A method for preparing azithromycin using a microchannel reactor

Abstract

The invention discloses a method for preparing azithromycin by using a microchannel reactor. The method uses erythromycin as a starting material and prepares azithromycin through oximation, rearrangement, reduction and methylation reactions. During the oximation reaction, the contact time of the feed liquid in the microchannel reactor is very short, which greatly reduces the safety risk of the oximation reaction. The reduction reaction is carried out in the microchannel reactor, and neither explosive sodium (potassium) borohydride nor a high-pressure reactor is used, which reduces the safety risk. A tray layer of palladium carbon is laid on the reaction bed to achieve the hydrogenation target, while greatly improving the utilization efficiency of palladium carbon. In the rearrangement reaction, a milder leaving group, sodium 2-naphthalenesulfonate, is used to replace the existing leaving group. Water is used as a solvent and the reaction is carried out at room temperature. The method is green, safe, and has a high yield, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to a method for preparing azithromycin, and belongs to the technical field of chemical synthesis medicine. Background Art

[0002] Azithromycin is a 15-ring nitrogen-containing macrolide drug that is widely used in respiratory, urinary, and skin and soft tissue infections. It has a broad antibacterial spectrum and few adverse reactions. Therefore, the prospects for azithromycin APIs and preparations in the domestic anti-infective drugs are very broad. Azithromycin was originally developed by Pliva Company in Croatia and was first launched in Yugoslavia. Its molecular formula is: C 38 H 72 N2O 12 , molecular weight 749.00, structural formula is as follows:

[0003]

[0004] In 1981, Pfizer Inc. of the United States obtained the patent rights to azithromycin, which was sold under the trade name Zithromax and began to be sold worldwide. Over the next decade or so, global sales of azithromycin have steadily increased. In 2008, azithromycin produced in the United States had a global market share of 30.78%. In China, the production of azithromycin began in 1995, and its raw materials and preparations have been included in the 2005 edition of the Chinese Pharmacopoeia. China and the United States are the largest consumers of azithromycin.

[0005] Currently, the azithromycin synthesis methods used by domestic and foreign manufacturers are relatively consistent. Most of them use erythromycin thiocyanate or erythromycin as the starting material, and obtain azithromycin through a four-step reaction of oximation, rearrangement, sodium (potassium) borohydride reduction or high-pressure hydrogenation reduction, and methylation, such as CN201410480463.2, CN201910858408.5, CN201210564825.7, CN201510222010.4, etc.

[0006] The first three steps of the reaction currently have the following problems:

[0007] 1. The first step of the oximation reaction is a Level 5 risk reaction (the highest level risk identified in chemical production), which is very likely to cause explosion risk. For example, patent CN104892697A describes: erythromycin thiocyanate and hydroxylamine are reacted at 30-33°C for 12 hours, and then heated to 58-60°C for 24 hours. The reaction time is far longer than T D24 If the cooling device fails, there is a high risk of explosion. In addition, the hydroxylamine aqueous solution used is highly explosive and poses a great risk in transportation.

[0008] 2. In the second rearrangement reaction, existing patents generally use a mixture of acetone and water as the reaction solvent, with methanesulfonyl chloride or p-toluenesulfonyl chloride as the leaving group. However, methanesulfonyl chloride is a highly toxic substance and is not suitable for commercial production. p-Toluenesulfonyl chloride requires low temperatures (below -10°C) throughout the entire process, which places high demands on equipment costs. Furthermore, the large amount of acetone used generates a large amount of high-COD wastewater that is difficult to treat. Furthermore, acetone has a certain solubility in the product, resulting in a reduced yield.

[0009] 3. The third step reduction reaction, whether it is reduction using sodium (potassium) borohydride or hydrogenation reduction using a high-pressure reactor, is a high-risk reaction.

[0010] Given the dangers of the first and third step reactions and the problems with the leaving group in the second step rearrangement reaction, it is particularly urgent to develop a green, safe and low-risk process flow. Summary of the Invention

[0011] To address the high risks of oximation and reduction reactions, as well as the issues with leaving groups in rearrangement reactions, the applicant, after extensive experimentation and equipment commissioning, has developed a method for preparing azithromycin using a microchannel reactor. This method utilizes a microchannel reactor in the first and third steps to accelerate the reaction and reduce operational risks. In the second step, a milder leaving group, sodium 2-naphthalenesulfonate, is used to replace the existing leaving group. The reaction solvent is also changed, resulting in a green, safe, high-yield method suitable for industrial production.

