

The present invention relates to a halogenation method of a cephalosporin derivative, and more particularly, halogenated cephalosporin represented by the following Chemical Formula 2 by halogenating the hydroxyl group of the C-3 position of the cephalosporin derivative represented by the following Chemical Formula 1 In the preparation of derivatives, cyanuric halide is used as the halogenating agent and N, N-dimethylformamide is selected as the reaction solvent, so that the halogenation reaction can be performed smoothly even at room temperature. The present invention relates to a new halogenation method of cephalosporin derivatives, which increases the yield and purity of the product and shows a significant improvement of the working environment when applied in industrial field due to the simplification of the treatment method.

Wherein R, R ₁ and n are as defined in the detailed description of the invention, respectively.

Description

New Halogenation of Cephalosporin Derivatives {Halogenation of cephalosporin}

The present invention relates to a halogenation method of a cephalosporin derivative, and more particularly, halogenation of the cephalosporin derivative represented by the following Chemical Formula 1 to produce a halogenated cephalosporin derivative represented by the following Chemical Formula 2; As cyanuric halide is used as the reaction solvent and N, N-dimethylformamide is selected as the reaction solvent, the halogenation reaction can be performed smoothly even at room temperature, so that the yield and purity of the product are increased compared with the conventional halogenation reaction method. The present invention relates to a new halogenation method of cephalosporin derivative which shows a significant improvement of the working environment when applied in industrial field by the simplification of treatment method.

In the above, R is a hydrogen atom or Wherein R ₂ is a linear or branched C ₁ -C ₅ alkyl group which is optionally substituted with one or more hydrogen or phenyl groups or a C ₁ -C ₅ alkoxy group; C ₁ -C ₅ alkoxy group; Benzyl groups; Benzyloxy group; Phenoxy C ₁ ~C ₅ alkyl group; Nitrophenoxy C _{1 to} C ₅ alkyl groups; A benzyl group in which a nitro group or at least one linear or branched C ₁ -C ₅ alkyl or alkoxy group is substituted; Linear or branched C _{1 to} C ₅ alkyl groups each having a carboxylic acid and an amine group protected or unsubstituted or substituted at the same time; Or a silyl group in which at least one substituted or unsubstituted linear or branched C _{1 to} C ₅ alkyl group is substituted, R ₁ is an alkali metal; Linear or branched C ₁ -C ₅ alkyl groups which are optionally substituted with one or more hydrogen or phenyl groups or C ₁ -C ₅ alkoxy groups; Phenyl group; Phenoxy C ₁ ~C ₅ alkyl group; Benzyl groups; A benzyl group in which a nitro group or at least one linear or branched C ₁ -C ₅ alkyl or alkoxy group is substituted; One or more substituted or unsubstituted linear or branched C _{1 to} C ₅ alkyl groups represent a silyl group, X represents a halogen atom, and n represents 0 or 1.

In the prior art of halogenating cephalosporin derivatives, SOCl ₂ , POCl ₃ , PCl ₃ or PCl ₅ and the like are generally used as chlorination reagents [ J. Org. Chem ., 41 , 2276 1976 ; J. Am. Chem. Soc. , 96 , 4986, 1974 ; J. Med. Chem. , 18 , 403, 1975 ]. However, when the chlorination reaction is carried out using the above reagents, the yield of the product is relatively low, such as 60 to 70%, and the produced chlorine compound is brownish in most cases, requiring additional decolorization. As a decolorizing method, there is a disadvantage in that decolorization is difficult.

In addition, a method of chlorinating the cephalosporin derivative using dichlorotriphenylphosphoran (PPh ₃ Cl ₂ ) or triphenylphosphite dichloride (P (OPh) ₃ Cl ₂ ) or the like as a chlorination reagent [ J. Org. Chem ., 46 , 3526 1981 ; US Patent No. 4,226,986; J. Org. Chem ., 59 , 5724, 1981 . In the case of this method, the yield increased to about 80%. However, the chlorine gas, which is a very toxic gas to the human body, must be used during the reaction. Therefore, it contains considerable risks when handling it. In the case of industrialization, there is a problem, and there is a disadvantage in that the reaction must proceed at a very low temperature around -15 ~ -20 ℃, this method also does not overcome the disadvantages of decolorization.

On the other hand, 2,4,6-trichloro-1,3,5-triazine aka, cyanuric chloride as a halogenation reagent is a reaction for the chlorination of alcohols [ J Org. Chem. , 35 , 3967, 1970 ] has been used intermittently, but the drawback is that the reaction conditions require heat. For this reason, the use of heat unstable substances such as cephalosporins is extremely limited.

