Preparation method of nikethamide

Abstract

The invention relates to the field of organic chemistry, in particular to a preparation method of nikethamide, which comprises the following specific steps: mixing chlorobenzene, nicotinic acid, diethylamine hydrochloride and a metal-based mesoporous catalyst; reacting for 50-100 minutes at the temperature of 70-90 DEG C under normal pressure; adding water, and separating out an organic phase; further, the metal-based mesoporous catalyst is prepared by soaking a mesoporous silicon material in a metal precursor solution, reducing the mesoporous silicon material in a hydrogen atmosphere, and sintering the reduced mesoporous silicon material. According to the method, nikethamide is efficiently synthesized under normal-pressure and low-temperature conditions by adopting the metal-based mesoporous catalyst, so that the dependence on high temperature is reduced, the performance of the catalyst is optimized, and the reaction efficiency and selectivity are improved. The energy consumption is lower under mild conditions, the equipment load is reduced, side reaction and catalyst deactivation are avoided, and high purity and high yield of the product are ensured.

Description

Technical Field

[0001] The present invention relates to the field of organic chemistry, and in particular to a method for preparing nikethamide. Background Art

[0002] Niclosamide, also known as nicotinic acid diethylamine or N,N-diethyl nicotinamide, is an important organic compound with the chemical formula C10H 14 N2O, molecular weight is 178.23. This compound usually appears as a colorless to light yellow clear oily liquid with a slight special odor, and can be mixed with water, ethanol, chloroform or ether. Its physical properties are: relative density (25℃) is 1.058-1.066, freezing point is 22-24℃, refractive index (25℃) is 1.522-1.524, melting point is 23℃, boiling point is 296-300℃, flash point is 141.1±20.4℃. Nikethamide is mainly used for central excitation and is widely used in first aid for the treatment of poisoning by anesthetics and other central depressants.

[0003] Physiologically, nikethamide can deepen and accelerate breathing by directly stimulating the respiratory center in the medulla oblongata. In addition, it can reflexively stimulate the respiratory center by stimulating the chemoreceptors in the carotid sinus and aortic body, increasing the respiratory center's sensitivity to carbon dioxide. Its excitatory effect on the cerebral cortex, vasomotor center, and spinal cord is weak, and it has no direct excitatory effect on other organs. The toxicity of this substance is relatively small and its safety range is wide. Therefore, it is widely used in emergency treatment of central respiratory and circulatory failure, anesthetic poisoning, and other central depressant drug poisoning, especially for respiratory depression caused by morphine poisoning.

[0004] Traditional nikethamide production methods mainly use nicotinic acid and diethylamine as raw materials for reaction. However, from the perspective of organic synthesis, the direct reaction activity between nicotinic acid and diethylamine is low. In order to improve the reaction activity, it is usually necessary to introduce an activating agent, such as thionyl chloride or phosphorus oxychloride, the role of these activators is to convert nicotinic acid into an active intermediate (such as acyl halide, anhydride or ester), thereby promoting the reaction with diethylamine. However, the use of these activators often leads to environmental pollution problems, especially in the post-processing process, a large amount of waste water and waste gas are generated, and the waste composition is complex, usually containing at least two acids or salts. Such waste treatment not only increases production costs, but also increases the difficulty of "three wastes" treatment, bringing greater pressure to environmental protection.

[0005] Therefore, how to reduce the generation of environmental pollutants and simplify the production process while maintaining a high yield is an urgent problem to be solved in the current nikethamide preparation method. Summary of the invention

[0006] The object of the present invention is to provide a method for preparing nikethamide to solve the problems raised in the above background technology.

[0007] A method for preparing nikethamide comprises the following steps:

[0008] Step 1: mixing chlorobenzene, nicotinic acid, diethylamine hydrochloride and a metal-based mesoporous catalyst;

[0009] Step 2: react at 70-90°C and 200-400 rpm for 50-100 minutes under normal pressure;

[0010] Step 3: Add water and separate the organic phase;

[0011] Step 4: distill under reduced pressure to obtain the nikethamide.

[0012] Preferably, the metal-based mesoporous catalyst in step 1 is prepared by sintering a mesoporous silicon material into a metal precursor solution, reducing the solution in a hydrogen atmosphere, and then sintering the solution.