[0012] The technical solution of the present invention is: a method for preparing azithromycin using a microchannel reactor, characterized in that erythromycin is used as a starting material and azithromycin is prepared through oximation, rearrangement, reduction and methylation reactions, characterized in that:

[0013] The oximation reaction is as follows: a microchannel reactor is used, the core structure of the reactor is two preheating pipes and a microchannel exchanger, two feed liquids (erythromycin and sodium bicarbonate ethanol solution, hydroxylamine hydrochloride ethanol solution) are preheated to 72-76 ° C through the preheating pipe, contacted in the microchannel exchanger for 20-30 seconds for oximation reaction, and then discharged from the discharge port, and purified water is added dropwise to crystallize by utilizing the solubility difference to obtain intermediate 1;

[0014] The rearrangement reaction is as follows: using water as solvent, sodium 2-naphthalenesulfonate as a leaving group to react with intermediate 1 at room temperature, and after the reaction is completed, adjusting the pH of the liquid to 11-12 for crystallization to obtain intermediate 2;

[0015] The reduction reaction is as follows: a microchannel reactor is used, the core structure of the reactor is a microchannel exchanger and a medium-pressure pipeline equipped with a one-way valve, and the medium-pressure pipeline is used to transport a hydrogen source; a palladium-carbon tray box is laid inside the microchannel exchanger; a methanol solution of intermediate 2 is contacted with hydrogen in the microchannel exchanger laid with the palladium-carbon tray box for 5-10 seconds to undergo a reduction reaction, and then flows out from the discharge port and crystallizes to obtain intermediate 3.

[0016] Furthermore, the methylation reaction is as follows: using chloroform as a solvent, dissolving the intermediate 3 and reacting with formaldehyde and formic acid, heating to reflux for reaction; after completion of the reaction, quenching the reaction, cooling and adding seed crystals to induce crystallization to produce a crude azithromycin product; the crude azithromycin product is recrystallized from acetone-water (volume ratio 2.0-3.0:1) to obtain azithromycin dihydrate; in terms of molar ratio, the intermediate 3: formaldehyde: formic acid = 1:2.4-2.9:2.4-2.9.

[0017] The reaction scheme is shown below, and the reaction process is as follows Figure 1 As shown, Figures AD are the processes of oximation, rearrangement reaction, reduction, and methylation reaction.

[0018]

[0019] Furthermore, the oximation reaction is carried out in a molar ratio of erythromycin: sodium bicarbonate: hydroxylamine hydrochloride = 1:2.5-3.0:2.25-2.5, and after the liquid is dissolved, a microchannel reactor is used for rapid contact reaction.

[0020] Furthermore, in the rearrangement reaction, the molar ratio of the intermediate 1:sodium 2-naphthalenesulfonate is 1:2.2-2.6, and the temperature is controlled at 20-25° C., and the sodium 2-naphthalenesulfonate aqueous solution is added dropwise, and the temperature is kept for reaction.

[0021] Furthermore, in the reduction reaction, the methanol solution of the intermediate 2 and the hydrogen gas simultaneously enter the palladium-carbon tray box in the microchannel exchanger.

[0022] Compared with the prior art, the present invention achieves breakthroughs in three aspects, as follows:

[0023] 1. During the oximation reaction, the contact time of the feed liquid in the exchanger is very short and cannot reach T D24 and the minimum of MTSR, so this method greatly reduces the safety risk of oximation reaction.

[0024] 2. The use of sodium 2-naphthalenesulfonate as a leaving group in this application has the following advantages: sodium 2-naphthalenesulfonate is easily soluble in water, and the reaction solvent can be improved from an acetone-water system to a pure water system. Organic solvents are no longer used, which reduces the dissolution of the product by organic solvents, thereby greatly improving the rearrangement yield. Sodium 2-naphthalenesulfonate is inexpensive as a salt, easy to obtain and store, non-toxic and harmless, and has more advantages than methanesulfonyl chloride and p-toluenesulfonyl chloride. In addition, the reaction temperature is improved from low temperature (below -10°C) to room temperature, which is more suitable for commercial production.

