Efficient preparation method of montelukast sodium production raw material
By using a copper catalyst in a continuous flow tube reactor, the problems of long reaction time and low purity in the preparation of sodium montelukast are solved, and high efficiency is achieved. Low-cost high-purity product preparation, in line with the principles of green chemistry.
Patent Information
- Application Number
- CN202411342091.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-25
- Publication Date
- 2025-01-03
AI Technical Summary
There is a lack of efficient preparation method for sodium montelukast in the prior art, especially in the application of continuous flow reactors, resulting in problems such as long reaction time, high cost and low purity.
Using a continuous flow tube reactor, 2-bromobenzaldehyde and tert-butyl hydrogen peroxide are reacted under the action of a copper catalyst, the reaction conditions are controlled to shorten the reaction time, and high purity is obtained through quenching, extraction and purification. montelukast intermediate methyl ortho-benzoate.
The reaction time is shortened, the product yield and high purity are achieved, and the use of green catalysts through the free radical reaction mechanism is improved, and the preparation efficiency and environmental protection of the product are improved.
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Figure CN119241361A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a high-efficiency preparation method of raw materials for the production of montelukast sodium, and belongs to the field of drug intermediate preparation. Background Art
[0002] Montelukast Sodium is a non-hormonal anti-inflammatory drug developed by Merck in the United States. It was first launched in Finland and Mexico in February 1998, and in the United Kingdom and the United States in April and October of the same year, respectively. It was launched in China in 2002. It is a leukotriene receptor antagonist that can inhibit the biosynthesis of leukotrienes and has a significant inhibitory effect on FBS-induced GM-CSF, IL-6 and IL-8 secretion in nasal mucosa and polyp epithelial cells. It can be used as an antiasthmatic, antiallergic agent, etc. in pharmacy.
[0003] The derivative of methyl (E)-2-[3-[3-[2-(7-chloro-2-quinolyl)vinyl]phenyl]-3-oxopropyl]benzoate is a key intermediate for the synthesis of montelukast sodium, and its structural formula is shown below: Methyl o-bromobenzoate is a key raw material in the synthesis of (E)-methyl 2-[3-[3-[2-(7-chloro-2-quinolyl)vinyl]phenyl]-3-oxopropyl]benzoate derivatives. Its efficient synthesis method is a key and hot issue that technicians in this field are concerned about.
[0004] Continuous flow reactor is an emerging industrial technology in recent years. Its advantages lie in the safety, high yield, high purity and low cost of this type of reactor in synthetic applications. At the same time, since the continuous flow reactor can strictly control the reaction conditions such as reaction time, reaction pressure, reaction temperature, and does not have the headspace volume of the kettle reactor, it can not only improve the safety of the synthetic process, but also can synthesize the target compound more efficiently and at a lower cost. It is an emerging synthetic method that conforms to the modern green synthesis concept. Therefore, exploring the possible application of continuous flow reactors in the preparation of montelukast sodium raw materials has become one of the research hotspots for those skilled in the art. Summary of the invention
[0005] In view of the defects existing in the above prior art, the present invention provides an efficient preparation method for raw materials for the production of montelukast sodium, and solves the problem of exploring the application of continuous flow reactors in the production of montelukast sodium raw materials.
[0006] The object of the present invention is achieved by the following technical scheme: an efficient preparation method for raw materials for the production of montelukast sodium, wherein the intermediate raw material of montelukast sodium is methyl o-bromobenzoate, and the preparation method comprises the following steps: S1: Mixing the raw material compound 2-bromobenzaldehyde of formula 3 with an organic solvent to prepare a material solution A; S2: mixing tert-butyl hydroperoxide of formula 2 with an organic solvent to prepare a material solution B; S3: adjusting the flow rate of the constant flow infusion pump to cool down the continuous flow tubular reactor; S4: Feeding solution A and solution B and a copper catalyst material mixed solution into a continuous flow tubular reactor simultaneously for reaction, and after the reaction, quenching, extraction and purification are performed to obtain an intermediate represented by the compound of formula I.
[0007] Furthermore, the copper catalyst is selected from copper fluoride, copper oxide and copper-zinc alloy.
[0008] Furthermore, the feed ratio of the compound of formula 3, the compound of formula 2 and the copper catalyst is 1:1.1~1.5:0.1~0.3.
[0009] Furthermore, in the steps S1 and S2, the organic solvent is selected from one of ethanol, ether and water.
[0010] Furthermore, in step S4, when the copper catalyst is copper fluoride, the solvent of the material mixture is selected from ethanol and water; when the copper catalyst is copper oxide, the solvent of the material mixture is selected from dilute acid solution; when the copper catalyst is copper-zinc alloy, ethanol is selected to be configured as a suspension.
[0011] Furthermore, in step S4, the feeding rate of solution A and solution B is 1-5 mL / min.
[0012] Furthermore, in step S4, the feeding rate of the copper catalyst material mixture is 0.3-0.5 mL / min.
[0013] In summary, compared with the prior art, the present invention has the following advantages: 1. In the present invention, the continuous flow tubular reactor is applied to the preparation of montelukast raw materials, which can control the reaction time within several hundred seconds, thereby greatly shortening the reaction time and greatly simplifying the reaction steps. At the same time, the target product can be obtained with high yield and high purity through the continuous flow reaction process; 2. In the present invention, tert-butyl hydroperoxide (TBHP) is used as a catalyst to synthesize methyl ester from aromatic aldehydes by copper catalysis through a free radical reaction mechanism. In this conversion process, TBHP is not only an effective oxidant but also a green methyl source. BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Figure 1 The present invention is a preparation route map. DETAILED DESCRIPTION
[0015] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.