The present invention was completed by developing a new halogenation reaction condition that can effectively apply cyanuric halides as a reagent for halogenating cephalosporin derivatives.

Accordingly, an object of the present invention is to provide a method of halogenating cephalosporin derivatives in high yield and high purity even under normal temperature conditions by the use of cyanuric halides and N, N-dimethylformamide solvents.

The present invention is a method for producing a halogenated cephalosporin derivative represented by the following formula (2) by halogenating the hydroxyl group of the C-3 position of the cephalosporin derivative represented by the following formula (1), wherein the halogenation reaction is cyanuric halide It is characterized in that it is carried out at room temperature using a reagent of N, N- dimethylformamide solvent.

In the above, R is a hydrogen atom or Wherein R ₂ is a linear or branched C ₁ -C ₅ alkyl group which is optionally substituted with one or more hydrogen or phenyl groups or a C ₁ -C ₅ alkoxy group; C ₁ -C ₅ alkoxy group; Benzyl groups; Benzyloxy group; Phenoxy C ₁ ~C ₅ alkyl group; Nitrophenoxy C _{1 to} C ₅ alkyl groups; A benzyl group in which a nitro group or at least one linear or branched C ₁ -C ₅ alkyl or alkoxy group is substituted; Linear or branched C _{1 to} C ₅ alkyl groups each having a carboxylic acid and an amine group protected or unsubstituted or substituted at the same time; Or a silyl group in which at least one substituted or unsubstituted linear or branched C _{1 to} C ₅ alkyl group is substituted, R ₁ is an alkali metal; Linear or branched C ₁ -C ₅ alkyl groups which are optionally substituted with one or more hydrogen or phenyl groups or C ₁ -C ₅ alkoxy groups; Phenyl group; Phenoxy C ₁ ~C ₅ alkyl group; Benzyl groups; A benzyl group in which a nitro group or at least one linear or branched C ₁ -C ₅ alkyl or alkoxy group is substituted; One or more substituted or unsubstituted linear or branched C _{1 to} C ₅ alkyl groups represent a silyl group, X represents a halogen atom, and n represents 0 or 1

Referring to the present invention in more detail as follows.

The cyanuric halide is a halogenation reagent corresponding to a triazine-based compound, and since the halogenation reaction is performed only when the heating reaction conditions are maintained, it is not easy to apply to heat-stable compounds such as cephalosporin derivatives. That is, although cyanuric halides are superior to other halogenation reagents, they are not applicable to the halogenation of cephalosporin derivatives, although the effect of improving the working environment is excellent.

The present invention has the characteristics of the technical configuration to configure the optimum reaction conditions so that the cyanuric halide reagent can be effectively applied to the cephalosporin derivative halogenation reaction. In other words, by using a small amount of N, N-dimethylformamide to activate the cyanuric halide reactivity, the halogenation reaction can proceed even at room temperature, thereby preventing side reactions such as thermal decomposition of cephalosporin derivatives.

In the cephalosporin derivative represented by Chemical Formula 1 to which the halogenation method according to the present invention is applied, R is preferably a hydrogen atom or Where R ₂ is benzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, phenoxymethyl group, nitrophenoxymethyl group, benzyloxy group, methoxy group, ethoxy group, t-butoxy group, 4-butyl Acid group (4-carboxybutyl group), 4-methoxycarbonylbutyl group, 4-ethoxycarbonylbutyl group, 4-t-butoxycarbonylbutyl group, 4-benzyloxycarbonylbutyl group, 4-di Phenylmethoxycarbonylbutyl group, 4-amino-5-carboxypentyl group, 4-amino-5-methoxycarbonylpentyl group, 4-amino-5-ethoxycarbonylpentyl group, 4-amino-5- t-butoxycarbonylpentyl group, 4-amino-5-benzyloxycarbonylpentyl group, 4-amino-5-diphenylmethoxycarbonylpentyl group, trimethylsilyl group, triethylsilyl, triisopropylsilyl group , t-butyldimethylsilyl group or t-butyldiphenylsilyl group, R ₁ represents lithium atom, sodium atom, potassium atom, methyl group, ethyl group, propyl group, t-butyl group, benzyl group, nitrobenzyl group, Toxi Benzyl group, diphenylmethyl group, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, or t-butyldiphenylsilyl group; X represents a chlorine atom.

