A process for the preparation of nicotellamine

Abstract

The application relates to the field of organic chemistry, in particular to a preparation method of nicotine, and specifically comprises the following steps: mixing chlorobenzene, nicotinic acid, diethylamine hydrochloride and a metal-based mesoporous catalyst; reacting at 70-90 DEG C under normal pressure for 50-100 minutes; adding water, separating an organic phase; and performing reduced-pressure distillation to obtain the nicotine; and further, the metal-based mesoporous catalyst is sintered after being reduced by hydrogen atmosphere and soaked in a metal precursor solution from a mesoporous silica material. The metal-based mesoporous catalyst is used to efficiently synthesize the nicotine under normal pressure and low-temperature conditions, the dependence on high temperature is reduced, the catalyst performance is optimized, and the reaction efficiency and selectivity are improved. The energy consumption is lower under mild conditions, the equipment load is reduced, side reactions and catalyst deactivation are avoided, and the high purity and high yield of the product are ensured.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic chemistry, in particular to a preparation method of nicotinamide. BACKGROUND

[0002] Nicotinamide, also known as nicotinic acid diethylamine or N,N-diethyl nicotinamide, is an important organic compound with the chemical formula C10H 14 N2O and a molecular weight of 178.23. The compound usually appears as a colorless to light yellow clear oily liquid with a slight peculiar odor and can be mixed with water, ethanol, chloroform or diethyl ether at will. Its physical properties are as follows: 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℃, and flash point is 141.1±20.4℃. Nicotinamide is mainly used for central excitatory effect and is widely used in the emergency treatment of narcotic and other central depressant poisoning.

[0003] Nicotinamide can directly stimulate the medullary respiratory center in physiology, deepen and accelerate respiration, and can also stimulate the chemoreceptors of the carotid sinus and aortic body to reflexively stimulate the respiratory center and increase the sensitivity of the respiratory center to carbon dioxide. Its excitatory effect on the cerebral cortex, vasomotor center and spinal cord is weak and has no direct excitatory effect on other organs. The toxicity of the substance is relatively small and the safety range is wide, so it is widely used in the emergency treatment of central respiratory and circulatory failure, narcotic poisoning and other central depressant drug poisoning, and has good effect on respiratory depression caused by morphine poisoning.

[0004] The traditional production method of nicotinamide mainly uses 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 activating agents such as thionyl chloride or phosphorus oxychloride, which can convert nicotinic acid into active intermediates (such as acyl halide, anhydride or ester) to promote the reaction with diethylamine. However, the use of these activating agents often leads to environmental pollution problems, especially in the post-processing process, a large amount of wastewater and waste gas is generated, and the waste composition is complex, usually containing at least two acids or salts. The treatment of such waste not only increases the production cost, but also increases the difficulty of "three wastes" treatment, which brings great pressure to environmental protection.

[0005] Therefore, how to reduce the generation of environmental pollutants while maintaining a high yield and simplify the production process is a problem that needs to be solved in the current preparation method of nicotinamide. SUMMARY

[0006] The present application aims to provide a preparation method of nicotine, to solve the problems in the background art.

[0007] The present application aims to provide a preparation method of nicotine, to solve the problems in the background art.

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

[0009] Step two: reacting at 70-90℃ under normal pressure, 200-400rpm for 50-100 minutes;

[0010] Step three: adding water, and separating the organic phase;

[0011] Step four: reducing pressure distillation, to obtain the nicotine.

[0012] Preferably, the metal-based mesoporous catalyst in step one is sintered after soaking the mesoporous silica material in a platinum precursor solution obtained by dissolving a metal precursor in water and reducing it in a hydrogen atmosphere.

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

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

[0015] S2: drying, and reducing 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: soaking the mesoporous silica material in a platinum precursor solution obtained by dissolving a metal precursor in water;

[0019] S2: drying, and reducing in a hydrogen atmosphere; controlling the hydrogen flow rate at 30-80mL / min, the reduction temperature at 150-250℃, and the reduction time at 3-7 hours;

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

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

[0022] Preferably, the platinum precursor is at least one of chloroplatinic acid, sodium chloroplatinate, potassium chloroplatinate, ammonium platinic acid, 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 combination of a platinum precursor and a nickel precursor. Further preferably, the molar ratio of the platinum precursor and the nickel precursor is 20:(1-3), and most preferably, the molar ratio of the platinum precursor and the nickel precursor is 10:1.

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

[0027] Preferably, the step S1 is 15-35℃ soaking for 3-5 hours.

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

[0029] Preferably, the step S0 is soaking the mesoporous silica material in acid solution, followed by washing and drying.

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

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

[0032] Preferably, step three is adding water and adjusting the pH to 7.5-8.5 with sodium hydroxide aqueous solution, and separating the organic phase.

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

[0034] Preferably, step four is reduced pressure distillation, and the target product is collected at 152-154℃ / 10mmHg to obtain the nicotinic acid amide.

[0035] The present application uses a metal-based mesoporous catalyst to efficiently synthesize nicotinic acid amide under mild conditions of 70-90℃ at normal pressure, which not only greatly reduces the dependence on high temperature conditions in traditional processes, but also realizes the dual improvement of reaction efficiency and selectivity by optimizing the structure and performance of the catalyst. The mild reaction conditions reduce energy consumption and equipment thermal load, effectively reduce production costs, and at the same time avoid the problems of side reactions and catalyst deactivation that may occur in high temperature environment, thereby ensuring the 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 1.178 cm 3 / g, BET specific surface area ≥600 m 2 / g, pore size range 7-9 nm.

