Method for synthesizing azithromycin intermediate by aqueous phase method

Abstract

The invention discloses a method for synthesizing an azithromycin intermediate by an aqueous phase method. The azithromycin intermediate 9-deoxy-9a-aza-9a-cis-erythromycin A is obtained by taking erythromycin oxime as an initial raw material and carrying out rearrangement and reduction reaction, and is characterized in that paratoluensulfonyl chloride is taken as a rearrangement reagent, the rearrangement reaction and the reduction reaction are carried out in a water phase by a one-pot method, and the azithromycin intermediate 9-deoxy-9a-aza-9a-cis-erythromycin A is obtained. Polymer PEG-CS is introduced as a solubilizer, an acid-binding agent, a defoaming agent and a hydrolysis promoting agent to participate in rearrangement and reduction reactions, other auxiliary agents and auxiliary materials do not need to be additionally added, the problem that excessive auxiliary agents and auxiliary materials need to be used in existing rearrangement and reduction reactions is solved from the source, and the recovery cost of the solvent and the use and post-treatment cost of the auxiliary materials are remarkably reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis and relates to a method for synthesizing an azithromycin intermediate through an aqueous phase method. Background Art

[0002] As a second-generation semi-synthetic 15-membered aza-macrolide antibiotic, azithromycin is widely used in clinical practice due to its broad antibacterial spectrum, low gastrointestinal irritation, rapid oral absorption, strong tissue permeability, and long half-life. It has a good effect on respiratory tract, urinary system, skin and soft tissue infections and sexually transmitted diseases caused by common sensitive bacteria, and is widely used in anti-infection, with a very broad market prospect.

[0003] At present, the methods for synthesizing azithromycin at home and abroad are relatively consistent. Most of them use erythromycin thiocyanate as the starting material, and undergo an oximation reaction with hydroxylamine hydrochloride to obtain erythromycin thiocyanate A9-oxime. Erythromycin thiocyanate A9-oxime is freed to obtain erythromycin A9-oxime (intermediate 1), which is then rearranged to obtain A6,9-imino ether (intermediate 2), and then subjected to a reduction reaction to obtain 9-deoxy-9a-aza-9a-cis-erythromycin A (intermediate 3), and finally subjected to a methylation reaction to obtain azithromycin. The reaction equation is shown below. In the preparation process of azithromycin, the oximation and methylation reaction processes have been well studied, the process conditions are simple, and the yield and quality are relatively excellent. However, the rearrangement and reduction reaction processes are complicated, which will ultimately affect the yield and quality of azithromycin. Therefore, the rearrangement and reduction reactions are the key reactions in the preparation process of azithromycin. A6,9-imidoether (intermediate 2) and 9-deoxy-9a-aza-9a-cis-erythromycin A (intermediate 3) are the key intermediates in the preparation process of azithromycin.

[0004]

[0005] At present, there are many literature reports for improving rearrangement reactions and reduction reactions. There are two main ideas, one is to optimize only the rearrangement reaction or the reduction reaction. CN118165055A mentions the use of a one-step three-phase extraction method to catalytically purify 9-deoxy-9a-aza-9a-cis-erythromycin A, specifically: adding a dichloromethane / platinum catalytic system in the reaction stage to promote the reaction, and adding dichloromethane / platinum, ammonium sulfate and methanol to form a three-phase extraction system to separate the product in the post-treatment stage; CN110684056A mentions the use of potassium borohydride and zinc trifluoromethanesulfonate as catalysts to jointly reduce A6,9-imino ether dissolved in methanol, and using resin for deboronation in the post-treatment stage. The other is the one-pot method, which combines rearrangement and reduction reactions. There is no need to get A6,9-iminoether solid in the middle. CN103880898A mentions that erythromycin A9-oxime is used as a raw material for rearrangement reaction, and then potassium borohydride solution is directly added for reduction reaction; CN105481913A also mentions that erythromycin thiocyanate A9-oxime is used as a raw material for rearrangement reaction, and potassium borohydride solution is added after the reaction is completed for reduction reaction. Although the above two ideas can improve the quality of intermediates and simplify the operation steps to a certain extent, a large amount of organic solvents, additives, and catalysts are still required. Using too much material is relatively simple to handle at the small test level, but for continuous industrial production, it will increase the cost of solvent recovery and material post-processing, which is obviously not conducive to industrial production and the development of green chemistry.