[0025] 3. During the reduction reaction, neither explosive sodium (potassium) borohydride nor high-pressure reactors are used, which reduces safety risks. The hydrogenation goal is achieved by laying a palladium-carbon plate layer on the reaction bed, while greatly improving the utilization efficiency of palladium-carbon, which is in line with the goal of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The reaction process of azithromycin of the present invention is shown in Figure AD, where the process of oximation, rearrangement, reduction, and methylation reactions is shown in sequence;

[0027] Figure 2 Schematic diagram of the microchannel reactor structure for the oximation reaction step, including: 1. starting material preheating dissolver, 2. hydroxylamine preheating dissolver, 3. microchannel exchanger, 4. cooling device, 5. filtration device, 6. multi-plate reaction bed;

[0028] Figure 3 Schematic diagram of the microchannel reactor structure for the reduction reaction step, including: 1. feed liquid delivery pipeline, 2. hydrogen cylinder, 3. medium-pressure pipeline, 4. one-way check valve, 5. microchannel exchanger; 6. palladium carbon tray box, 7. cooling device, 8. filtration device;

[0029] Figure 4 The DSC curve and analysis of hydroxylamine hydrochloride;

[0030] Figure 5 The temperature and pressure of the reaction solution (hydroxylamine free reaction solution, WO220214-a) vs. time curve;

[0031] Figure 6 is the powder diffraction pattern of azithromycin;

[0032] Figure 7 This is the powder diffraction pattern of azithromycin published by Pfizer, the original developer of azithromycin. DETAILED DESCRIPTION

[0033] The present invention is further described below with reference to the accompanying drawings and specific embodiments, but the protection scope of this application is not limited thereto.

[0034] The microchannel reactor structure of the oximation reaction step is as follows Figure 2As shown, the reactor comprises a starting material preheating dissolver (1), a hydroxylamine preheating dissolver (2), a microchannel exchanger (3), a cooling device (4), and a suction filtration device (5) connected by pipelines, and a multi-plate reaction bed (6) is provided inside the exchanger. During the oximation reaction, the core structure of the reactor is two preheating pipes and an exchanger. The preheating pipes are feed liquid conveying pipes, and the exchanger serves as a reaction bed. The two preheated feed liquids contact in the exchanger for 20-30 seconds to carry out the oximation reaction, and then are cooled by the cooling device (4) and filtered by the suction filtration device (5) before flowing out from the discharge port.

[0035] The structure of the microchannel reactor for the reduction reaction step is as follows Figure 3 As shown, the reactor comprises a feed liquid delivery pipeline (1), a hydrogen cylinder (2), a medium-pressure pipeline (3), a microchannel exchanger (5), a cooling device (7) and a suction filtration device (8) connected by pipelines, a palladium-carbon tray box (6) is laid inside the microchannel exchanger (5), and a one-way check valve (4) is installed on the medium-pressure pipeline (3). During the reduction reaction, the core structure of the reactor is a medium-pressure pipeline (3) with a one-way valve installed and a microchannel exchanger, the medium-pressure pipeline is a hydrogen source delivery pipeline, and the microchannel exchanger serves as a reaction bed (laid with a palladium-carbon tray layer). The feed liquid contacts the hydrogen in the reaction bed for 5-10 seconds to undergo a reduction reaction, and after being cooled by the cooling device (7) and filtered by the suction filtration device (8), it flows out from the discharge port.

[0036] This embodiment uses the G1-5FM microchannel glass reactor produced by Corning Equipment Manufacturing Company of the United States as an example for illustration:

[0037] Example 1:

[0038] Add 5 kg of erythromycin, 7.5 kg of anhydrous ethanol, and 1.6 kg of sodium bicarbonate into a clean 25 L reactor, start stirring until the liquid becomes a thin turbid liquid, and set aside.

[0039] In another clean 25L reactor, add 1.2kg of hydroxylamine hydrochloride and 7.5kg of anhydrous ethanol, start stirring, and stop stirring after the hydroxylamine hydrochloride is dissolved. Set aside.

[0040] The siphon pumps of the two preheating pipes were immersed in the prepared feed liquid respectively, and the pump speed was adjusted to 2.5-2.8 L / min. The two feed liquids (ethanol solution of erythromycin and sodium bicarbonate, and ethanol solution of hydroxylamine hydrochloride) were sucked into the preheating pipe via the siphon pump. After being preheated to 72-76°C in the preheating pipe, they were kept in contact for 20-30 seconds in a microchannel exchanger for oximation reaction. The discharge port was connected to another 50L reactor. After all the discharge was completed, 15 kg of purified water was added dropwise to the reactor. After the addition was completed, the reactor was incubated for 1 hour, and the solid was filtered and dried to obtain a white solid, which was azithromycin intermediate 1. The salt content of this intermediate was not counted in the yield, and the HPLC purity was 92.5%.

[0041] Comparative Example: Oximation without using a microreactor

[0042] As described in patent CN104892697A: 1.0 times the amount of methanol, based on the amount of erythromycin thiocyanate, is pumped into a reaction tank, the temperature is controlled at 20-25°C, hydroxylamine hydrochloride is added with stirring, ammonium bicarbonate is added, and erythromycin thiocyanate is added. After the addition, the temperature is raised and the internal temperature is controlled at 30-33°C. After reacting for 12 hours, the temperature is raised to 58-60°C and reacted for 24 hours.