[0013] Preferably, the metal-based mesoporous catalyst is prepared by the following method:

[0014] S1: immersing the mesoporous silicon material in a platinum precursor solution obtained by dissolving a metal precursor in water;

[0015] S2: After drying, reduction in a hydrogen atmosphere;

[0016] S3: high temperature sintering to obtain the metal-based mesoporous catalyst.

[0017] Preferably, the metal-based mesoporous catalyst is prepared by the following method:

[0018] S1: immersing the mesoporous silicon material in a platinum precursor solution obtained by dissolving a metal precursor in water;

[0019] S2: After drying, reduction is carried out in a hydrogen atmosphere; the hydrogen flow rate is controlled to be 30-80 mL / min, the reduction temperature is 150-250°C, and the reduction time is 3-7 hours;

[0020] S3: sintering at 300-400° C. for 2-6 hours to obtain the metal-based mesoporous catalyst.

[0021] Preferably, the metal precursor is at least one of a platinum precursor, a palladium precursor and a nickel precursor.

[0022] Preferably, the platinum precursor is at least one of chloroplatinic acid, sodium chloroplatinate, potassium chloroplatinate, ammonium platinate, platinum nitrate and platinum acetate.

[0023] Preferably, the palladium precursor is at least one of sodium tetrachloropalladate, potassium tetrachloropalladate, palladium nitrate and palladium acetate.

[0024] Preferably, the nickel precursor is at least one of nickel sulfate, nickel nitrate, nickel oxalate, nickel acetate and nickel chloride.

[0025] Preferably, the metal precursor is a composition of a platinum precursor and a nickel precursor. Further preferably, the molar ratio of the platinum precursor to the nickel precursor is 20:(1-3), and optimally, the molar ratio of the platinum precursor to the nickel precursor is 10:1.

[0026] Preferably, in step S1, the mass ratio of the mesoporous silicon material, the metal precursor and water is 100 g: (0.06-0.12 mol): (800-1400 g).

[0027] Preferably, in step S1, the mixture is immersed at 15-35° C. for 3-5 hours.

[0028] Preferably, before step S1, there is step S0: acid treatment of the mesoporous silica material.

[0029] Preferably, the step S0 is to soak the mesoporous silicon material in an acid solution, and then wash and dry it.

[0030] Preferably, the usage ratio of the chlorobenzene, nicotinic acid, diethylamine hydrochloride and the metal-based mesoporous catalyst is (200-400 mL):100 g:(89-105 g):(16-30 g).

[0031] Preferably, the amount of water added in step three is 0.6-1.2 times by weight of nicotinic acid.

[0032] Preferably, the step three is to add water, and then adjust the pH to 7.5-8.5 with a sodium hydroxide aqueous solution, and separate the organic phase.

[0033] Preferably, the concentration of the sodium hydroxide aqueous solution in step three is 1-3 mol / L.

[0034] Preferably, the step four is vacuum distillation, and the target product is collected under the condition of 152-154°C / 10 mmHg to obtain the nikethamide.

[0035] The present invention uses a metal-based mesoporous catalyst to efficiently synthesize nikethamide under mild conditions of 70-90°C at normal pressure, which not only greatly reduces the dependence of traditional processes on high temperature conditions, but also achieves a dual improvement in reaction efficiency and selectivity by optimizing the structure and performance of the catalyst. Mild reaction conditions reduce energy consumption and equipment heat load, effectively reduce production costs, and avoid side reactions and catalyst deactivation problems that may occur in high temperature environments, thereby ensuring high purity and high yield of the target product. DETAILED DESCRIPTION

[0036] SBA-15 mesoporous molecular sieve, provided by Shanghai Zhuoyue Chemical Technology Co., Ltd., pore volume 1.178cm 3 / g, BET specific surface area ≥ 600m 2 / g, and the pore size range is 7-9nm.