[0006] In addition, the inventors found that most rearrangement reactions use toluenesulfonyl chloride or methanesulfonyl chloride as rearrangement reagents. CN105481913A and CN103880898A all mention the use of toluenesulfonyl chloride to participate in the reaction. Due to the water-insoluble nature of toluenesulfonyl chloride, the rearrangement reaction must have the participation of an organic solvent to promote the reaction. Usually toluenesulfonyl chloride is excessive in the reaction. If the organic solvent is not removed and a reduction reaction is carried out, too much material will be brought into the next reduction reaction, resulting in an incomplete reaction, excessive impurities, and a series of problems such as impurity removal difficulties; if toluenesulfonyl chloride is removed after the rearrangement reaction ends, the organic reagent needs to be separated, which may take away a part of the rearrangement product, which will eventually lead to a decrease in overall yield. In view of the above problems, the idea of ​​using methanesulfonyl chloride as a rearrangement reagent has been proposed, and CN104892697A and CN107739397A all mention the use of methanesulfonyl chloride to participate in the reaction. Methanesulfonyl chloride is an active catalyst that decomposes when exposed to water. After the reaction is completed, water can be added to remove it without the need for stratification, filtration, and other operations. However, the property of methanesulfonyl chloride to decompose when exposed to water makes it unsuitable for reaction in an aqueous system. In addition, methanesulfonyl chloride is a highly toxic chemical, and its purchase and use are more stringent. Therefore, for rearrangement reactions, it is particularly important to avoid the use of organic solvents and choose a method suitable for reaction in an aqueous phase.

[0007] The reduction reaction mainly uses chemical reduction method. CN107141324A, CN110483594A, and CN113929721A all mention the use of potassium (sodium) borohydride as a catalyst. However, this method will cause two major problems during the reduction reaction:

[0008] 1) After many experiments by the inventors, it was found that adding potassium (sodium) borohydride system to the reduction reaction with water as solvent will generate a large number of bubbles, and the bubbles take a long time to disappear, thus occupying a lot of reaction space, resulting in reduced utilization and low reaction efficiency. At the same time, the instantaneous generation of bubbles will lead to the risk of spraying, which increases the risk of reaction.

[0009] 2) After the reduction reaction, a mixture of 9-deoxy-9a-aza-9a-cis-erythromycin A borate and 9-deoxy-9a-aza-9a-cis-erythromycin A is obtained, so the borate needs to be hydrolyzed in the post-reduction treatment stage. CN113929721A mentions that after the reduction reaction, the product is inverted by pH change, and the borate is removed by 5 liquid separations, but this method consumes a large amount of reagents and is complicated to operate. At the same time, there is a risk of product loss during liquid separation, which affects the product yield; CN103214531A and CN110684056B mention the removal of borate with the assistance of a hydrolysis promoter, which is effective but also requires the use of an additional hydrolysis promoter. Summary of the invention

[0010] In view of the above problems, the present invention provides a method for synthesizing an azithromycin intermediate (9-deoxy-9a-aza-9a-cis-erythromycin A) by an aqueous phase method. The present invention creatively uses a polymer PEG-CS (polyethylene glycol-chitosan) to participate in the rearrangement and reduction reactions. The rearrangement reaction and the reduction reaction are carried out in a one-pot method in the aqueous phase. PEG-CS plays four roles in the reaction: as a solubilizer and acid binding agent for the rearrangement reaction; as a defoaming agent and hydrolysis promoter for the reduction reaction. The present invention does not require the addition of other auxiliary agents and excipients, and solves the problem of the need to use too many auxiliary agents and excipients in the rearrangement and reduction reactions from the source, significantly reducing the solvent recovery cost and the use and post-processing cost of the excipients.

[0011] The technical scheme of the present invention is: a method for synthesizing an azithromycin intermediate by an aqueous phase method, which uses erythromycin oxime as a starting material, and obtains an azithromycin intermediate 9-deoxy-9a-aza-9a-cis-erythromycin A through rearrangement and reduction reactions. The method is characterized in that p-toluenesulfonyl chloride is used as a rearrangement reagent, the rearrangement reaction and the reduction reaction are carried out in an aqueous phase in a one-pot method, and a polymer PEG-CS (polyethylene glycol-chitosan) is introduced as a solubilizer, an acid binding agent, a defoaming agent and a hydrolysis promoter to participate in the rearrangement and reduction reactions.