[0043] The oximation reaction was subjected to a heat test by my team, which showed that this step of the reaction was a Level 5 risk reaction (the highest level of risk recognized in chemical production).

[0044] according to Figure 4 DSC curve and analysis of hydroxylamine hydrochloride, Figure 5 The temperature, pressure vs. time curves of the reaction solution (hydroxylamine free reaction solution, WO220214-a), as well as the reaction process hazard assessment standards in Table 1 and the reaction process hazard assessment conclusions in Table 2.

[0045] Table 1 Reaction process hazard assessment standards

[0046] grade temperature as a result of 1 <![CDATA[T p <MTSR<MTT<T D24 ]]> Low risk of reaction 2 <![CDATA[T p <MTSR<T D24 <MTT]]> Potential decomposition risk 3 <![CDATA[T p ≤MTT<MTSR<T D24 ]]> There is a risk of material impact and decomposition 4 <![CDATA[T p ≤MTT<T D24 <MTSR]]> High risk of material impact and decomposition, potential explosion risk 5 <![CDATA[T p <T D24 <MTSR<MTT]]> Higher risk of explosion

[0047] Table 2 Conclusion of reaction process hazard assessment

[0048] Hydroxylamine Free Process Oximation reaction Tp=25℃ <![CDATA[T D24 =53.25℃]]> MAT=28.28℃ Tp=60℃ <![CDATA[T D24 =43.91℃]]> MAT=60℃ MTT=64.7℃ MTT=64.7℃

[0049] Note: MTT is the maximum technical temperature of the system, which is the boiling point of methanol at normal pressure.

[0050] According to the process hazard assessment standards, the hazard assessment level of the hydroxylamine free process is level 2 (potential decomposition risk); the hazard assessment level of the oximation reaction is level 5 (the highest level of risk recognized in chemical production).

[0051] Example 2:

[0052] To a clean 50 L reactor, the intermediate 1 obtained in the previous step was added, 30 kg of water was added, stirring was started, the temperature was controlled at 20-25°C, and 26.2 kg of a 15% aqueous solution of sodium 2-naphthalenesulfonate was slowly added dropwise. The reaction was incubated for 1 h. After the incubation was completed, NaOH solution was added dropwise to adjust the pH of the solution to 11-12. The reaction was incubated for 1 h, and the reaction was filtered and dried to obtain 4.2 kg of a white solid, which was azithromycin intermediate 2, with a yield of 90.5% and an HPLC purity of 96.6%.

[0053] Example 3:

[0054] Take out the 12-layer tower plate in the reactor, lay 14g of palladium carbon on each tower plate, press it with a tetrafluoroethylene sheet, and then put it back into the exchanger; put the intermediate 2 obtained in the previous step into a clean 25L reactor, add 25.2kg of methanol, and stir until the feed liquid is dissolved; immerse the siphon pump of the atmospheric pressure pipeline into the dissolved methanol feed liquid, and pump the feed liquid into the exchanger through the atmospheric pressure pipeline equipped with a one-way valve. At the same time, another person opens the main valve on the hydrogen cylinder and the pressure reducing valve on the medium-pressure pipeline, and Hydrogen was introduced into the exchanger through a medium-pressure pipeline. The pump speed was adjusted to ensure that the feed rate of the feed liquid was 2.0-2.5 L / min. The hydrogen pressure reducing valve was adjusted to maintain the pressure at 0.16-0.2 MPa. The feed liquid and hydrogen were in contact in the exchanger for 5-10 seconds for a reduction reaction, and then flowed out from the discharge port at any time. After all the discharge was completed, crystallization was carried out, and the solid was filtered and dried to obtain 3.8 kg of white solid, which was azithromycin intermediate 3, with a yield of 92.5% and a HPLC purity of 97.8%.

[0055] Example 4:

[0056] To a clean 25L reactor, add intermediate 3 obtained in the previous step, add chloroform, and stir while adding until the liquid is dissolved. Stop adding chloroform, add 0.4kg formaldehyde and 0.62kg formic acid, raise the temperature to reflux, and reflux for 1h. After reflux, add a small amount of NaOH to quench excess formic acid and formic acid, cool to -3~3°C, add seed crystals to induce crystallization, and filter and dry to obtain 3.42kg of crude azithromycin with a yield of 90% and a purity of 99.2%.

