Preparation method of dabigatran etexilate intermediate p-aminobenzonitrile

Abstract

The invention relates to the preparation of p-aminobenzonitrile. In the case of adding a dispersant and benzoyl peroxide, p-nitrobenzamide is dehydrated in toluene by phosphorus oxychloride to obtain p-nitrobenzamide, and then p-nitrobenzonitrile is obtained by selective reduction. The preparation method of the invention is more conducive to the safe, economical and convenient preparation of p-aminobenzonitrile.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and more particularly to dabigatran etexilate mesylate. The structures of compound I p-aminobenzonitrile and compound II p-nitrobenzonitrile are as follows:

[0002] Background Art

[0003] Dabigatran etexilate mesylate was developed by Boehringer-Ingelheim and was first approved for marketing in Germany and the United Kingdom by the European Medicines Agency (EMA) on March 18, 2008; it was approved for marketing by the U.S. Food and Drug Administration (FDA) on October 19, 2010; and it was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on January 21, 2011, under the trade name On February 22, 2013, it was approved by the National Medical Products Administration (NMPA) for marketing in China under the trade name

[0004] Dabigatran etexilate and its metabolites acyl glucuronides are competitive direct thrombin inhibitors, and the active ingredients can inhibit free and clot-bound thrombin, as well as thrombin-induced platelet aggregation.

[0005] Para-aminobenzonitrile is one of the key intermediates for preparing dabigatran etexilate. Currently, the methods for preparing compound I para-aminobenzonitrile mainly include the following:

[0006] 1. Compound II is obtained by reducing the nitro group:

[0007]

[0008] The nitro group can be reduced with hydrazine hydrate under the catalysis of elements such as iron, cobalt, and nickel to obtain p-aminobenzonitrile; it can be reduced with hydrogen, formic acid, and ammonium formate under the catalysis of elements such as iron, cobalt, nickel, copper, silver, gold, and platinum to obtain p-aminobenzonitrile; it can be reduced with iron, nickel, and zinc under the action of acid to obtain p-aminobenzonitrile; it can be reduced with carbon monoxide under the catalysis of Ru and Rh to obtain p-aminobenzonitrile; it can be reduced with elemental sulfur or sulfide to obtain p-aminobenzonitrile. Among the above preparation methods, the reduction with hydrazine hydrate is suitable for a small amount of research and development reaction under laboratory conditions. If it is used for industrial production, there is a relatively large safety hazard due to the safety problem of hydrazine hydrate itself; the cost of using formic acid or ammonium formate as a hydrogen source is relatively high compared to hydrogen; using carbon monoxide as a reducing agent requires the use of expensive metal rhodium and a large amount of carbon monoxide, which is a great safety hazard in the event of leakage; using elemental sulfur or metal sulfide, hydrogen sulfide derivatives may be generated in the process, which may undergo hydrogen sulfide decomposition with cyano groups to generate thioamide impurities.

[0009] In summary, in combination with industrial production, it is easier to control costs by using a heterogeneous noble metal catalytic hydrogenation method (it is easier to recover noble metals from heterogeneous catalysts) to reduce the nitro group to obtain p-aminobenzonitrile, or by using reduced iron powder and hydrochloric acid to reduce the nitro group to obtain p-aminobenzonitrile.

[0010] 2. Compound III-x is replaced by ammonia to obtain:

[0011]

[0012] Where X = Cl, Br, I, CF3SO3;

[0013] Compound III-x is reacted with liquid ammonia or aqueous ammonia in the presence of alkali metal carbonate, sodium alcoholate, potassium alcoholate under the catalysis of copper salt or palladium to obtain p-aminobenzonitrile. In the above preparation method, copper or copper salt catalysis is generally required, and even a homogeneous palladium catalyst is required. When the leaving group X is trifluoromethanesulfonate or iodine, the reaction yield is relatively high, followed by bromine, and chlorine is even lower; when the leaving group is trifluoromethanesulfonate, iodine, or bromine, the starting material III-x is difficult to obtain or expensive, and the reaction process is relatively sensitive to air, and the reaction conditions may not be well controlled in industrial production.