[0012] The specific steps include:

[0013] 1) Rearrangement reaction: using erythromycin oxime as the starting material and water as the solvent, adding PEG-CS and a rearrangement reagent, toluenesulfonyl chloride, to carry out a rearrangement reaction, and adjusting the pH of the feed solution to 4-6 after the reaction is completed;

[0014] 2) Reduction reaction: Take the aqueous solution of step 1) and add potassium borohydride to carry out reduction reaction. No large amount of bubbles are generated in the system during the addition of potassium borohydride;

[0015] 3) Post-treatment: After the reaction is completed, dichloromethane is added to the system, hydrochloric acid is added to adjust the pH of the feed solution to <3.0, and after stirring, alkali solution is added to adjust the pH of the feed solution to >9.5. The organic layer is separated and water is added to adjust the pH of the feed solution to <7.0. The aqueous layer is separated and alkali is added to pH>11. The residual dichloromethane in the aqueous phase is removed by evaporation, and the crystallization is stirred and filtered to obtain solid 9-deoxy-9a-aza-9a-cis-erythromycin A.

[0016] The structural formula of PEG-CS (polyethylene glycol-chitosan) in step 1) is as follows. Preferably, the average molecular weight of polyethylene glycol is 1000Da, the average molecular weight of chitosan is 5000Da, and the total molecular weight is 6000Da.

[0017]

[0018] Furthermore, after the stratification in step 3), the water layer containing PEG-CS is collected for centralized recovery treatment (freeze-drying after dialysis can directly obtain purified PEG-CS).

[0019] Preferably, the reaction temperature in steps 1) and 2) is 0-10°C.

[0020] Preferably, in step 1), the mass ratio of PEG-CS to p-toluenesulfonyl chloride is 0.38-0.42:1, preferably 0.404:1.

[0021] The overall idea of ​​this method is as follows: 1. PEG-CS, as a solubilizer, increases the solubility of p-toluenesulfonyl chloride in water, enables p-toluenesulfonyl chloride to participate in the reaction more effectively, promotes the rearrangement reaction in the aqueous phase, and at the same time, the use of p-toluenesulfonyl chloride also effectively avoids the use of highly toxic chemicals; 2. Since CS in PEG-CS contains amino groups, the polymer has a strong protonation ability and can be used as an acid binding agent for the rearrangement reaction to promote the reaction and improve the reaction capacity of the rearrangement reaction; 3. After the reaction is completed, potassium borohydride can be directly added to the solution after the pH value is adjusted for reduction reaction. PEG-CS has been protonated as an acid-binding agent in the rearrangement reaction, so the protonated PEG-CS can be used as a cationic surfactant as a defoaming agent in the reduction reaction stage to defoam, which can significantly reduce the bubbles in the system and solve the risk of liquid overflow and spraying from the source; 4. Since CS contains a large number of hydroxyl groups, it can be used as a polyhydroxy polymer as a hydrolysis promoter in the post-treatment stage of the reduction reaction. Only one acid adjustment is required to completely remove the boric acid ester, and no excessive operations are required. The removed PEG-CS can be directly applied to the next batch of production or recycled after simple treatment. In summary, this method only requires the introduction of one reagent to participate in all reactions and post-treatments, significantly reducing the use of solvents and excipients, fundamentally avoiding the production pressure caused by the production of additives and excipients and post-treatment, and reducing production costs. Therefore, the method of the present invention is very suitable for industrial production.

[0022] The beneficial effects of the present invention are:

[0023] 1. PEG-CS deeply participates in the reaction. First, it can act as a solubilizer and acid-binding agent to participate in the rearrangement reaction. Second, it can act as a defoaming agent and hydrolysis promoter to participate in the reduction reaction. One reagent can play multiple roles in the entire reaction, and it has multiple functions and good effects, which effectively avoids the use of too many auxiliary materials and additives. At the same time, the removed polyethylene glycol-chitosan can be recycled through simple treatment. Therefore, this method is very suitable for industrial production and meets the requirements of green chemistry.

