Preparation method of cefixime intermediate

Abstract

The invention relates to a preparation method of a cefixime intermediate, which belongs to the technical field of drug intermediate synthesis, and comprises the following steps: 1, synthesizing an oxime ether intermediate by using tert-butyl acetoacetate as an initial raw material and using a two-step one-pot method; in the second step, a chlorination-cyclization one-pot reaction is adopted, wherein the oxime ether intermediate reacts with NOCl generated by hydrochloric acid and tert-butyl nitrite, and a chlorination product is generated; carrying out cyclization reaction with thiourea and triethylamine to obtain an acid intermediate; and 3, in order to avoid decomposition of the product, respectively pulping the acid intermediates-dichloromethane, DM-triethylamine and triphenylphosphine-dichloromethane, and mixing and reacting in the microchannel to finally obtain the cefixime intermediate. The whole synthesis route avoids strong acid and other raw materials with great environmental pollution, avoids generation of byproducts, obtains high-yield and high-purity products, and shows better economic advantages.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of cefixime intermediate, and belongs to the technical field of chemical synthesis. BACKGROUND

[0002] Cefixime is an important third-generation oral cephalosporin antibiotic (Chinese Journal of Pharmaceuticals, 2011, 42 (7): 487-488), which was approved by FDA in 1987 and has been widely used in more than 80 countries. It is used for respiratory tract infection, urinary tract infection, meningitis, otolaryngology infection, biliary tract infection, etc. caused by sensitive bacteria.

[0003] At present, the mainstream method for synthesizing cefixime intermediate in industry usually involves the following steps (Chinese Journal of Antibiotics, 2010, 35 (5): 357-358): the chloride is reacted with thiourea in a mixed solvent of water and methanol, and after the reaction is completed, the pH is adjusted to strong acidity (about pH 2.0-2.3) at low temperature by using concentrated hydrochloric acid to precipitate the product. This method has disadvantages, such as high water content in the reaction system, which may cause side reactions. Or use acyl chloride method, the side chain acid is prepared, but the ester obtained is easy to hydrolyze, which will obtain byproduct, and the operation process is very harsh, and the environmental pollution is large, which is not conducive to industrial production. In addition, there are many methods for generating acid intermediates, such as using aminoacetonitrile as raw material for synthesis, so that the product can be obtained, but the starting material or intermediate may be expensive or not easy to obtain, and the synthesis technology is high. Enzyme catalysis is also high in cost, and the production cycle is also long. Therefore, it is necessary to find a green and safe, low-cost, low-impurity and high-yield synthesis method. SUMMARY

[0004] Therefore, the purpose of the present application is to provide a safe, green and simple preparation method of cefixime intermediate.

[0005] The technical scheme adopted by the present application is as follows: A preparation method of cefixime intermediate, comprising the following steps: (1) Synthesis of oxime ether intermediate (I) Take tert-butyl acetoacetate as the starting material, add hydroxylamine hydrochloride and sodium hydroxide for oximation reaction to generate oxime, then add methyl chloroacetate and alkali, and then alkylate to obtain the oxime ether intermediate (I).

[0006] (I).

[0007] The reaction equation is as follows: .

[0008] Further settings are as follows: The oximation reaction is carried out in the presence of a solvent selected from water, ethanol or a mixture of the two.

[0009] The oximation reaction is carried out at a temperature of 0-12°C, preferably 10°C.

[0010] The oximation reaction is carried out at a molar ratio of sodium hydroxide to tert-butyl acetoacetate of 1-3:1, preferably 2:1.

[0011] The alkylation reaction is carried out in the presence of a base selected from lithium carbonate, sodium carbonate, potassium carbonate, preferably potassium carbonate.

[0012] The alkylation reaction is carried out in the presence of a solvent, preferably N, N-dimethylformamide (DMF).

[0013] The alkylation reaction is carried out in the presence of a catalyst, preferably triethylbenzylammonium chloride (TEBA).

[0014] The alkylation reaction is carried out by first adding potassium carbonate at -2°C and stirring for 35 minutes, then warming to 0, 5, 8°C and holding for 35 minutes each time, during which potassium carbonate is added again and stirred, which can smoothly release the reaction heat, control the reaction rate, avoid side reactions and improve the purity and yield of the product.