[0014] 3. Compound IV-y is obtained by replacing Y with cyano:

[0015]

[0016] Where Y = Cl, Br, I;

[0017] Compound IV-y reacts with cyanides such as sodium cyanide, potassium cyanide, potassium ferrocyanide, trimethylsilyl cyanide, 2-hydroxyisobutyronitrile, cuprous cyanide, zinc cyanide, nickel cyanide, etc. under Pd catalysis to obtain p-aminobenzonitrile. In the above preparation method, various types of cyanides are used as the source of cyanide, most of which are highly toxic, and the three wastes require special treatment and need to be ensured to be completely handled, otherwise it will cause great safety and environmental protection risks; the price of relatively low toxicity is also relatively expensive. In addition, homogeneous Pd catalysts are also required in many reaction processes, which poses a relatively large challenge to cost control and is not suitable for industrial production.

[0018] 4. Compound V is dehydrated to obtain:

[0019]

[0020] Compound V is dehydrated under the action of incompletely substituted silane to obtain p-aminobenzonitrile; it is dehydrated under the action of dehydrating agents such as thionyl chloride [1], phosphorus pentoxide, and trifluoromethanesulfonic anhydride to obtain p-aminobenzonitrile; propylphosphoric anhydride (T3P) can be used as a dehydrating agent and zinc bromide can be used to catalyze the formation of p-aminobenzonitrile. In the above preparation method, trifluoromethanesulfonic anhydride and propylphosphoric anhydride (T3P) are extremely expensive and not suitable for industrial production; phosphorus pentoxide is also very likely to cause phosphorylation of the amino group, and it is unknown whether the phosphoramide can be completely hydrolyzed to the amino group without affecting the cyano group.

[0021] Among them, the method of dehydrating p-aminobenzamide (compound V) with a dehydrating agent thionyl chloride to generate p-aminobenzonitrile is likely to be through the following reaction process: a p-aminobenzamide molecule first reacts with a molecule of thionyl chloride to generate an N-sulfenylanilide derivative (VA) [6] The enol structure of the VA amide group then reacts with another molecule of thionyl chloride to form chlorosulfinate (VB); VB then undergoes an elimination reaction to form a cyano group (VC). [7] VC's N-sulfenylanilide is hydrolyzed to give an amino group to generate the target product, p-aminobenzonitrile (compound I).

[0022]

[0023] During the reaction, a large amount of solid matter will appear, and the situation that stirring cannot be achieved is likely caused by the low solubility of the intermediate state VA or VB in the reaction solvent; even if the amount of the reaction solvent is doubled at the beginning, the situation that stirring cannot be achieved due to the precipitation of the intermediate state is not significantly improved. If the amount of solvent is continued to be increased, the problem of increased cost will inevitably be caused. In addition, the reaction process will release a large amount of hydrogen chloride gas and sulfur dioxide gas, which are very corrosive to equipment and are also very unfriendly to the environment. In the post-treatment process, a large amount of alkali needs to be consumed to neutralize the acid generated during the reaction process, and p-aminobenzonitrile hydrochloride is dissociated into p-aminobenzonitrile before it can be precipitated from water, which will lead to increased costs and increase the difficulty of three waste treatment.

[0024] Without good protection, when this method is used to prepare p-aminobenzonitrile in large quantities, cyanide poisoning may occur to personnel, thus limiting the application of this method to a great extent. It may be that the N-sulfenylanilide derivatives (VA, VC) in the reaction process are left, which easily causes poisoning to personnel; it may also be due to the influence of the -N=S=O group, causing the cyanide bond at the para position to break during the preparation process, releasing hydrocyanic acid and causing cyanide poisoning to personnel.

[0025] Hydrocyanic acid is a highly toxic liquid with a boiling point of about 26°C under standard conditions. It is commonly used in electroplating industries such as gold plating, silver plating, and copper plating, as well as mining industries such as gold and silver mining. The content of hydrocyanic acid in the environment reaches 200 mg / m 3 When the concentration reaches 500mg / m 3 When it is exposed to the sun, it will cause human breathing to be inhibited, pupils to dilate, and coma. The maximum allowable concentration in the working environment is 0.3mg / m 3 The lethal dose is 1 mg / kg (body weight). A cyanide concentration of about 0.5 μg / ml in the blood will cause poisoning, and a concentration of ≥1 μg / ml can be fatal.