[0037] Embodiment 1:

[0038] The preparation method of the metal-based mesoporous catalyst is as follows:

[0039] S0: Soak 100 g of SBA-15 mesoporous molecular sieve in a 0.3 mol / L hydrochloric acid aqueous solution at room temperature for 1 hour, wash with water, and dry at 70°C to constant weight to obtain an acid-treated mesoporous silicon material;

[0040] S1: dissolving a metal precursor in 1200 g of water and stirring to obtain a precursor solution; then immersing the acid-treated mesoporous silicon material in the platinum precursor solution at 25° C. and stirring at 100 rpm for 4 hours;

[0041] S2: After drying, reduction was carried out in a hydrogen atmosphere; the hydrogen flow rate was controlled to be 55 mL / min, the reduction temperature was 200°C, and the reduction time was 5 hours;

[0042] S3: sintering at 350° C. for 4 hours to obtain the metal-based mesoporous catalyst.

[0043] The metal precursor is 0.087 mol nickel chloride.

[0044] The preparation method of nikethamide is as follows:

[0045] 300 mL of chlorobenzene, 100 g of nicotinic acid, 98 g of diethylamine hydrochloride and 20 g of the metal-based mesoporous catalyst prepared above were mixed uniformly at room temperature;

[0046] The mixture was stirred at 80°C and 300 rpm under normal pressure for 80 minutes;

[0047] Then add 80 ml of water, add 2 mol / L sodium hydroxide aqueous solution dropwise to adjust the pH value to 8, and then separate the organic phase;

[0048] The target product was collected by distillation under reduced pressure at 153°C / 10 mmHg to obtain the nikethamide.

[0049] Embodiment 2:

[0050] The adjustment from Example 1 is that the metal precursor is 0.087 mol sodium chloroplatinate.

[0051] The collected target products were tested by NMR data, and the specific results are as follows:

[0052] 1 H NMR (400MHz, DMSO-d6): δ (ppm): 9.25 (s, 1H, Py-H2), 8.72 (d, J=5.0Hz, 1H, Py-H6), 7.85 (d, J=5.0H z,1H,Py-H4),7.45(s,1H,Py-H5),3.35(q,J=7.2Hz,4H,2×CH2-N),1.10(t,J=7.2Hz,6H,2×CH3-N).

[0053] Embodiment 3:

[0054] The adjustment from Example 1 is that the metal precursor is 0.087 mol sodium tetrachloropalladate.

[0055] Embodiment 4:

[0056] The adjustment from Example 1 is that the metal precursor is 0.0791 mol sodium tetrachloropalladate and 0.00791 mol nickel chloride.

[0057] Embodiment 5:

[0058] The adjustment from Example 1 is that the metal precursor is 0.0791 mol sodium chloroplatinate and 0.00791 mol nickel chloride.

[0059] Embodiment 6:

[0060] The adjustment from Example 1 is that the metal precursor is 0.08286 mol sodium chloroplatinate and 0.00414 mol nickel chloride.

[0061] Embodiment 7:

[0062] The adjustment from Example 1 is that the metal precursor is 0.07565 mol sodium chloroplatinate and 0.01135 mol nickel chloride.

[0063] Embodiment 8:

[0064] The adjustment from Example 1 is that the metal precursor is 0.0725 mol sodium chloroplatinate and 0.0145 mol nickel chloride.

[0065] Test example:

[0066] The nikethamide yield of embodiment is tested, and the results are shown in Table 1.

[0067] Table 1: Nicothamide yield table

[0068] Nicothamide yield, % Example 1 65.1 Example 2 94.4 Example 3 87.9 Example 4 83.5 Example 5 95.1 Example 6 94.7 Example 7 94.5 Example 8 90.3

[0069] The experimental data in Table 1 show that the metal-based mesoporous catalysts exhibit excellent catalytic performance in the synthesis of nikethamide, and different metals and their combinations have a significant effect on the reaction yield. The platinum catalytic system (Examples 2, 5-7) exhibits the highest reaction efficiency and selectivity, especially under the conditions of synergistic effect of platinum and nickel (Examples 5-7), the yields all reach more than 94.5%, with the highest being 95.1% (Example 5). This shows that nickel as a co-catalyst can optimize the electronic environment of the platinum active center, enhance substrate adsorption and reaction rate, and effectively reduce the use of precious metal platinum, reflecting a good balance between economy and catalytic efficiency.