As the halogenating agent, cyanuric halide is used in the range of 0.3 to 3 equivalents with respect to the cephalosporin derivative, and more preferably, the product yield and purity are the best when reacted at about 0.5 equivalents. The reaction solvent may be N, N-dimethylformamide alone or a mixed solvent of N, N-dimethylformamide and a general organic solvent. In the case of using a mixed solvent of N, N-dimethylformamide and a general organic solvent, N, N-dimethylformamide contains more than a catalytic amount, and a general organic solvent is an organic solvent used in a conventional organic reaction, preferably alcohols It is to use a general organic solvent except. When the reaction conditions are stirred at room temperature for about 12 hours, a high yield of about 95% or more at an optimum condition and a high purity of 97% and an off-white product on HPLC can be obtained. Therefore, no special temperature control process is required during the reaction, especially water-miscible solvents such as N, N-dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran (THF), dioxane, aceto When nitrile (Acetonitr1le), dimethoxyethane (DME), acetone, etc. are used as a mixed solvent, the reaction process is drastically simplified compared to the post-treatment process of the conventional method by crystallizing by dropwise addition directly to water without a general reaction termination process. Therefore, when applied to industrial sites, it is possible to achieve a drastic improvement of the working environment.

Such a present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1:

3-Chloro-8-oxo-7-phenylacetamino-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester

1 g of 3-hydroxy-8-oxo-7-phenylacetamino-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester (2 × 10 ^-3 mol) was dissolved in 10 mL of N, N-dimethylformamide, and then 1.08 g (3 equivalents) of powdery cyanuric chloride was added. The reaction mixture was stirred while observing by thin layer chromatography (TLC) at room temperature. After about 12 hours, after confirming that the reaction was terminated, a small amount of methanol was added to extinguish the activity of the unreacted cyanuric chloride. The reaction solution was slowly added dropwise into excess distilled water at room temperature to crystallize the target compound.

Yield 0.94 g (90%); Purity 94% (HPLC); ¹ H NMR (CDCl ₃ ) δ 7.27 to 7.42 (m, 15H, aromatic), 7.00 (s, 1H), 6.08 (d, 1H), 5.85 (dd, 1H), 5.02 (d, 1H), 3.77 ( d, 1H), 3.65 (dd, 2H), 3.45 (d, 1H); ¹³ C NMR (CDCl ₃ ) δ 171.64, 164.71, 159.82, 139.43, 134.07, 127.5 to 129.86 (aromatic), 126.08, 124.82, 80.28, 59.35, 57.69, 43.60, 31.50

Performed by the method of Example 1, but the halogenation reaction was carried out by changing the reaction conditions as shown in Table 1 and Table 2, the results are shown in Table 1 and Table 2.

division Halogenating agent (eq) Reaction solvent yield water Example 1 Cyanuric chloride (3 eq) DMF (10 mL) 90% 94% Example 2 Cyanuric chloride (2 eq) DMF (10 mL) 90% 94% Example 3 Cyanuric chloride (1 eq) DMF (10 mL) 94% 95% Example 4 Cyanuric chloride (0.5 eq) DMF (10 mL) 96% 97% Example 5 Cyanuric chloride (0.3 eq) DMF (10 mL) 85% 92%

division Halogenating agent (eq) Reaction solvent yield water Example 4 Cyanuric chloride (0.5 eq) DMF (10 mL) 96% 97% Example 6 Cyanuric chloride (0.5 eq) DMF / DMAc (1/1, 10 mL) 92% 94% Example 7 Cyanuric chloride (0.5 eq) DMF / THF (1/1, 10 mL) 92% 96% Example 8 Cyanuric chloride (0.5 eq) DMF / CH ₃ CN (1/1, 10 mL) 90% 95% Example 9 Cyanuric chloride (0.5 eq) DMF / CH ₃ CN (1/9, 10 mL) 85% 92% Example 10 Cyanuric chloride (0.5 eq) DMF / AcOH (1/9, 10 mL) 85% 90% Example 11 Cyanuric chloride (0.5 eq) DMF / CH ₂ Cl ₂ (1/9, 10 mL) 82% 88% Comparative Example 1 Cyanuric chloride (0.5 eq) CH ₂ Cl ₂ (10 mL) No reaction Comparative Example 2 Cyanuric chloride (0.5 eq) DMAc (10 mL) No reaction Comparative Example 3 Cyanuric chloride (0.5 eq) DMAc / CH ₂ Cl ₂ (1 / 1,10 mL) No reaction Comparative Example 4 Cyanuric chloride (0.5 eq) THF (10 mL) No reaction Comparative Example 5 Cyanuric chloride (0.5 eq) CH ₃ CN (10 mL) No reaction

Example 12:

3-Chloro-8-oxo-7-phenylacetylamino-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid 4-nitrobenzyl ester

1 g of 3-hydroxy-8-oxo-7-phenylacetylamino-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid 4-nitrobenzyl ester (2.13 X10 ^-3 mol) was dissolved in 10 mL of N, N-dimethylformamide and then 0.19 g (0.5 equiv) of powdery cyanuric chloride was added. The reaction mixture was stirred while observing by TLC at room temperature. After about 12 hours, after confirming that the reaction was terminated, a small amount of methanol was added to extinguish the activity of the unreacted cyanuric chloride. The reaction solution was slowly added dropwise into excess distilled water at room temperature to crystallize the target compound.