[0024] 2. The present invention makes it possible to carry out the rearrangement reaction in the aqueous phase, and can be carried out in one pot with the reduction reaction in the aqueous phase, avoiding the use of organic reagents in the rearrangement reaction stage, making the two-step reaction coherent and orderly, and simplifying the operation steps. The material loss caused by the use of organic solvents can be avoided from the source, and the risk of reducing the yield can be greatly reduced. The method can greatly reduce the storage, transportation, and use of auxiliary materials in industrial production, and the use and recovery of organic solvents. At the same time, the method can provide ideas for other reactions, solve several problems in the production process by selecting suitable auxiliary materials, and reduce production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 During the addition of potassium borohydride in Example 1, no bubbles were generated in the system;

[0026] Figure 2 During the addition of potassium borohydride in Comparative Example 2, a large amount of bubbles were generated in the system, almost filling up the space of the reaction bottle;

[0027] Figure 3 HPLC chart of the product 9-deoxy-9a-aza-9a-cis-erythromycin A of Example 1;

[0028] Figure 4 This is the HPLC chart of the feed liquid of Comparative Example 1 after 5 hours of rearrangement reaction. DETAILED DESCRIPTION

[0029] The technical solution of the present invention is further described below in conjunction with embodiments and drawings, but the protection scope of the present invention is not limited thereto.

[0030] 250g of erythromycin thiocyanate was subjected to oximation reaction, the oxime salt was freed, and then dried to obtain 220g of erythromycin oxime (purity ≧99.0%) for the experiments of Example 1 and Comparative Example 1; 120g of erythromycin oxime was subjected to rearrangement reaction to obtain 110g of A6,9-imidoether (purity ≧99.0%) for the experiments of Comparative Examples 2 and 3.

[0031] The PEG-CS described in the examples is purchased. In industrial production, PEG-CS can be synthesized first and then used. It can be recycled after being synthesized only once. The specific parameters are: PEG-CS, polyethylene glycol average molecular weight of 1000Da, chitosan average molecular weight of 5000Da, and total molecular weight of 6000Da.

[0032] Embodiment 1:

[0033] Add 50g erythromycin oxime to a 1000ml three-necked flask, add 300ml water, start stirring, cool to 0-10°C, add 6.71g PEG-CS and 16.61g p-toluenesulfonyl chloride, and react at low temperature for 5h. After the reaction, adjust the pH of the liquid to 4-6, filter and take the water phase for use, add 8.32g potassium borohydride to the system, keep warm at 0-10°C for 6h, and no bubbles are generated in the system during the addition of potassium borohydride ( Figure 1 ). After the reaction, 620 ml of dichloromethane was added to the system, and the pH of the feed solution was adjusted to <3.0 by adding hydrochloric acid. After stirring for 20 minutes, alkali solution was added to adjust the pH of the feed solution to >9.5. The organic layer was separated by layers, and the aqueous layer containing PEG-CS was collected for centralized recovery treatment (purified PEG-CS can be directly obtained by freeze-drying after dialysis). 500 ml of water was added to the organic layer to adjust the pH of the feed solution to <7.0. The aqueous layer was separated by layers, and alkali was added to the aqueous layer until the pH of the feed solution was >11.0. The residual dichloromethane in the aqueous phase was removed by evaporation, the pH of the feed solution was maintained, and the crystallization was stirred for 2 hours. 42.75 g of 9-deoxy-9a-aza-9a-cis-erythromycin A was obtained by filtration, with a purity of 98.06%. No borate impurities were detected in the product (see Figure 3 ).

[0034] Comparative Example 1:

[0035] Add 50g erythromycin oxime and 300ml water to a 1000ml three-necked flask, start stirring, cool to 0-10°C, add 16.61g p-toluenesulfonyl chloride, and react at low temperature for 5h. After the reaction, take the feed liquid for HPLC detection to monitor the reaction. The results are as follows Figure 4 As shown, HPLC showed that there was still 54.86% erythromycin oxime in the feed solution (in the HPLC graph, A6,9-imidoether peaked at 28.083 min, and erythromycin oxime peaked at 44.377 min) that could not react. Since the reaction was not complete, the feed solution could not undergo reduction reaction.