[0015] Preferably, the oxime ether intermediate (I) is synthesized by a two-step one-pot method, specifically: after the completion of the oximation reaction in the first step, the oximation product does not need to be separated, and the alkylation reaction is directly carried out by adding methyl chloroacetate and a base in the same reaction pot to obtain the oxime ether intermediate (I).

[0016] (2) Synthesis of acid intermediate (II) The oxime ether intermediate (I) is subjected to a chlorination reaction with a chlorinating agent to generate a chlorinated product, and then subjected to a cyclization reaction with thiourea and triethylamine to obtain the acid intermediate (II).

[0017] (II).

[0018] The reaction equation is as follows: .

[0019] Further provided is: The chlorination reaction is carried out in the presence of a chlorinating agent selected from sulfuryl chloride, N-chlorosuccinimide, or a mixture of tert-butylamine nitrite and hydrochloric acid, preferably a mixture of tert-butylamine nitrite and hydrochloric acid.

[0020] The chlorination reaction is carried out in the presence of a solvent, preferably a mixture of acetonitrile / water, with a volume ratio of acetonitrile / water of 3:1.

[0021] The alkylation reaction is carried out in the presence of a catalyst, which is preferably trifluoroacetic acid.

[0022] The chlorination reaction is carried out at a temperature of 0-5°C.

[0023] The chlorination reaction and the cyclization reaction are preferably carried out by one-pot method, specifically as follows: the oxime ether intermediate (I) is dissolved in an acetonitrile / water mixed solvent, placed in a reaction kettle, a catalytic amount of trifluoroacetic acid is added, a stoichiometric amount of tert-butyl nitrite is added, and thiourea and triethylamine are added; at 0-5°C, HCl solution is added to the above reaction system, and the hydrochloric acid reacts with tert-butyl nitrite in situ to generate NOCl, which immediately reacts with the oxime ether intermediate (I) to generate the chlorination product; after the addition of hydrochloric acid is completed, the temperature is gradually increased to room temperature, and since the chlorination product is generated, thiourea and triethylamine are already present in the system, and the cyclization reaction will automatically follow and proceed, and the reaction is stirred until completion to obtain the product acid intermediate (II), realizing the one-pot reaction of “chlorination-cyclization”.

[0024] (3) Synthesis of cefixime intermediate (III) The acid intermediate (II), 2,2'-dithiodibenzothiazole, and triphenylphosphine are reacted to prepare the cefixime intermediate (III).

[0025] (III).

[0026] The reaction equation is as follows: .

[0027] Further provided is that: The molar ratio of the acid intermediate (II), 2,2'-dithiodibenzothiazole, and triphenylphosphine is 1:1-1.5:1-1.5.

[0028] The reaction temperature is 5-15°C, and the reaction time is 2-10 min.

[0029] Preferably, the reaction is carried out by continuous flow process, specifically as follows: the acid intermediate (II)-dichloromethane, DM-triethylamine, and triphenylphosphine-dichloromethane are slurried, respectively, and are injected into a microchannel reactor through three feeding pumps according to the molar ratio of the reactants, and the mixing and reaction are completed in the microchannel reactor, and finally the cefixime intermediate (III) is obtained. The continuous flow process can effectively avoid the decomposition of the product, and improve the yield and purity of the product.

[0030] The application provides a safe, green and simple-to-operate preparation method of cefixime intermediate. The application uses tert-butyl acetoacetate as a starting material, uses a two-step one-pot method to synthesize an oxime ether intermediate in the first step, generates an oxime in situ from the tert-butyl acetoacetate, does not need to be separated, and directly alkylates in the same reaction pot to obtain the oxime ether intermediate. In the second step, a one-pot method of "chlorination-cyclization" is adopted: the oxime ether intermediate reacts with NOCl generated from hydrochloric acid and tert-butyl nitrite to generate a chlorination product; and then cyclization reaction is carried out with thiourea and triethylamine to obtain an acid intermediate. In the third step, in order to avoid product decomposition, the acid intermediate-dichloromethane, DM-triethylamine, triphenylphosphine-dichloromethane are respectively slurried, mixing and reaction are completed in a microchannel, and finally the cefixime intermediate is obtained. The whole synthesis route avoids the use of strong acid and other environmental pollution materials, avoids the generation of by-products, obtains a product with high yield and high purity, and shows better economic advantages. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 The nuclear magnetic hydrogen spectrum of the oxime ether intermediate (I) prepared in the embodiment of the application.