[0026] Cyanide ions released from hydrogen cyanide can inhibit the activity of more than 40 enzymes in tissue cells. Among them, cytochrome oxidase is the most sensitive to cyanide ions: Fe in oxidized cytochrome oxidase 3+ ions can be quickly combined with cyanide ions and cannot be reduced to Fe 2+ The ions lose the ability to transport oxygen, causing the cell tissue to be in a state of hypoxia, unable to synthesize ATP, hindering the normal physiological functions of the tissue cells, and causing the body to be unable to maintain normal activities and fall into a state of internal suffocation. The central nervous system is extremely sensitive to hypoxia. Cyanide poisoning will cause the brain to be damaged first, leading to central respiratory failure and death. Therefore, avoiding or promptly eliminating the cyanide ions produced during the reaction is very necessary for the safety of production personnel.

[0027] In summary, the method for preparing p-aminobenzonitrile by dehydrating p-aminobenzamide (compound V) with thionyl chloride will inevitably encounter the problem of difficult stirring under the requirements of reducing the reaction solvent and improving the production efficiency of the reactor; the problem of environmental pollution caused by the decomposition product of the dehydrating agent thionyl chloride being sulfur dioxide; the problem of high cost of three wastes treatment; and the major safety hazard involving personnel health caused by the generation of cyanide in the preparation process; this method is not suitable for industrial production.

[0028] 5. Compound VI is converted into the corresponding compound VI-a and then dehydrated to obtain:

[0029]

[0030] Compound VI reacts with hydroxylamine hydrochloride to generate oxime, which is then dehydrated to generate p-aminobenzonitrile. In the above preparation method, the starting material p-aminobenzaldehyde is relatively expensive, and the intermediate compound VI-a aldoxime undergoes Beckmann rearrangement to obtain p-aminobenzamide during the dehydration process, thereby affecting the product quality. This method is not suitable for industrial production.

[0031] The methods for preparing compound II p-aminobenzonitrile are mainly as follows:

[0032] 1. Compound VII is dehydrated to obtain:

[0033]

[0034] Compound VII was reacted with oxalyl chloride and phosphorus oxychloride [2][4][5] , sulfamic acid, alkoxyphosphoryl chloride, BrCCl3-PPh3, incompletely substituted silane + metal catalyst, cyanuric chloride, chloroformate, trifluoromethanesulfonic anhydride, sodium metavanadate, thionyl chloride [3] Dehydration under the action of dehydrating agents such as oxalyl chloride gives p-nitrobenzonitrile. In the above preparation methods, oxalyl chloride is expensive, and the reaction process releases carbon monoxide and carbon dioxide, which is not friendly to the environment, especially the operators, in industrial production; trifluoromethanesulfonic anhydride and incompletely substituted silane + metal catalyst are expensive; sodium metavanadate requires a reaction condition of nearly 200°C; thionyl chloride releases a large amount of hydrogen chloride gas and sulfur dioxide gas, which are severely corrosive to equipment and are not friendly to the environment; it is not suitable for industrial production. Using phosphorus oxychloride as a dehydrating agent, document [2] uses pyridine as a solvent for the reaction. Pyridine is relatively expensive and difficult to recover, and the production cost is high. At the same time, it also greatly increases the work of wastewater treatment, which is not suitable for industrial production; documents [4][5] need to use DMF as a solvent or need to use a large amount of DMF and other solvents in the preparation process. Post-treatment will make the wastewater extremely difficult to treat, and the recovery of the mixed solvent is also quite difficult, which is not suitable for industrial production.

[0035] 2. Compound VIII-z is obtained by replacing Z with cyano:

[0036]

[0037] Where Z = Cl, Br, I, CF3SO3;

[0038] Compound VIII-z reacts with cyanides such as sodium cyanide, potassium cyanide, potassium ferrocyanide, trimethylsilyl cyanide, 2-hydroxyisobutyronitrile, cuprous cyanide, zinc cyanide, nickel cyanide, etc. under Pd catalysis to obtain p-nitrobenzonitrile. The above preparation method has the same disadvantages as the preparation of compound I from compound IV-y. It is not suitable for industrial production.