[0036] Comparative Example 2:

[0037] Take 45g A6,9-iminoether, add 300ml water, and adjust the pH of the solution to 4-6 with hydrochloric acid to simulate the solution after the rearrangement reaction is completed and without PEG-CS. Cool down to 0-10℃, add 8.32g potassium borohydride to the system and start the heat preservation reaction for 6h. During the addition of potassium borohydride, a large number of bubbles are generated in the system, almost filling up the space of the reaction bottle ( Figure 2 ). After the reaction, 620 ml of dichloromethane and 19.21 g of deboronized resin were added to the system, and the pH of the feed solution was adjusted to <3.0 by adding hydrochloric acid. After stirring for 20 min, alkali solution was added to adjust the pH of the feed solution to >9.5. The organic layer was separated and 500 ml of water was added to the organic layer to adjust the pH of the feed solution to <7.0. The aqueous layer was separated and alkali was added to the aqueous layer until the pH of the feed solution was >11.0. The residual dichloromethane in the aqueous phase was removed by evaporation, the pH of the feed solution was maintained and stirred for crystallization for 2 h, and filtered to obtain 40.95 g of 9-deoxy-9a-aza-9a-cis-erythromycin A with a purity of 92.35%.

[0038] Comparative Example 3:

[0039] Take 45g A6,9-iminoether, add 300ml water, and adjust the pH of the solution to 4-6 with hydrochloric acid to simulate the solution after the rearrangement reaction and without PEG-CS. Cool down to 0-10℃, add 8.32g potassium borohydride to the system and start the heat preservation reaction for 5h. During the addition of potassium borohydride, a large number of bubbles are generated in the system, almost filling up the space of the reaction bottle. After the reaction, 620 ml of dichloromethane was added to the system, and the pH of the feed solution was adjusted to <3.0 by adding hydrochloric acid. After stirring for 20 minutes, alkali solution was added to adjust the pH of the feed solution to >9.5. The organic layer was separated and 500 ml of water was added to the organic layer to adjust the pH of the feed solution to <7.0. The aqueous layer was separated and alkali was added to the aqueous layer until the pH of the feed solution was >11.0. The residual dichloromethane in the aqueous phase was removed by evaporation, the pH of the feed solution was maintained and stirred for crystallization for 2 hours, and 41.18 g of 9-deoxy-9a-aza-9a-cis-erythromycin A was obtained by filtration with a purity of 80.79%.

[0040] It can be seen from the examples and comparative examples that the present invention creatively uses polymer PEG-CS (polyethylene glycol-chitosan) to participate in the rearrangement and reduction reactions. PEG-CS plays four roles in the reaction: as a solubilizer and acid binding agent for the rearrangement reaction; as a defoaming agent and hydrolysis promoter for the reduction reaction. During the addition of potassium borohydride, no large amount of bubbles are generated in the system, and the total yield of the product is improved.

[0041] Embodiment 2:

[0042] Add 50g erythromycin oxime to a 1000ml three-necked flask, add 300ml water, start stirring, cool to 0-10°C, add 6.73g PEG-CS and 16.65g p-toluenesulfonyl chloride, and react at low temperature for 5.5h. After the reaction, adjust the pH of the liquid to 4-6, filter and take the water phase for use, add 8.35g potassium borohydride to the system, keep warm at 0-10°C for 5.5h, and no bubbles are generated in the system during the addition of potassium borohydride. After the reaction, 650 ml of dichloromethane was added to the system, and the pH of the feed solution was adjusted to <3.0 by adding hydrochloric acid. After stirring for 20 minutes, alkali solution was added to adjust the pH of the feed solution to >9.5. The organic layer was separated and the aqueous layer containing PEG-CS was collected for centralized recovery (purified PEG-CS can be directly obtained by freeze-drying after dialysis). 500 ml of water was added to the organic layer to adjust the pH of the feed solution to <7.0. The aqueous layer was separated and alkali was added to the aqueous layer until the pH of the feed solution was >11.0. The residual dichloromethane in the aqueous phase was removed by evaporation, the pH of the feed solution was maintained and stirred for crystallization for 2 hours, and 42.78 g of 9-deoxy-9a-aza-9a-cis-erythromycin A was obtained by filtration with a purity of 98.22%. No borate impurities were detected in the product.