[0070] In contrast, the palladium catalytic system (Examples 3-4) was suboptimal, with yields ranging from 83.5% to 87.9%. The single palladium system (Example 3) was more active, but its combination with nickel (Example 4) did not show a significant synergistic effect, probably because palladium itself had already achieved a high efficiency in substrate activation, and further addition of nickel failed to optimize the reaction pathway.

[0071] The nickel single catalytic system (Example 1) performed the worst, with a yield of only 65.1%. This verifies the limitations of non-precious metal catalysts under this reaction condition. Although nickel has a certain catalytic activity, due to limited catalytic sites, it is easily passivated by the intermediates generated in the reaction, and may even promote the occurrence of side reactions, resulting in a decrease in overall efficiency. This further proves that nickel is more suitable as an auxiliary catalyst rather than a main catalyst.

[0072] Experimental data fully demonstrate that the synergistic catalytic system of platinum and nickel effectively reduces the amount of platinum while maintaining a high yield, and is the best choice for optimizing catalyst performance. Although the palladium catalytic system is suboptimal, it has a strong ability to activate the substrate and still has certain practical value.

Claims

1. A method for preparing nikethamide, characterized in that: The steps include: Step 1: mixing chlorobenzene, nicotinic acid, diethylamine hydrochloride and a metal-based mesoporous catalyst; Step 2: react at 70-90°C for 50-100 minutes under normal pressure; Step 3: Add water and separate the organic phase; Step 4: distill under reduced pressure to obtain the nikethamide.

2. The method for preparing nikethamide according to claim 1, wherein The metal-based mesoporous catalyst in step 1 is prepared by sintering a mesoporous silicon material in a metal precursor solution, reducing it in a hydrogen atmosphere, and then sintering it.

3. The method for preparing nikethamide according to claim 2, characterized in that: The metal-based mesoporous catalyst is prepared by the following method: S1: immersing the mesoporous silicon material in a platinum precursor solution obtained by dissolving a metal precursor in water; S2: After drying, reduction in a hydrogen atmosphere; S3: high temperature sintering to obtain the metal-based mesoporous catalyst.

4. The method for preparing nikethamide according to claim 3, characterized in that: The metal-based mesoporous catalyst is prepared by the following method: S1: immersing the mesoporous silicon material in a platinum precursor solution obtained by dissolving a metal precursor in water; S2: After drying, reduction is carried out in a hydrogen atmosphere; the hydrogen flow rate is controlled to be 30-80 mL / min, the reduction temperature is 150-250°C, and the reduction time is 3-7 hours; S3: sintering at 300-400° C. for 2-6 hours to obtain the metal-based mesoporous catalyst.

5. The method for preparing nikethamide according to claim 3, characterized in that: The metal precursor is at least one of a platinum precursor, a palladium precursor and a nickel precursor.

6. The method for preparing nikethamide according to claim 5, characterized in that: The platinum precursor is at least one of chloroplatinic acid, sodium chloroplatinate, potassium chloroplatinate, ammonium platinate, platinum nitrate and platinum acetate; the palladium precursor is at least one of sodium tetrachloropalladate, potassium tetrachloropalladate, palladium nitrate and palladium acetate; the nickel precursor is at least one of nickel sulfate, nickel nitrate, nickel oxalate, nickel acetate and nickel chloride.

7. The method for preparing nikethamide according to claim 3, characterized in that: In the step S1, the mass ratio of the mesoporous silicon material, the metal precursor and water is 100 g: (0.06-0.12 mol): (800-1400 g).

8. The method for preparing nikethamide according to claim 3, characterized in that: The usage ratio of the chlorobenzene, nicotinic acid, diethylamine hydrochloride and the metal-based mesoporous catalyst is (200-400 mL):100 g:(89-105 g):(16-30 g).

9. The method for preparing nikethamide according to claim 3, characterized in that: The step three is to add water, and then adjust the pH to 7.5-8.5 with a sodium hydroxide aqueous solution, and separate the organic phase.

10. The method for preparing nikethamide according to claim 3, characterized in that: The step 4 is to perform reduced pressure distillation, and the target product is collected under the condition of 152-154°C / 10 mmHg to obtain the nikethamide.