[0039] 3. Compound IX is converted into the corresponding compound IX-a and then dehydrated to obtain:

[0040]

[0041] Compound IX reacts with hydroxylamine hydrochloride to generate oxime, which is then dehydrated to generate p-nitrobenzonitrile. The above preparation method has similar disadvantages as the preparation of compound I from compound VI. It is not suitable for industrial production.

[0042] References:

[0043] [1].CN111269144

[0044] [2].Compt.rend.(1956), 242, 2644-6.

[0045] [3].CN104610096

[0046] [4].IN2011CH01592

[0047] [5].Indian Journal of Chemistry, Section B: Organic Chemistry IncludingMedicinal Chemistry(2003), 42B(12), 3148-3151.

[0048] [6].Organic Synthese(1969), 49, 70.

[0049] [7].Journal of Organic Chemistry(1962), 27(12), 4608-4610. Summary of the invention

[0050] The method for preparing p-nitrobenzonitrile by dehydrating p-nitrobenzamide with phosphorus oxychloride is likely to involve phosphorus oxychloride reacting with the enol structure of the amide group of compound VII to form bischlorophosphate (VII-P), which is then eliminated to form a cyano group to obtain p-nitrobenzonitrile (compound II).

[0051]

[0052] During the reaction, an extremely viscous colloid will settle at the bottom of the reactor, making stirring very difficult and the reaction effect very poor. Even if the temperature is increased and the reaction is carried out for a long time, the conversion rate is not very high and the obtained p-nitrobenzonitrile has poor purity. Therefore, it is very necessary to find a preparation method that can reduce the viscosity of the reaction system and allow the mass transfer and heat transfer of the reaction to proceed smoothly.

[0053] The method of preparing p-nitrobenzonitrile by dehydrating p-nitrobenzamide with thionyl chloride should be similar to the reaction process of preparing p-nitrobenzonitrile by dehydrating with phosphorus oxychloride: p-nitrobenzamide and thionyl chloride generate chlorosulfinate (VII-S); VII-S then generates cyano group through elimination reaction to obtain the product p-nitrobenzonitrile (Compound II). However, dehydrating with thionyl chloride releases both hydrogen chloride gas and sulfur dioxide gas that can cause acid rain, which is very corrosive to production equipment, harmful to the health of operators, and seriously pollutes the environment.

[0054]

[0055] The present invention finds that dehydration with phosphorus oxychloride only releases hydrogen chloride gas, and compared with dehydration with thionyl chloride, sulfur dioxide will not be released. It is only necessary to use a relatively simple device to absorb hydrogen chloride gas; dehydration with thionyl chloride not only requires absorption of hydrogen chloride gas, but also requires additional equipment to absorb sulfur dioxide; the method of dehydration with phosphorus oxychloride reduces the treatment equipment and links of the three wastes, and is also more environmentally friendly. In the process of dehydration with phosphorus oxychloride, if an appropriate amount of dispersant such as sodium chloride, potassium chloride, and sodium sulfite is added, the properties of the viscous colloidal substance will be greatly improved, so that the entire reaction system can be well stirred, and the viscous colloidal substance can be dispersed by the dispersant, and normal mass transfer and heat transfer can be performed, so that the reaction is carried out smoothly, and a good yield is obtained, and the purity of the separated product is also greatly improved. The present invention also finds that adding benzoyl peroxide in the reaction system can oxidatively decompose a small amount of cyanide generated in the reaction system, and adding an appropriate amount of benzoyl peroxide in the reaction can greatly improve the safety in the reaction and post-treatment process, and has no effect on the quality of the product.

[0056] The reaction scheme of the present invention is as follows:

[0057]

[0058] p-Nitrobenzonitrile is prepared by using p-nitrobenzamide as a raw material, toluene as a reaction solvent, phosphorus oxychloride as a dehydrating agent, sodium chloride, potassium chloride and sodium sulfite as dispersants, and adding benzoyl peroxide to capture and oxidatively decompose a small amount of cyanide generated during the preparation process.

[0059] Adding a dispersant in the preparation method can solve the problem of low yield and poor purity caused by the inability to stir the viscous colloid and the reaction cannot proceed normally; adding benzoyl peroxide and a small amount of cyanide generated by the oxidative decomposition reaction can solve the problem of personnel safety in the production process.

