Method for preparing 2-propylthio-isonicotinamide intermediate through continuous pipeline
A continuous pipeline process for synthesizing 2-propylthioisonicotinamide intermediate addresses the issues of poor selectivity and high energy consumption by using a controlled pipeline reactor, achieving high yield and purity suitable for industrial production.
Patent Information
- Application Number
- CN202411306147.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-19
- Publication Date
- 2024-12-10
AI Technical Summary
Existing methods for preparing 2-propylthioisonicotinamide intermediate face issues of poor selectivity, long reaction time, and high energy consumption, which are not suitable for industrial-scale production.
A continuous pipeline process is employed using 4-cyanopyridine and n-butyric acid as starting materials, oxidized by persulfate and silver nitrate in a pipeline reactor, with controlled pH and temperature, to synthesize 2-propylthioisonicotinamide intermediate, where the reaction is carried out in a pipeline reactor, the pH and temperature are controlled to optimize the reaction.
The method achieves high yield and purity, with a yield of over 95% and purity of over 99%, reducing equipment occupation, energy consumption, and simplifying post-processing, making it suitable for industrial production.
Smart Images
Figure CN119100978A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of compound synthesis, in particular to a method for preparing a 2-propylthioisonicotinamide intermediate in a continuous pipeline. Background Art
[0002] Prothionamide is one of the important drugs for the treatment of tuberculosis. It has been on the market in China for many years. The only dosage form on the market is tablets. It is widely used in clinical practice and has a definite effect. At present, prothionamide preparations have been included in the World Health Organization's second-line anti-tuberculosis drug procurement catalog. It is often used in combination with other anti-tuberculosis drugs to treat various types of tuberculosis. It is mostly used for retreatment cases that have failed to respond to other anti-tuberculosis drugs, or patients who cannot tolerate other anti-tuberculosis drugs. This product has an antibacterial effect on Mycobacterium tuberculosis, and its antibacterial activity is only one-tenth of that of isoniazid. This product is easily absorbed orally, widely distributed in the body, can penetrate into the body fluids (including cerebrospinal fluid), and is completely metabolized into ineffective substances in the body. It has a good effect on exudative and infiltrative caseous lesions. It is rarely used alone and is often used in combination with other anti-tuberculosis drugs to enhance the efficacy and avoid drug resistance. Although the cure rate of tuberculosis is close to 100% nowadays, it is still a major problem threatening public health. With the increasing commonness of drug-resistant tuberculosis bacteria, tuberculosis has become the second leading cause of death from infectious diseases worldwide.
[0003] Data from the World Health Organization (WHO) Global Tuberculosis Report show that the global incidence of tuberculosis is declining slowly. WHO estimates that there are 900,000 new cases of pulmonary tuberculosis in my country each year, accounting for about 10% of the world's total. The number of cases is second only to India and Indonesia, making it the third country with the highest burden of tuberculosis in the world. Among all Class A and C infectious diseases, it ranks second only to viral hepatitis.
[0004] In recent years, the proportion of patients with drug-resistant tuberculosis has increased. The reasons for the emergence of such patients can be summarized into the following two points: first, there is a lack of infection control measures in spaces where people gather, such as medical institutions and prisons, which leads to primary drug resistance; second, incomplete treatment, especially for patients with sputum smear-positive results in acquired drug resistance, and the phenomenon of multi-drug use is becoming increasingly serious.
[0005] Drug resistance to anti-tuberculosis drugs is an important public health issue, threatening the successful implementation of DOTS (the World Health Organization recommended treatment for the detection and treatment of tuberculosis) and global tuberculosis control. However, after years of clinical observation, prothionamide has been shown to be used for retreatment cases that have failed to respond to other anti-tuberculosis drugs or patients who cannot tolerate other anti-tuberculosis drugs, becoming one of the effective drugs in the treatment of multidrug-resistant tuberculosis.
[0006] There are many reports about its preparation method in the literature. Patent GB800250 and FR2091338 have many steps, involve many raw materials, high cost, and use a variety of phosphorus-containing raw materials, which pollutes the environment. At present, the most commonly used route in the market is to use 4-cyanopyridine and butyric acid as raw materials, but this route has problems such as poor selectivity, long reaction time, large equipment occupation, and high energy consumption. Summary of the invention
[0007] The object of the present invention is to provide a method for preparing 2-propylthioisonicotinamide intermediate in a continuous pipeline to solve the problems of poor selectivity, long reaction time, large number of occupied equipment and high energy consumption proposed in the above background technology.