[0032] Figure 2 The liquid phase spectrum of the oxime ether intermediate (I) prepared in the embodiment of the application.

[0033] Figure 3 The nuclear magnetic hydrogen spectrum of the acid intermediate (II) prepared in the embodiment of the application.

[0034] Figure 4 The liquid phase spectrum of the acid intermediate (II) prepared in the embodiment of the application.

[0035] Figure 5 The nuclear magnetic hydrogen spectrum of the cefixime intermediate (III) prepared in the embodiment of the application.

[0036] Figure 6 The liquid phase spectrum of the cefixime intermediate (III) prepared in the embodiment of the application. DETAILED DESCRIPTION

[0037] The application is further described below in combination with the drawings and specific embodiments. The raw materials and reagents used in the embodiments are known technologies or commercially available products in the art, unless otherwise specified.

[0038] Example 1

[0039] This embodiment carries out preparation of the oxime ether intermediate.

[0040] In a reaction bottle, 1.2 g of sodium hydroxide, 5 mL of water and 15 mL of ethanol were added in sequence, after stirring, 2.5 g of tert-butyl acetoacetate and 1.05 g of hydroxylamine hydrochloride were added, then sealed and shaken, reacted in an ice bath for 60 min, and warmed to 10°C for 2 h, then 2.2 g of methyl chloroacetate, 0.38 g of DMF and 0.2 g of TEBA were directly added in the reaction bottle, stirred and dissolved, cooled to -2°C, 1 g of potassium carbonate was slowly added and stirred for 35 min, then warmed to 0, 5, 8°C and each kept for 35 min, during which 1 g of potassium carbonate was added again and stirred (the total amount of potassium carbonate added was 4 g), which could smoothly release the reaction heat, control the reaction rate, avoid side reactions and improve the purity and yield of the product, finally stirred for 12 h, then extracted with ethyl acetate, the organic phase was separated, activated carbon and anhydrous sodium sulfate were added, stirred and decolorized, the filtrate was combined and distilled under reduced pressure to obtain the product, the yield was 97%.

[0041] The product confirmation: the prepared oxime ether intermediate nuclear magnetic hydrogen spectrum, liquid chromatogram is shown in Figure 1 、 Figure 2 respectively.

[0042] Substitution examples 1-1~1-8 The preparation method and example 1 are the same, the difference is that the amount of NaOH, the temperature of oximation reaction, the type of base are adjusted, as shown in table 1, and the effect on the reaction is tested respectively.

[0043] Table 1 .

[0044] According to table 1, it can be seen that when the oximation reaction temperature is 10°C, the molar ratio of sodium hydroxide to tert-butyl acetoacetate is 2:1, and the base is potassium carbonate, the reaction yield is the highest, which is 97%.

[0045] Example 2

[0046] This example carries out the preparation of acid intermediate (II).

[0047] 3.8 g of oxime ether intermediate (I) was dissolved in a mixed solvent of acetonitrile / water in a ratio of 3:1 in a reaction kettle. 0.19 g of trifluoroacetic acid was added. 1.8 mL of tert-butyl nitrite was added, which was a liquid and easy to feed and mix. 1.1 g of thiourea and 2.8 mL of triethylamine were added. The chlorination reaction was started, and about 8 mL of 2M HCl solution was slowly added to the reaction system through a dropping funnel at 3°C. After the addition was completed, the temperature was gradually increased to room temperature, and the stirring was continued until the reaction was completed. The solvent was removed by rotary evaporation, and the by-product was dissolved in water and filtered to obtain the product acid intermediate (II). After washing with methanol and acetone, the product was purified by adding 10 mL of water, dropping ammonia water and adding activated carbon to decolorize, adjusting the pH to 2, crystallizing and filtering, and weighing to obtain the fine product, the yield was 88%.