[0060] The p-nitrobenzonitrile prepared by the above method is then selectively reduced by heterogeneous catalytic hydrogenation to obtain p-aminobenzonitrile, or selectively reduced by reducing iron powder and hydrochloric acid to obtain p-aminobenzonitrile.

[0061] The attached figure of the specification is a typical liquid phase spectrum of the target product of the embodiment.

[0062] Attached Figure 1 : The liquid phase spectrum of p-nitrobenzonitrile prepared in Example 1, without adding a dispersant;

[0063] Attached Figure 2 : Liquid phase spectrum of large-scale preparation of p-nitrobenzonitrile in Example 21, with the addition of sodium chloride as a dispersant;

[0064] Attached Figure 3 : The liquid phase spectrum of preparing p-aminobenzonitrile by reducing p-nitrobenzonitrile with iron powder and hydrochloric acid in Example 23;

[0065] Attached Figure 4 : Liquid phase spectrum of large-scale hydrogenation reduction of p-nitrobenzonitrile to prepare p-aminobenzonitrile in Example 24. DETAILED DESCRIPTION

[0066] General operation A: Add toluene, 166g (1 mol) of p-nitrobenzamide, and dispersants (sodium chloride, potassium chloride, sodium sulfite) to a reaction bottle, then add 2.42g (0.01 mol) of benzoyl peroxide, dropwise add phosphorus oxychloride (1.3 mol), and heat to react. TLC shows that the raw material disappears completely or monitor every about 1 hour. If there is no obvious progress of the reaction, it is considered to be the end point of the reaction. Cool, quench with water, and separate p-nitrobenzonitrile. Specific reference table 1:

[0067] Table 1 Dispersant screening

[0068]

[0069] According to the data in Table 1 above, in the case of no dispersant, even if the reaction temperature is higher, the purity of the obtained p-nitrobenzonitrile is very low, and the main impurity is p-nitrobenzamide that is not dehydrated; after adding 50g of sodium chloride, the yield decreases, but the purity is significantly improved, and the stirring condition during the reaction is also improved to a certain extent; after adding 100g of sodium chloride, the yield is improved again, and the purity rises to more than 99%. When the amount of sodium chloride is further increased to 166g or 200g, there is no significant difference and improvement in the yield and purity compared to when 100g is added. On the contrary, when the dispersant sodium chloride is added to 200g, more water is needed to dissolve the added sodium chloride; when the dispersant is replaced by potassium chloride, the change trend of the result is similar to that of sodium chloride; when the dispersant is replaced by sodium sulfite, it can be clearly seen that more gas is released during the reaction, and it is the sulfur dioxide gas released by the acid decomposition of sodium sulfite during the reaction.

[0070] Based on the above results, considering that sodium sulfite as a dispersant will release additional sulfur dioxide; the price of potassium chloride is much higher than that of sodium chloride; we chose sodium chloride as a dispersant. Excessive use of sodium chloride will not significantly improve the other party, increase waste, and also produce more waste liquid, and the workload of wastewater treatment will also increase accordingly. We use about 1 mol of p-nitrobenzamide as a feed and add about 100g of sodium chloride as a dispersant.

[0071] General operation B: Add toluene, 166 g (1 mol) of p-nitrobenzamide, 100 g of sodium chloride, and then add 2.42 g (0.01 mol) of benzoyl peroxide to a reaction bottle, add phosphorus oxychloride dropwise, and react at about 90°C. After the reaction is completed, cool, quench with water, and separate p-nitrobenzonitrile. For details, refer to Table 2

[0072] Table 2 Phosphorus oxychloride dosage screening

[0073]

[0074] Combining the data in Example 4 in Table 1 and Table 2, the yield and purity of p-nitrobenzonitrile obtained by dehydration with almost equivalent phosphorus oxychloride are low, and the impurities are mainly p-nitrobenzamide that is not dehydrated; when phosphorus oxychloride is about 1.2 times the molar amount, it is more appropriate. Increasing the amount of phosphorus oxychloride has a relatively small effect on the results, but it causes a waste of reagents, and more water is required for post-treatment to quench the reaction, which greatly increases the workload of three waste treatment.

[0075] Based on the above results, we used 1.1 to 1.3 times the molar amount of phosphorus oxychloride for dehydration.