[0016] 185.02 g of the compound of formula III and 500 ml of ethanol solution were mixed to obtain solution A; 117.156 g of the compound of formula II and 350 ml of ethanol solution were mixed to obtain solution B; 20.308 g of copper fluoride and 100 ml of ethanol solution were mixed to obtain a copper catalyst material mixed solution.
[0017] Adjust the flow rates of constant flow pumps A, B, and C, wherein the flow rates of constant flow pumps A, B, and C are 3.0 ml / min, 3.0 ml / min, and 0.4 ml / min; cool the tubular reactor of the continuous flow equipment to 5°C-10°C, and then inject solution A and solution B into the preheating zone 1 of the tubular reactor using constant flow pumps A and B respectively, and inject the copper catalyst material mixed liquid into the preheating zone 2 of the tubular reactor using constant flow pump C, set the preheating temperature and reaction temperature to 30°C, and after the two streams of materials are preheated for 20 minutes respectively, enter the reaction zone for mixed reaction, and send the reaction liquid to the collection storage area after it flows out.
[0018] The product was collected from the outlet, extracted with tetrahydrofuran, recrystallized at room temperature for 1 hour, filtered at 10 mbar for 1 hour, and dried at 70° C. for 4 hours to obtain 191.82 g of the compound of formula I, methyl o-bromobenzoate, with a product yield of 89.2% and a product purity of 99.7%.
[0019] This is a comparative example of Example 1, in which the copper catalyst is replaced by copper oxide from copper fluoride, and dilute hydrochloric acid (concentration of 0.2 mol / L) is used to prepare the copper catalyst material mixture, and the other conditions remain unchanged, and finally 179.78 g of the compound of formula I, methyl o-bromobenzoate, is obtained, the product yield is 83.6%, and the product purity is 99.5%.
[0020] This is a comparative example of Example 1, in which the copper catalyst was replaced by copper zinc alloy from copper fluoride, an ethanol solution was used to prepare the material suspension, and the feed rate of the material suspension was adjusted to 0.5 mL / min, and finally 159.35 g of the compound of formula I, methyl o-bromobenzoate, was obtained, the product yield was 74.1%, and the product purity was 99.4%.
[0021] This is a comparative example of Example 1. The feed ratio of the compound of Formula 3, the compound of Formula 2 and the copper catalyst is adjusted to 1:1.1:0.1, and the other conditions remain unchanged. Finally, 187.31 g of the compound of Formula I, methyl o-bromobenzoate, is obtained, the product yield is 87.1%, and the product purity is 99.7%.
[0022] This is a comparative example of Example 1. The feed ratio of the compound of Formula 3, the compound of Formula 2 and the copper catalyst is adjusted to 1:1.5:0.3, and the other conditions remain unchanged. Finally, 192.47g of the compound of Formula I, methyl o-bromobenzoate, is obtained, the product yield is 89.5%, and the product purity is 99.7%.
[0023] The implementation of the present invention is not limited to the above-mentioned embodiments. Without departing from the spirit and scope of the present invention, ordinary technicians in this field can make various changes and improvements to the present invention in form and detail, and these are considered to fall within the protection scope of the present invention.
Claims
1. An efficient preparation method for raw materials for the production of montelukast sodium, characterized in that: The intermediate raw material of montelukast sodium is methyl o-bromobenzoate, and its preparation method comprises the following steps: S1: Mixing the raw material compound 2-bromobenzaldehyde of formula 3 with an organic solvent to prepare a material solution A; S2: mixing tert-butyl hydroperoxide of formula 2 with an organic solvent to prepare a material solution B; S3: adjusting the flow rate of the constant flow pump to cool down the continuous flow tubular reactor; S4: Feeding solution A and solution B and a copper catalyst material mixed solution into a continuous flow tubular reactor simultaneously for reaction, and after the reaction, quenching, extraction and purification are performed to obtain an intermediate represented by the compound of formula I.
2. The method for efficiently preparing a raw material for the production of montelukast sodium according to claim 1, characterized in that: The copper catalyst is selected from copper fluoride, copper oxide and copper-zinc alloy.
3. The method for efficiently preparing a raw material for the production of montelukast sodium according to claim 2, characterized in that: The feed ratio of the compound of formula 3, the compound of formula 2 and the copper catalyst is 1:1.1-1.5:0.1-0.
3.
4. The method for efficiently preparing a raw material for the production of montelukast sodium according to claim 3, characterized in that: In the steps S1 and S2, the organic solvent is selected from one of ethanol, ether and water.
5. The method for efficiently preparing a raw material for the production of montelukast sodium according to claim 4, characterized in that: In step S4, when copper fluoride is used as the copper catalyst, the solvent of the material mixture is selected from ethanol and water; when copper oxide is used as the copper catalyst, the solvent of the material mixture is selected from dilute acid solution; when copper zinc alloy is used as the copper catalyst, ethanol is selected to prepare a suspension.
6. The method for efficiently preparing a raw material for the production of montelukast sodium according to claim 5, characterized in that: In step S4, the feeding rate of solution A and solution B is 1-5 mL / min.
7. The method for efficiently preparing a raw material for the production of montelukast sodium according to claim 6, characterized in that: In the step S4, the feeding rate of the copper catalyst material mixture is 0.3-0.5 mL / min.