[0048] Product confirmation: The 1H NMR spectrum and liquid chromatography spectrum of the prepared product acid intermediate (II) are shown below. Figure 3 , Figure 4 As shown.

[0049] Replacement Examples 2-1 to 2-2 The preparation method is the same as in Example 2, except that the type of chlorinating agent is adjusted as shown in Table 2, and its effect on the reaction is tested respectively.

[0050] Table 2 .

[0051] As can be seen from Table 2, under the same preparation conditions, the reaction yield is the highest when tert-butyl nitrite and hydrochloric acid are used as chlorinating agents.

[0052] Example 3

[0053] In this embodiment, a continuous flow process was used to prepare cefixime intermediate (Ⅲ). The continuous flow process was carried out in a microchannel reactor, and in this embodiment, a Corning G1 reactor was used as the microchannel reactor.

[0054] Acid intermediate (II)-dichloromethane solution, DM-triethylamine solution, and triphenylphosphine-dichloromethane solution were slurried separately: 100g of acid intermediate (II) was dissolved in 700mL of dichloromethane and then slurried; 154g of DM was dissolved in 1L of triethylamine and then slurried; 75g of triphenylphosphine was dissolved in 580mL of dichloromethane and then slurried. These solutions were then injected into a microchannel reactor (0.5mm inner diameter) using three feed pumps. Mixing and reaction were completed in the microchannel reactor (temperature 10℃, residence time 5min). The mixture was then introduced into a crystallization module (temperature 0℃, residence time 30min). Finally, the product was collected through a filtration module; followed by washing with dichloromethane and drying to obtain the final product. The product yield was found to be 91%.

[0055] Product confirmation: The 1H NMR spectrum and liquid chromatography spectrum of the prepared cefixime intermediate (III) are as follows: Figure 5 , Figure 6 As shown: the 1H NMR spectrum shows that the peak positions and hydrogen counts are consistent with those of the product standard, and the liquid chromatography spectrum also verifies the purity of the product.

[0056] Replacement Examples 3-1 to 3-7 The preparation method is the same as in Example 3, except that the reaction residence time, reaction temperature and raw material molar ratio are adjusted and their effects on the reaction are tested respectively.

[0057] Table 3 .

[0058] As can be seen from Table 3, under the same experimental conditions, the lowest overall cost, the fastest reaction rate, and the highest product yield are achieved when the reaction residence time is 5 minutes, the reaction temperature is 10℃, and the molar ratio of acid intermediate (II)-dichloromethane, DM-triethylamine, and triphenylphosphine-dichloromethane reactants is 1:1.2:1.1.

[0059] Comparative Example The preparation method is the same as in Example 3, except that a conventional process is used, i.e., the reaction is carried out in a reactor. A comparison is made with the continuous flow process of Example 3, as shown in Table 4.

[0060] Table 4 .

[0061] As shown in Table 4, the continuous flow process offers advantages in terms of safety and operability. It only requires adjusting the feed pump flow rate and ensuring the feed enters the reaction column proportionally. Conventional processes, on the other hand, require multiple feeding steps, suffer from transfer losses, and are more cumbersome and potentially dangerous. Furthermore, they are prone to inaccurate feeding, difficulties in feeding during the reaction, incomplete reactions, and the inability to obtain solids, resulting in products remaining entirely in the solvent without crystallization. Consequently, the product yield is lower than that of continuous flow. However, the continuous flow process offers faster discharge and reaction rates, facilitating condition selection and variable adjustment to prepare for final crystal precipitation. Therefore, the continuous flow process is more suitable for this reaction.

[0062] Summarize: This invention provides a method for preparing cefixime intermediate (III). This method reduces production costs and solves the problems of low product yield in existing processes. The method of this invention ensures the safety of reaction conditions, has a simple post-processing procedure, and uses safe, clean, and inexpensive solvents.