[0076] We used cyanide detection test paper to detect the mother liquor of all embodiments in Table 1 and Table 2, and no cyanide was detected.

[0077] General operation C: Add toluene, 166 g (1 mol) of p-nitrobenzamide, 100 g of sodium chloride, benzoyl peroxide, and 185 g (1.2 mol) of phosphorus oxychloride to a reaction bottle, and react at about 90°C. After the reaction is completed, cool, quench with water, and separate p-nitrobenzonitrile. For details, refer to Table 3

[0078] Table 3 Benzoyl peroxide amount screening

[0079]

[0080] We used cyanide detection test paper to detect the mother liquor of all the examples in Table 3, where cyanide was detected in Examples 17 and 18, but not in Examples 19 and 20; this indicates that when the amount of benzoyl peroxide added is ≥ 3‰ times the molar amount, a small amount of cyanide in the system can be oxidized and decomposed. In addition, the amount of benzoyl peroxide added in all the examples in Tables 1 and 2 is 10‰ times the molar amount, and cyanide was detected in all of them.

[0081] Based on the above results, we used 5‰ to 7‰ times the molar amount of benzoyl peroxide to capture the hydrogen radicles generated during the preparation process.

[0082] Example 21 Preparation of p-Nitrobenzonitrile

[0083]

[0084] Add 1900kg toluene to a 6300L reactor; add 650kg (3.912kmol) of p-nitrobenzamide; add 400kg of sodium chloride; then add 5kg (20.64mol) of benzoyl peroxide; add 715kg (4.663kmol) of phosphorus oxychloride, and control the temperature not to exceed 60°C during the addition process; heat to 80-90°C, stir and react until the p-nitrobenzamide is completely converted; cool the reaction solution to 10-20°C; control the temperature not to exceed 30°C, and slowly add about 2000kg of drinking water; after the addition is complete, cool to 0-5°C, stir and crystallize for about 5 hours; centrifuge and filter; collect the solid, dry and obtain 516.1kg (theoretical amount: 579.52kg) of p-nitrobenzonitrile. Yield: 89.0%. HPLC purity: 99.84%.

[0085] The mother liquor of Example 21 was tested with cyanide detection test paper, and no cyanide was detected.

[0086] Example 22 Preparation of p-aminobenzonitrile

[0087]

[0088] Add 100g (675.1mmol) of p-nitrobenzonitrile, 500g of methanol, 10g of Pd / C catalyst with a loading of 5% to the hydrogenation kettle, replace with nitrogen 3 times, replace with hydrogen 3 times, heat to 45°C, and keep the pressure in the kettle below 2atm until the absorption of hydrogen is complete. Filter to remove the Pd / C catalyst, collect the filtrate, concentrate to dryness under reduced pressure, add drinking water, stir to disperse the residue, filter, collect the solid, and dry to obtain 75.2g (theoretical amount: 79.76g) of p-aminobenzonitrile as a light yellow solid. Yield: 94.3%.

[0089] Example 23 Preparation of p-aminobenzonitrile

[0090]

[0091] Add 800g of methanol, 100g (675.1mmol) of p-nitrobenzonitrile, 125g (2.238mol) of reduced iron powder to the reaction bottle, slowly drop 1260g of 12% hydrochloric acid, keep warm at no more than 50℃, after the dropwise addition, heat to 65-70℃ and react for 1-2hr; after the reaction is completed, filter and collect the filtrate for standby use; collect the solid, beat with 400g of methanol, filter, collect the filtrate; combine the filtrate, concentrate under reduced pressure to obtain 1600-1800g of fraction, cool the residue to 10-15℃, stir and keep warm for 1-2hr; filter, collect the solid, dry, and obtain 60.3g (theoretical amount: 79.76g) of p-aminobenzonitrile as a brown-red solid. Yield: 75.6%. HPLC purity: 98.62%.