[0037] Example 1:

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

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

[0040] S1: metal precursor is dissolved in 1200 g of water to obtain a precursor solution; and the acid-treated mesoporous silica material is soaked in the platinum precursor solution at 25°C for 4 hours with stirring at 100 revolutions / min;

[0041] S2: after drying, reduction is carried out in a hydrogen atmosphere; the hydrogen flow rate is controlled at 55 mL / min, the reduction temperature is 200°C, and the reduction time is 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 of nickel chloride.

[0044] The preparation method of nicotinic acid dimethylamide 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 are mixed uniformly at room temperature;

[0046] Stirring at 300 revolutions / min at 80°C under normal pressure, reaction time is 80 minutes;

[0047] 80 ml of water is added, 2 mol / L sodium hydroxide aqueous solution is added dropwise to adjust the pH value to 8, and the organic phase is separated again;

[0048] Vacuum distillation, target product is collected at 153°C / 10 mmHg to obtain the nicotinic acid dimethylamide.

[0049] Example 2:

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

[0051] The collected target product was subjected to nuclear magnetic data test, and the specific results were as follows:

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

[0053] Example 3:

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

[0055] Example 4:

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

[0057] Example 5:

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

[0059] Example 6:

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

[0061] Example 7:

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

[0063] Example 8:

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

[0065] Test Example:

[0066] The nicotiana tabacum yield of the example was tested, and the results are shown in Table 1.

[0067] Table 1: Nicotiana tabacum yield table

[0068] Nicotine 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 nicotiana, and the effects of different metals and their combinations on the reaction yield are significant. The platinum catalytic system (Examples 2, 5-7) exhibits the highest reaction efficiency and selectivity, especially under the condition of platinum and nickel synergy (Examples 5-7), the yield reaches more than 94.5%, and the highest is 95.1% (Example 5). This shows that nickel as a cocatalyst can optimize the electronic environment of platinum active centers, enhance substrate adsorption and reaction rate, and effectively reduce the amount of noble metal platinum, reflecting a good balance between economic efficiency and catalytic efficiency.

[0070] In contrast, the palladium catalytic system (Examples 3-4) is suboptimal, with a yield ranging from 83.5% to 87.9%. The single palladium system (Example 3) has higher activity, but its combination with nickel (Example 4) does not show obvious synergistic effect, which may be due to the fact that palladium itself has reached a high efficiency in substrate activation, and further addition of nickel fails to optimize the reaction path.

[0071] The nickel single catalytic system (Example 1) performs the worst, with a yield of only 65.1%. This verifies the limitations of non-noble metal catalysts under this reaction condition. Although nickel has certain catalytic activity, due to the limited catalytic sites, it is easy to be 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] The experimental data fully demonstrate that the platinum and nickel synergistic catalytic system effectively reduces the amount of platinum while maintaining high yield, which is the best choice for optimizing catalyst performance. Although the palladium catalytic system is suboptimal, it has strong activation ability for the substrate and still has certain practical value.

Claims

1. A process for the preparation of Nicotinic Acid Methyl Ester, characterized in that, The method comprises the following steps: Step 1: mixing chlorobenzene, nicotinic acid, diethylamine hydrochloride and the metal-based mesoporous catalyst; Step 2: reacting at 70-90 DEG C under normal pressure for 50-100 minutes; Step 3: adding water and separating the organic phase; Step 4: reducing pressure distillation to obtain the nicotinic acid dimethylamide; The metal-based mesoporous catalyst is prepared by the following method: S1: immersing the mesoporous silica material in a platinum precursor solution obtained by dissolving a metal precursor in water; S2: drying and reducing in a hydrogen atmosphere; S3: high-temperature sintering to obtain the metal-based mesoporous catalyst; The metal precursor is a combination of a platinum precursor and a nickel precursor.

2. The process for the preparation of nicotine according to claim 1, characterized in that, The molar ratio of the platinum precursor to the nickel precursor is 20:(1-3).

3. The process for the preparation of nicotine according to claim 1, characterized in that, The platinum precursor is at least one of chloroplatinic acid, sodium chloroplatinate, potassium chloroplatinate, ammonium platinic acid, platinum nitrate and platinum acetate; and the nickel precursor is at least one of nickel sulfate, nickel nitrate, nickel oxalate, nickel acetate and nickel chloride.

4. The process for the preparation of Nicotine according to any one of claims 1 to 3, characterized in that, The metal-based mesoporous catalyst is prepared by the following method: S1: immersing the mesoporous silica material in a platinum precursor solution obtained by dissolving a metal precursor in water; S2: drying and reducing in a hydrogen atmosphere; the hydrogen flow rate is controlled to be 30-80 mL / min, the reduction temperature is 150-250 DEG C, and the reduction time is 3-7 hours; S3: sintering at 300-400 DEG C for 2-6 hours to obtain the metal-based mesoporous catalyst.

5. The process for the preparation of nicotine according to claim 4, characterized in that, The mass ratio of the mesoporous silica material, the metal precursor and water in step S1 is 100 g:(0.06-0.12 mol):(800-1400 g).

6. The process for the preparation of nicotine according to claim 4, wherein, The amount ratio of the chlorobenzene, the nicotinic acid, the diethylamine hydrochloride and the metal-based mesoporous catalyst is (200-400 mL):100 g:(89-105 g):(16-30 g).

7. The process for the preparation of nicotine according to claim 4, wherein, The step 3 is adding water, adjusting the pH to 7.5-8.5 with a sodium hydroxide aqueous solution, and separating the organic phase.

8. The process for the preparation of nicotine according to claim 4, wherein, The step 4 is reducing pressure distillation, and the target product is collected under the condition of 152-154 DEG C / 10 mmHg to obtain the nicotinic acid dimethylamide.