Claims

1. A method for preparing a cefixime intermediate, characterized in that, Includes the following steps: (1) Synthesis of oxime ether intermediate (Ⅰ) Starting with tert-butyl acetoacetate, hydroxylamine hydrochloride and sodium hydroxide were added to carry out an oxime reaction to generate an oxime, and then methyl chloroacetate and a base were added to carry out an alkylation reaction to obtain an oxime ether intermediate (Ⅰ). （Ⅰ）； (2) Synthesis of acid intermediate (II) The oxime ether intermediate (Ⅰ) is chlorinated with a chlorinating agent to generate a chlorinated product; then it undergoes a cyclization reaction with thiourea and triethylamine to obtain the acid intermediate (Ⅱ). （Ⅱ）； (3) Synthesis of cefixime intermediate (III) Cefixime intermediate (III) was prepared by reacting acid intermediate (II) and 2,2'-dibenzothiazole disulfide under the action of triphenylphosphine. （Ⅲ）。 2. The method for preparing a cefixime intermediate according to claim 1, characterized in that: In step (1): the oxime reaction is carried out in the presence of a solvent, which is selected from any one or a mixture of two of water and ethanol; the reaction temperature of the oxime reaction is 0-12℃; the molar ratio of sodium hydroxide to tert-butyl acetoacetate is 1-3:

1.

3. The method for preparing a cefixime intermediate according to claim 1, characterized in that: In step (1): the alkylation reaction uses a base selected from any one of lithium carbonate, sodium carbonate, or potassium carbonate.

4. The method for preparing a cefixime intermediate according to claim 1, characterized in that: In step (1): the alkylation reaction is carried out in the presence of a solvent and a catalyst, wherein the solvent is N,N-dimethylformamide and the catalyst is triethylbenzylammonium chloride.

5. The method for preparing a cefixime intermediate according to claim 1, characterized in that: In step (1): the oxime ether intermediate (Ⅰ) is synthesized by a two-step one-pot method: after the oxime reaction in the first step is completed, the oxime does not need to be separated. In the same reaction pot, methyl chloroacetate and base are directly added to carry out the alkylation reaction to obtain the oxime ether intermediate (Ⅰ).

6. The method for preparing a cefixime intermediate according to claim 1, characterized in that: In step (2): the chlorination reaction is carried out by a chlorinating agent, which is a mixture of sulfonyl chloride, N-chlorosuccinyl ester, or tert-butyl amine nitrite and hydrochloric acid.

7. The method for preparing a cefixime intermediate according to claim 1, characterized in that: In step (2): the chlorination reaction is carried out in the presence of a solvent and a catalyst. The solvent is a mixed solvent of acetonitrile and water, and the catalyst is trifluoroacetic acid. The reaction temperature of the chlorination reaction is 0-5℃.

8. The method for preparing a cefixime intermediate according to claim 1, characterized in that: In step (2): the chlorination reaction and cyclization reaction are carried out in a one-pot method: the oxime ether intermediate (I) is dissolved in an acetonitrile / water mixed solvent, placed in a reaction vessel, and a catalytic amount of trifluoroacetic acid, a stoichiometric amount of tert-butyl nitrite, thiourea and triethylamine are added; at 0-5℃, HCl solution is added to the above reaction system, hydrochloric acid reacts with tert-butyl nitrite to generate NOCl in situ, and NOCl reacts with the oxime ether intermediate (I) to generate a chlorinated product; after the hydrochloric acid is added dropwise, the temperature is gradually raised to room temperature to carry out the cyclization reaction to obtain the product acid intermediate (II).

9. The method for preparing a cefixime intermediate according to claim 1, characterized in that: In step (3): the molar ratio of the acid intermediate (II), 2,2'-dibenzothiazole disulfide, and triphenylphosphine is 1:1-1.5:1-1.5; the reaction temperature is 5-15℃, and the reaction time is 2-10 min.

10. The method for preparing a cefixime intermediate according to claim 1, characterized in that: The reaction in step (3) adopts a continuous flow process: acid intermediate (II) is slurried with dichloromethane, DM with triethylamine, and triphenylphosphine with dichloromethane respectively, and injected into the microchannel reactor through three feed pumps according to the reaction molar ratio. The mixing and reaction are completed in the microchannel reactor to obtain cefixime intermediate (III).

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