[0057] The crude azithromycin product was recrystallized in an acetone-water system, specifically, after adding the crude azithromycin product, 17.2 kg of acetone was added, the temperature was raised to 45-50° C. and stirred for 30-60 minutes, during the stirring process, another 10 L glass reaction bottle was taken, 6.8 kg of water was added, and the temperature was raised to 45-50° C. for standby use; after the stirring of the feed liquid was completed, the flow rate of the peristaltic pump was adjusted to control the flow rate to 0.5 L / min, and the prepared 6.8 kg of water was added dropwise to the feed liquid. After the addition was completed, the mixture was stirred at 45-50° C. for 1-1.5 hours, then cooled to 0-10° C. and stirred for 1-1.5 hours. After filtering, the mixture was dried to obtain 3.1 kg of azithromycin dihydrate product with a yield of 92% and a purity of 99.5%.

[0058] The powder diffraction pattern of azithromycin prepared by the present invention is as follows: Figure 6 As shown, the powder diffraction pattern of azithromycin published by Pfizer, the original research company of azithromycin, is as follows Figure 7 As shown, after comparison, Figure 6 and Figure 7 The characteristic absorption peak is consistent with that of azithromycin, which means that the azithromycin prepared by the process provided by the present invention is completely consistent with the product structure published by the original research company Pfizer Pharmaceuticals, USA, and has guiding significance for the existing azithromycin production.

Claims

1. A method for preparing azithromycin using a microchannel reactor, characterized in that: Azithromycin is prepared from erythromycin as a starting material through oximation, rearrangement, reduction and methylation reactions, and is characterized in that: The oximation reaction comprises: using a microchannel reactor, the core structure of the reactor being two preheating pipes and a microchannel exchanger, wherein two feed liquids are preheated to 72-76° C. in the preheating pipes, contacted in the microchannel exchanger for 20-30 seconds for oximation reaction, and then discharged from a discharge port. Purified water is then added dropwise to crystallize the solution by utilizing the solubility difference to obtain intermediate 1; the two feed liquids are: an ethanol solution of erythromycin and sodium bicarbonate, and an ethanol solution of hydroxylamine hydrochloride; The rearrangement reaction is as follows: using water as solvent, sodium 2-naphthalenesulfonate as a leaving group to react with intermediate 1 at room temperature, and after the reaction is completed, adjusting the pH of the liquid to 11-12 for crystallization to obtain intermediate 2; The reduction reaction comprises: using a microchannel reactor, the core structure of the reactor being a microchannel exchanger and a medium-pressure pipeline equipped with a one-way valve, the medium-pressure pipeline being used for hydrogen source delivery; a palladium-carbon tray box is laid inside the microchannel exchanger; a methanol solution of intermediate 2 is contacted with hydrogen in the microchannel exchanger equipped with the palladium-carbon tray box for 5-10 seconds to undergo a reduction reaction, and then the intermediate 2 flows out from the discharge port and crystallizes to obtain intermediate 3; 2. The method for preparing azithromycin using a microchannel reactor according to claim 1, wherein: The methylation reaction is as follows: using chloroform as solvent, dissolving the intermediate 3 and reacting with formaldehyde and formic acid, heating to reflux, quenching the reaction after the reaction is completed, cooling, adding seed crystals to induce crystallization to generate crude azithromycin.

3. The method for preparing azithromycin using a microchannel reactor according to claim 2, wherein: The crude azithromycin is recrystallized through acetone-water to obtain azithromycin dihydrate.

4. The method for preparing azithromycin using a microchannel reactor according to claim 3, wherein: The volume ratio of the acetone-water to the water is 2.0 to 3.0:

1.

5. The method for preparing azithromycin using a microchannel reactor according to claim 2, wherein: In terms of molar ratio, the intermediate 3: formaldehyde: formic acid = 1: 2.4-2.9: 2.4-2.

9.

6. The method for preparing azithromycin using a microchannel reactor according to claim 1, wherein: In the oximation reaction, the molar ratio of erythromycin: sodium bicarbonate: hydroxylamine hydrochloride is 1:2.5-3.0:2.25-2.

5.

7. The method for preparing azithromycin using a microchannel reactor according to claim 1, wherein: In the rearrangement reaction, the temperature is controlled at 20-25° C., an aqueous solution of sodium 2-naphthalenesulfonate is added dropwise, and the temperature is kept for reaction.

8. The method for preparing azithromycin using a microchannel reactor according to claim 1, wherein: In the rearrangement reaction, the molar ratio of the intermediate 1:sodium 2-naphthalenesulfonate is 1:2.2-2.

6.

9. A method for preparing azithromycin using a microchannel reactor according to any one of claims 1 to 8, characterized in that: In the reduction reaction, the methanol solution of intermediate 2 and hydrogen gas simultaneously enter the palladium carbon tray box in the microchannel exchanger.

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