[0008] To achieve the above object, the present invention provides the following technical solution: a method for preparing a 2-propylthioisonicotinamide intermediate in a continuous pipeline, the method comprising: Dissolving 4-cyanopyridine and n-butyric acid in an organic solvent, and oxidizing under the catalysis of silver nitrate and persulfate, while controlling the pH value of the reaction system with alkaline water to synthesize the 2-propylthioisonicotinamide intermediate 2-propyl-4-cyanopyridine, the above reaction is all carried out in a pipeline reactor; Among them, the 4-cyanopyridine and n-butyric acid are dissolved in an organic solvent as material 1 for feeding; the silver nitrate is dissolved in deionized water as material 2 for feeding; the persulfate is dissolved in deionized water as material 3 for feeding; and the alkaline water is used as material 4 for feeding.
[0009] Preferably, the molar ratio of the 4-cyanopyridine: n-butyric acid is 1:1.0-3.0; the molar ratio of the 4-cyanopyridine: silver nitrate is 1:0.005-0.03; the molar ratio of the 4-cyanopyridine: persulfate is 1:1.0-4.0; and the weight ratio of the 4-cyanopyridine: organic solvent is 1:3-6.
[0010] Preferably, the organic solvent is one or a combination of chloroform, dichloroethane, and dichloromethane; the persulfate is one or a combination of sodium persulfate, ammonium persulfate, and potassium persulfate; and the alkaline water is one or a combination of liquid caustic soda, ammonia water, and sodium carbonate aqueous solution.
[0011] Preferably, the feed rate of material 1 is controlled to be 30g / min to 100g / min; the feed rate of material 2 is controlled to be 10g / min to 60g / min; the feed rate of material 3 is controlled to be 60g / min to 150g / min; the feed rate of material 4 is controlled to be 10g / min to 50g / min.
[0012] Preferably, the pipeline reactor comprises a first module, a second module and a third module, and the first module, the second module and the third module are connected in sequence; the material 1 and the material 2 are introduced from the inlet of the first module, and the material 3 and the material 4 are introduced from the inlet of the second module, and the whole reaction time is controlled within 10 to 60 minutes.
[0013] Preferably, the temperature of the first module is 40-100°C, the temperature of the second module is 40-100°C, and the temperature of the third module is 10-30°C.
[0014] Preferably, the reaction liquid flowing out of the pipeline reactor is directly subjected to layering and desolventizing treatment to obtain the 2-propylthioisonicotinamide intermediate.
[0015] Compared with the prior art, the present invention has the following beneficial effects: the method for preparing 2-propylthioisonicotinamide intermediate by continuous pipeline: 1. Using 4-cyanopyridine and n-butyric acid as starting materials, a free radical reaction is carried out by oxidation catalysis with persulfate and silver nitrate. The reaction is carried out in a pipeline reactor with a yield of more than 95% and a product purity of more than 99%; 2. The pipeline continuous preparation method improves the selectivity of the reaction and avoids the generation of impurities by controlling the amount of each material entering the pipeline reactor per unit time. This method has simple process, convenient operation, low energy consumption, high production efficiency, less three wastes, simple post-processing and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1 Schematic diagram of the synthesis mechanism of the present invention; Figure 2 2-propyl-4-cyanopyridine is the intermediate of 2-propylthioisonicotinamide of the present invention 1 HNMR spectra; Figure 3 The figure is a flow chart of the continuous pipeline reaction of the present invention. DETAILED DESCRIPTION
[0017] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0018] See also Figure 1-Figure 3 The present invention provides a technical solution: a method for preparing a 2-propylthioisonicotinamide intermediate in a continuous pipeline, the method comprising: 4-cyanopyridine and n-butyric acid are dissolved in an organic solvent, and 2-propylthioisonicotinamide intermediate 2-propyl-4-cyanopyridine is synthesized under the catalytic oxidation of silver nitrate and persulfate, while the pH value of the reaction system is controlled by alkaline water. The above reaction is carried out in a pipeline reactor; Among them, 4-cyanopyridine and n-butyric acid are dissolved in an organic solvent as material 1 for feeding; silver nitrate is dissolved in deionized water for feeding as material 2; persulfate is dissolved in deionized water for feeding as material 3; and alkaline water is fed as material 4.