Yield 1.0 g (96%); Purity 97% (HPLC); ¹ H NMR (DMSO- d ₆ ) δ7.25-8.42 (m, 9H, aromatic), 5.85 (dd, 1H), 5.55 (s, 2H), 5.32 (d, 1H), 3.97 (dd, 2H), 3.65 (s, 2 H)

Example 13:

3-Chloro-8-oxo-7-phenoxyacetylamino-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid 4-nitrobenzyl ester

1 g of 3-hydroxy-8-oxo-7-phenoxyacetylamino-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid 4-nitrobenzyl ester 2.06 x 10 ^-3 mol) was dissolved in 10 mL of N, N-dimethylformamide, and then 0.19 g (0.5 equiv) of powdery cyanuric chloride was added. The reaction mixture was stirred while observing by TLC at room temperature. After about 12 hours, after confirming that the reaction was terminated, a small amount of methanol was added to extinguish the activity of the unreacted cyanuric chloride. The reaction solution was slowly added dropwise into excess distilled water at room temperature to crystallize the target compound.

Yield 1.0 g (95%); Purity 96% (HPLC); ¹ H NMR (CDCl ₃ ) δ6.84-8.44 (m, 9H, aromatic), 5.95 (dd, 1H), 5.45 (s, 2H), 5.12 (d, 1H), 4.58 (s, 2H), 3.68 ( ABq, 2H)

Example 14:

7- (4-benzyloxycarbonyl-butyrylamino) -3-chloro-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benz Hydryl ester

7- (4-benzyloxycarbonyl-butyrylamino) -3-hydroxy-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid 1 g (1.71 x 10 ^-3 mol) of benzhydryl ester was dissolved in 10 mL of N, N-dimethylformamide, and then 0.15 g (0.5 equiv) of powdery cyanuric chloride was added. The reaction mixture was stirred while observing by TLC at room temperature. After about 12 hours, after confirming that the reaction was terminated, a small amount of methanol was added to extinguish the activity of the unreacted cyanuric chloride. The reaction solution was slowly added dropwise into excess distilled water at room temperature to crystallize the target compound.

Yield 0.97 g (94%); Purity 96% (HPLC); Elemental Analysis C ₃₂ H ₂₉ ClN ₂ O ₆ S, Calculated C: 63.52, H: 4.83, N: 4.63, found C: 63.38, H: 4.90, N: 4.52.

Example 15:

7- (4-methoxycarbonyl-butyrylamino) -3-chloro-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benz Hydryl ester

7- (4-methoxycarbonyl-butyrylamino) -3-hydroxy-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid 1 g (1.96 × 10 ⁻³ mol) of benzhydryl ester was dissolved in 10 mL of N, N-dimethylformamide, followed by addition of 0.18 g (0.5 equiv) of powdery cyanuric chloride. The reaction mixture was stirred while observing by TLC at room temperature. After about 12 hours, after confirming that the reaction was terminated, a small amount of methanol was added to extinguish the activity of the unreacted cyanuric chloride. The reaction solution was slowly added dropwise into excess distilled water at room temperature to crystallize the target compound.

Yield 1.0 g (96%); Purity 97% (HPLC); Elemental Analysis C ₂₆ H ₂₅ ClN ₂ O ₆ S, Calculated C: 59.03, H: 4.76, N: 5.30, found C: 58.87, H: 4.85, N: 5.17.

Example 16:

7- (4-Diphenylmethoxycarbonyl-butyrylamino) -3-chloro-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxyl Acid benzhydryl ester

7- (4-Diphenylmethoxycarbonyl-butyrylamino) -3-hydroxy-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-car 1 g (1.51 x 10 ^-3 mol) of acid benzhydryl ester was dissolved in 10 mL of N, N-dimethylformamide, and then 0.14 g (0.5 equiv) of powdery cyanuric chloride was added. The reaction mixture was stirred while observing by TLC at room temperature. After about 12 hours, after confirming that the reaction was terminated, a small amount of methanol was added to extinguish the activity of the unreacted cyanuric chloride. The reaction solution was slowly added dropwise into excess distilled water at room temperature to crystallize the target compound.