[0043] Embodiment 3:

[0044] Add 50g erythromycin oxime to a 1000ml three-necked flask, add 300ml water, start stirring, cool to 0-10°C, add 6.70g PEG-CS and 16.60g p-toluenesulfonyl chloride, and react at low temperature for 5h. After the reaction, adjust the pH of the liquid to 4-6, filter and take the water phase for use, add 8.30g potassium borohydride to the system, keep warm at 0-10°C for 6h, and no bubbles are generated in the system during the addition of potassium borohydride. After the reaction was completed, 600 ml of dichloromethane was added to the system, and the pH of the feed solution was adjusted to <3.0 by adding hydrochloric acid. After stirring for 20 minutes, alkali solution was added to adjust the pH of the feed solution to >9.5. The organic layer was separated and the PEG-CS aqueous layer was collected for centralized recovery (purified PEG-CS can be directly obtained by freeze-drying after dialysis). 500 ml of water was added to the organic layer to adjust the pH of the feed solution to <7.0. The aqueous layer was separated and alkali was added to the aqueous layer until the pH of the feed solution was >11.0. The residual dichloromethane in the aqueous phase was removed by evaporation, the pH of the feed solution was maintained and stirred for crystallization for 2 hours, and 42.71 g of 9-deoxy-9a-aza-9a-cis-erythromycin A was obtained by filtration with a purity of 98.02%. No borate impurities were detected in the product.

Claims

1. A method for synthesizing an azithromycin intermediate by an aqueous phase method, using erythromycin oxime as a starting material, and obtaining an azithromycin intermediate 9-deoxy-9a-aza-9a-cis-erythromycin A through rearrangement and reduction reaction, wherein: Using p-toluenesulfonyl chloride as the rearrangement reagent, the rearrangement reaction and the reduction reaction are carried out in a one-pot method in the aqueous phase, and the polymer PEG-CS is introduced as a solubilizer, acid binding agent, defoaming agent and hydrolysis promoter to participate in the rearrangement and reduction reactions.

2. The method for synthesizing an azithromycin intermediate by an aqueous phase method according to claim 1, characterized in that: The specific steps include: 1) Rearrangement reaction: using erythromycin oxime as the starting material and water as the solvent, adding PEG-CS and a rearrangement reagent, toluenesulfonyl chloride, to carry out a rearrangement reaction, and adjusting the pH of the feed solution to 4-6 after the reaction is completed; 2) Reduction reaction: Take the aqueous solution of step 1) and add potassium borohydride to carry out reduction reaction. No large amount of bubbles are generated in the system during the addition of potassium borohydride; 3) Post-treatment: After the reaction is completed, dichloromethane is added to the system, hydrochloric acid is added to adjust the pH of the feed solution to <3.0, and after stirring, alkali solution is added to adjust the pH of the feed solution to >9.

5. The organic layer is separated and water is added to adjust the pH of the feed solution to <7.

0. The aqueous layer is separated and alkali is added to pH>11. The residual dichloromethane in the aqueous phase is removed by evaporation, and the crystallization is stirred and filtered to obtain solid 9-deoxy-9a-aza-9a-cis-erythromycin A.

3. A method for synthesizing an azithromycin intermediate by an aqueous phase method as claimed in claim 1 or 2, characterized in that: The structural formula of the PEG-CS is as follows, 4. The method for synthesizing an azithromycin intermediate by an aqueous phase method as claimed in claim 2, characterized in that: After the stratification in step 3), the PEG-CS-containing water layer is collected for centralized recovery treatment.

5. The method for synthesizing an azithromycin intermediate by an aqueous phase method as claimed in claim 4, characterized in that: The aqueous layer containing PEG-CS was dialyzed and freeze-dried to obtain purified PEG-CS.

6. The method for synthesizing an azithromycin intermediate by an aqueous phase method as claimed in claim 2, characterized in that: The reaction temperature in steps 1) and 2) is 0-10°C.

7. The method for synthesizing an azithromycin intermediate by an aqueous phase method as claimed in claim 2, characterized in that: In the step 1), the mass ratio of PEG-CS to p-toluenesulfonyl chloride is 0.38-0.42:1.

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