[0019] The feeding rate of material 1 is controlled to be 30 g / min to 100 g / min; the feeding rate of material 2 is controlled to be 10 g / min to 60 g / min; the feeding rate of material 3 is controlled to be 60 g / min to 150 g / min; the feeding rate of material 4 is controlled to be 10 g / min to 50 g / min; the whole reaction time is controlled to be 10 to 60 min; the pipeline reactor comprises a first module, a second module and a third module, and the first module, the second module and the third module are connected in sequence; material 1 and material 2 are introduced from the inlet of the first module, and material 3 and material 4 are introduced from the inlet of the second module; the temperature of the first module is 40 to 100° C., the temperature of the second module is 40 to 100° C., and the temperature of the third module is 10 to 30° C.; the reaction liquid flowing out of the pipeline reactor is directly subjected to layering and desolventizing treatment to obtain a 2-propylthioisonicotinamide intermediate.
[0020] The molar ratio of 4-cyanopyridine: n-butyric acid is 1:1.0-3.0; the molar ratio of 4-cyanopyridine: silver nitrate is 1:0.005-0.03; the molar ratio of 4-cyanopyridine: persulfate is 1:1.0-4.0; the weight ratio of 4-cyanopyridine: organic solvent is 1:3-6; the organic solvent is one or a combination of chloroform, dichloroethane, and dichloromethane; the persulfate is one or a combination of sodium persulfate, ammonium persulfate, and potassium persulfate; the alkaline water is one or a combination of liquid caustic soda, ammonia water, and sodium carbonate aqueous solution.
[0021] Embodiment 1: 4-cyanopyridine: 200g, n-butyric acid: 250g and dichloroethane: 750g are mixed until all are dissolved as material 1; silver nitrate: 3.0g and deionized water: 600g are mixed until all are dissolved as material 2; sodium persulfate: 560g and deionized water: 1120g are mixed and all are dissolved as material 3; ammonia water is material 4; the first module and the second module of the pipeline reactor are heated to 80°C, and the temperature of the third module is controlled at 20°C, and then material 1 and material 2 are simultaneously input into the first module for mixing and heating, wherein the material 1 conveying speed is 40g / min, and the material 2 conveying speed is 20.1g / min, and then material 3 and material 4 are input into the second module for reaction, wherein the material 3 conveying speed is 56g / min, and the material 4 conveying speed is 15g / min, and the reaction temperature is controlled at 75-80°C. The overall reaction time is about 35 minutes. The reaction liquid is cooled and flows out through the third module, and then stratified. After the lower oil layer is desolvated, 2-propyl-4-cyanopyridine is obtained: 271.2 g, purity: 99.3%, yield: 96.6% (theoretical amount: 280.8 g).
[0022] Embodiment 2: 4-cyanopyridine: 200g, n-butyric acid: 280g and chloroform: 1000g are mixed until all are dissolved as material 1; silver nitrate: 5.0g and deionized water: 600g are mixed until all are dissolved as material 2; ammonium persulfate: 608g and deionized water: 1216g are mixed and all are dissolved as material 3; liquid alkali is material 4; the first module and the second module of the pipeline reactor are now heated to 60°C, and the temperature of the third module is controlled at 25°C, and then material 1 and material 2 are simultaneously input into the first module for mixing and heating, wherein the material 1 conveying speed is 60g / min, and the material 2 conveying speed is 24.5g / min, and then material 3 and material 4 are input into the second module for reaction, wherein the material 3 conveying speed is 74g / min, and the material 4 conveying speed is 20g / min, and the reaction temperature is controlled at 55-60°C. The overall reaction time is about 30 minutes. The reaction liquid is cooled and flows out through the third module, and then stratified. After the lower oil layer is desolvated, 2-propyl-4-cyanopyridine is obtained: 267.3 g, purity: 99.1%, yield: 95.2% (theoretical amount: 280.8 g).