Yield 0.95 g (92%); Purity 97% (HPLC); ¹ H NMR (CDCl ₃ ) δ 7.20 to 7.45 (m, 20H, aromatic), 6.90 (s, 2H), 6.45 (d, 1H), 5.83 (dd, 1H), 5.00 (d, 1H), 3.42 ~ 3.72 (ABq, 2H), 2.50 (t, 2H), 2.25 (t, 2H), 1.98 (m, 2H)

As described above, in the halogenation reaction of the cephalosporin derivative according to the present invention, the halogenation reaction can be successfully performed at high temperature and high yield at room temperature conditions by the selective use of a specific halogenating agent and a solvent. Since the cephalosporin derivative is obtained in a light white color, it is advantageous in industrial use, such as no need for a separate decolorizing step.

Claims (4)

In the method for producing a halogenated cephalosporin derivative represented by the following formula (2) by halogenating the hydroxyl group of the C-3 position of the cephalosporin derivative represented by the following formula (1), Halogenation of cephalosporin derivatives, characterized in that the halogenation reaction is carried out at room temperature using a reagent of cyanuric halide and N, N-dimethylformamide solvent: In the above, R is a hydrogen atom or Wherein R ₂ is a linear or branched C ₁ -C ₅ alkyl group which is optionally substituted with one or more hydrogen or phenyl groups or a C ₁ -C ₅ alkoxy group; C ₁ -C ₅ alkoxy group; Benzyl groups; Benzyloxy group; Phenoxy C ₁ ~C ₅ alkyl group; Nitrophenoxy C _{1 to} C ₅ alkyl groups; A benzyl group in which a nitro group or at least one linear or branched C ₁ -C ₅ alkyl or alkoxy group is substituted; Linear or branched C _{1 to} C ₅ alkyl groups each having a carboxylic acid and an amine group protected or unsubstituted or substituted at the same time; Or a silyl group in which at least one substituted or unsubstituted linear or branched C _{1 to} C ₅ alkyl group is substituted, R ₁ is an alkali metal; Linear or branched C ₁ -C ₅ alkyl groups which are optionally substituted with one or more hydrogen or phenyl groups or C ₁ -C ₅ alkoxy groups; Phenyl group; Phenoxy C ₁ ~C ₅ alkyl group; Benzyl groups; A benzyl group in which a nitro group or at least one linear or branched C ₁ -C ₅ alkyl or alkoxy group is substituted; One or more substituted or unsubstituted linear or branched C _{1 to} C ₅ alkyl groups represent a silyl group, X represents a halogen atom, and n represents 0 or 1. The method of claim 1, wherein R is a hydrogen atom or Where R ₂ is benzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, phenoxymethyl group, nitrophenoxymethyl group, benzyloxy group, methoxy group, ethoxy group, t-butoxy group, 4-butyl Acid group (4-carboxybutyl group), 4-methoxycarbonylbutyl group, 4-ethoxycarbonylbutyl group, 4-t-butoxycarbonylbutyl group, 4-benzyloxycarbonylbutyl group, 4-di Phenylmethoxycarbonylbutyl group, 4-amino-5-carboxypentyl group, 4-amino-5-methoxycarbonylpentyl group, 4-amino-5-ethoxycarbonylpentyl group, 4-amino-5- t-butoxycarbonylpentyl group, 4-amino-5-benzyloxycarbonylpentyl group, 4-amino-5-diphenylmethoxycarbonylpentyl group, trimethylsilyl group, triethylsilyl group, triisopropylsilyl Group, t-butyldimethylsilyl group or t-butyldiphenylsilyl group, R ₁ represents lithium atom, sodium atom, potassium atom, methyl group, ethyl group, propyl group, t-butyl group, benzyl group, nitrobenzyl group, Metok A cibenzyl group, diphenylmethyl group, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, or t-butyldiphenylsilyl group; X is a halogenation method of a cephalosporin derivative, characterized in that represents a chlorine atom. The method of claim 1, wherein the reaction solvent is a halogenated method of cephalosporin derivatives, characterized in that N, N- dimethylformamide alone or an organic solvent mixture containing at least a catalytic amount of N, N-dimethylformamide. The halogenated cephalosporin derivative according to claim 1, wherein the cyanuric halide is used in the amount of 0.3 to 3 equivalents based on the compound of Formula 1.