[0092] Example 24 Preparation of p-aminobenzonitrile

[0093]

[0094] Add 210kg (1.418kmol) of p-nitrobenzonitrile to a 1500L hydrogenation reactor, add 840kg of methanol, add 18kg of Pd / C catalyst with a loading of 3%, replace with nitrogen 3 times, replace with hydrogen 3 times, heat to 45°C, and the pressure in the reactor does not exceed 2atm until the hydrogen absorption is completed. Remove the Pd / C catalyst by pressure filtration, collect the filtrate, and concentrate it under reduced pressure to about 400-500L, add about 800kg of drinking water, continue to concentrate under reduced pressure to about 400-500kg, stir, cool to 10-20°C, filter, collect the solid, and dry to obtain 161.8kg (theoretical amount: 167.5kg) of p-aminobenzonitrile as a light yellow solid. Yield: 96.6%. HPLC purity: 99.82%.

[0095] Comparative Example 1 Preparation of p-aminobenzonitrile

[0096]

[0097] Add 700g of toluene to a reaction bottle equipped with mechanical stirring, add 136.2g (1.0mol) of p-aminobenzamide, stir and heat to 90-100°C; add 360g (3.03mol) of dichlorothionyl, during the addition, a large amount of solid is generated in the system, causing the stirring to stop, keep warm and reflux, the solid gradually dissolves, continue to stir, and after complete dissolution, continue to keep warm and react for about 2-3 hours. After the reaction is completed, cool the reaction solution to 20-25°C, slowly transfer it to 1000g of ice water for quenching, quench and keep warm at no more than 20°C. After quenching, adjust the system pH to 7-8 with 40% potassium carbonate aqueous solution; cool to 5-10°C, stir and crystallize for about 2-3 hours; filter, collect solids, and rinse with water. The mother liquor is tested with cyanide test paper and is positive. Collect the solid and dry it to obtain 87.3g (theoretical amount: 118.2g) of p-aminobenzonitrile as a brown solid. Yield: 73.9%.

[0098] In Comparative Example 1, the reaction process causes the mechanical stirring to fail to work properly, and it takes a long time for the generated solid to gradually dissolve before stirring can continue. If the generation is enlarged, the stirring will be stopped, and the heat transfer of the reaction system will be greatly problematic, increasing the hidden danger of accidents. Cyanide is detected in the mother liquor, indicating that hydrocyanic acid is generated during the reaction process. Once industrialized production is carried out, it is very likely that enough hydrocyanic acid will be released, causing the hydrocyanic acid content in the local production site to exceed the safety threshold, resulting in accidents of hydrocyanic acid poisoning.

Claims

1. The preparation of p-nitrobenzonitrile is characterized in that: Compound VII p-nitrobenzamide is reacted in toluene with phosphorus oxychloride as a dehydrating agent, sodium chloride, potassium chloride, and sodium sulfite as dispersants, and benzoyl peroxide is added, and heated to react to obtain compound II p-nitrobenzonitrile.

2. The method for preparing p-nitrobenzonitrile according to claim 1, wherein: The reaction solvent is toluene, and the amount used is 2.5 to 3.5 times the weight of p-nitrobenzamide; the dehydrating agent is phosphorus oxychloride, and the amount used is 1.1 to 1.3 times the molar amount of p-nitrobenzamide; the dispersant is sodium chloride, potassium chloride, sodium sulfite or a combination thereof; the amount of the dispersant used is 0.3 to 1.2 times the weight of p-nitrobenzamide; the amount of benzoyl peroxide added is 3‰ to 10‰ times the molar amount of p-nitrobenzamide.

3. The preparation of p-aminobenzonitrile, characterized in that: According to the method of claim 2, p-nitrobenzonitrile is prepared by selective reduction with Pd / C catalytic hydrogenation to obtain compound I p-aminobenzonitrile, 4. The method for preparing p-aminobenzonitrile according to claim 3, characterized in that: The reaction solvent is methanol; the loading amount of Pd in ​​the Pd / C catalyst is 3% to 5%.

5. The preparation of p-aminobenzonitrile, characterized in that: According to the method of claim 2, p-nitrobenzonitrile is prepared by selective reduction with reduced iron powder and hydrochloric acid to obtain compound I p-aminobenzonitrile.

6. The method for preparing p-aminobenzonitrile according to claim 5, characterized in that: The reaction solvent is methanol; the reducing agent is iron powder, and the amount used is 3.2 to 3.6 times the molar amount of p-nitrobenzonitrile; and the amount of hydrochloric acid used is 1.85 to 1.95 times the molar amount of the iron powder.

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