[0023] Example 3: 200 g of 4-cyanopyridine, 230 g of n-butyric acid and 1200 g of ethylene dichloride were mixed until completely dissolved as material 1; 8.0 g of silver nitrate and 600 g of deionized water were mixed until completely dissolved as material 2; 480 g of ammonium persulfate and 960 g of deionized water were mixed and completely dissolved as material 3; ammonia water was material 4; the first and second modules of the pipeline reactor were heated to 70°C, and the temperature of the third module was controlled at 20°C, and then material 1 and material 2 were simultaneously input into the first module for mixing and heating, wherein the material 1 conveying speed was 80 g / min, and the material 2 conveying speed was 29.8 g / min, and then material 3 and material 4 were input into the second module for reaction, wherein the material 3 conveying speed was 70.7 g / min, and the material 4 conveying speed was 18.5 g / min, and the reaction temperature was controlled at 65 to 70°C. The overall reaction time is about 25 minutes. The reaction liquid is cooled and discharged through the third module, and then stratified. After the lower oil layer is desolvated, 2-propyl-4-cyanopyridine: 269 g, purity: 99.4%, yield: 95.8% (theoretical amount: 280.8 g) is obtained.
[0024] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.
Claims
1. A method for preparing 2-propylthioisonicotinamide intermediates in a continuous pipeline. Features: The method includes: Dissolving 4-cyanopyridine and n-butyric acid in an organic solvent, and oxidizing under the catalysis of silver nitrate and persulfate, while controlling the pH value of the reaction system with alkaline water to synthesize the 2-propylthioisonicotinamide intermediate 2-propyl-4-cyanopyridine, the above reaction is all carried out in a pipeline reactor; Among them, the 4-cyanopyridine and n-butyric acid are dissolved in an organic solvent as material 1 for feeding; the silver nitrate is dissolved in deionized water as material 2 for feeding; the persulfate is dissolved in deionized water as material 3 for feeding; and the alkaline water is used as material 4 for feeding.
2. The method for preparing 2-propylthioisonicotinamide intermediate by continuous pipeline according to claim 1, Features: The molar ratio of the 4-cyanopyridine: n-butyric acid is 1:1.0-3.0; the molar ratio of the 4-cyanopyridine: silver nitrate is 1:0.005-0.03; the molar ratio of the 4-cyanopyridine: persulfate is 1:1.0-4.0; the weight ratio of the 4-cyanopyridine: organic solvent is 1:3-6.
3. The method for preparing 2-propylthioisonicotinamide intermediate by continuous pipeline according to claim 1, Features: The organic solvent is one or a combination of chloroform, dichloroethane, and dichloromethane; the persulfate is one or a combination of sodium persulfate, ammonium persulfate, and potassium persulfate; and the alkaline water is one or a combination of liquid alkali, ammonia water, and sodium carbonate aqueous solution.
4. The method for preparing 2-propylthioisonicotinamide intermediate by continuous pipeline according to claim 1, Features: The feed rate of material 1 is controlled at 30 g / min to 100 g / min; the feed rate of material 2 is controlled at 10 g / min to 60 g / min; the feed rate of material 3 is controlled at 60 g / min to 150 g / min; the feed rate of material 4 is controlled at 10 g / min to 50 g / min.
5. The method for preparing 2-propylthioisonicotinamide intermediate in a continuous pipeline according to claim 1, Features: The pipeline reactor includes a first module, a second module and a third module, and the first module, the second module and the third module are connected in sequence; the material 1 and the material 2 are introduced from the inlet of the first module, and the material 3 and the material 4 are introduced from the inlet of the second module, and the entire reaction time is controlled within 10 to 60 minutes.
6. The method for preparing 2-propylthioisonicotinamide intermediate in a continuous pipeline according to claim 5, Features: The temperature of the first module is 40-100°C, the temperature of the second module is 40-100°C, and the temperature of the third module is 10-30°C.
7. The method for preparing 2-propylthioisonicotinamide intermediate in a continuous pipeline according to claim 1, Features: The reaction liquid flowing out of the pipeline reactor is directly subjected to layering and desolventizing treatment to obtain the 2-propylthioisonicotinamide intermediate.