A kind of synthetic method of 4-trifluoromethyl nicotinamide

Abstract

The invention belongs to the field of chemical synthesis, and specifically relates to a method for synthesizing 4-trifluoromethyl nicotinamide. The invention adopts 4,4,4-trifluoroacetoacetic acid ethyl ester as a raw material, performs cyclization alkaline hydrolysis to generate 2,6-dihydroxy-4-trifluoromethyl nicotinic acid, performs chlorination reaction to generate 2,6-dichloro-4-trifluoromethyl nicotinyl chloride, performs amidation to generate 2,6-dichloro-4-trifluoromethyl nicotinamide, and performs reduction reaction to generate 4-trifluoromethyl nicotinamide.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a synthesis method of 4-trifluoromethylnicotinamide. Background Art

[0002] 4-Trifluoromethylnicotinamide is an important chemical intermediate. It is obtained from ethyl 4,4,4-trifluoroacetoacetate through cyclization, chlorination, reduction, and acidolysis. Its industrial production process is as follows:

[0003] Process 1:

[0004]

[0005] Process 2:

[0006]

[0007] Production process 1 is to reduce first and then hydrolyze. During the reduction process, due to the strong electron-withdrawing effect of the cyano group, the C at position 2 of the reduction substrate has a strong electrophilicity, and a variety of coupling impurity isomers are produced in the presence of a hydrogenation catalyst. At the same time, due to the characteristics of the cyano group, a large amount of cyano reduction products are produced when the alkalinity of the reduction system is insufficient, which is not conducive to the stability of industrial production. Process 2 is to hydrolyze first and then reduce. The hydrolysis of the cyano group can be completed under acidic or alkaline conditions. Because under alkaline conditions, the amide is further hydrolyzed into carboxylic acid, it is necessary to hydrolyze under acidic conditions, and there are strict requirements on the water content. More water will generate carboxylic acid, and less water will not be completely hydrolyzed. Therefore, concentrated sulfuric acid with a content of 95%-96% is used. Due to the strong oxidizing and corrosive properties of sulfuric acid, the process has safety hazards. Summary of the invention

[0008] In view of the problems that the methods for synthesizing 4-trifluoromethylnicotinamide in the prior art have many side reactions and hidden dangers in production safety, the present invention provides a method for synthesizing 4-trifluoromethylnicotinamide to solve the above problems. The technical scheme of the present invention uses 4,4,4-trifluoroacetoacetic acid ethyl cyclohexane as a raw material to generate 2,6-dihydroxy-4-trifluoromethylnicotinic acid through alkaline hydrolysis, generates 2,6-dichloro-4-trifluoromethylnicotinyl chloride through chlorination reaction, generates 2,6-dichloro-4-trifluoromethylnicotinamide through amidation, and generates 4-trifluoromethylnicotinamide through reduction reaction.

[0009]

[0010] The specific steps include:

[0011] (1) A tertiary amine and cyanoacetamide are mixed, the temperature is raised to 90-92° C., and ethyl 4,4,4-trifluoroacetoacetate is added dropwise; after the addition is completed, the temperature is kept to react for 2-4 hours (preferably, the reaction is qualified when the residual ethyl 4,4,4-trifluoroacetoacetate is less than 0.5% as detected by high performance liquid chromatography).

[0012] (2) adding alkali solution, heating at normal pressure to desolventize and recover the tertiary amine, to a system temperature of 95-100° C., and keeping the temperature for 10-12 hours (preferably, the residual 3-cyano-2,6-dihydroxy-4-trifluoromethylpyridine is less than 1% by high performance liquid chromatography tracking), adjusting the pH of the system to 1.5-2 with hydrochloric acid, cooling to below 10° C., filtering, and drying to obtain 2,6-dihydroxy-4-trifluoromethylnicotinic acid.

[0013] (3) 2,6-dihydroxy-4-trifluoromethylnicotinic acid and phosphorus oxychloride are heated to 60-70°C, and a tertiary amine is added dropwise. After the addition is completed, the temperature is continued to be raised to 90-100°C and kept for reaction for 10-12 hours. The system gradually becomes clear, and the residual 2,6-dihydroxy-4-trifluoromethylnicotinic acid is detected to be less than 1%, indicating that the reaction is qualified.

[0014] (4) desolventizing and recovering phosphorus oxychloride to a temperature of 130-140° C. in the system, cooling to about 100° C., and dropping the desolventized chlorinated solution into an ammonia solution. During the dropping process, the ammonia solution is kept at -10-0° C. After the dropping is completed, the temperature is kept at -10-0° C. for reaction. The residual 2,6-dihydroxy-4-trifluoromethylnicotinyl chloride to be detected is less than 2%. The pH of the system is adjusted to 8-9 with an alkali solution. During the pH adjustment process, the temperature is maintained at 20-30° C., and 2,6-dichloro-4-trifluoromethylnicotinamide is obtained by filtering and drying.

[0015] (5) Dissolve 2,6-dichloro-4-trifluoromethylnicotinamide in methanol, add an acid-binding agent, use palladium carbon as a catalyst, and reduce with hydrogen at 25-30° C. until the residual 2-chloro-4-trifluoromethylnicotinamide is less than 1%, and the reaction is qualified.

[0016] (6) Filter and recover the palladium-carbon catalyst, add water and heat to distill and recover methanol, then cool and filter, wash with water, and dry to obtain 4-trifluoromethylnicotinamide.

[0017] Preferably, in step (1), ethyl 4,4,4-trifluoroacetoacetate is added dropwise for a period of 4-6 hours.

[0018] Preferably, in step (1), a tertiary amine is used as a solvent and a catalyst, the mass of the tertiary amine is 2-3 times that of cyanoacetamide, and the molar amount of cyanoacetamide is 1.1-1.3 times that of ethyl 4,4,4-trifluoroacetoacetate.

[0019] Preferably, the alkali solution in step (2) is a sodium hydroxide solution, the molar amount of sodium hydroxide is 3-5 times that of ethyl 4,4,4-trifluoroacetoacetate, and the mass concentration of the sodium hydroxide solution is 15-20%.

[0020] Preferably, in step (3), the mass of phosphorus oxychloride is 4-6 times that of 2,6-dihydroxy-4-trifluoromethylnicotinic acid; and the molar amount of the tertiary amine added dropwise is 2-2.5 times that of 2,6-dihydroxy-4-trifluoromethylnicotinic acid.

[0021] Preferably, the vacuum degree of the reduced pressure desolventizing in step (4) is set to be above -0.095 MPa.

[0022] Preferably, the molar amount of ammonia in step (4) (in terms of NH 3 The alkali solution is a sodium hydroxide solution, and the mass concentration of the sodium hydroxide solution is 15-20%; more preferably, stirring is continued for 0.5h after the pH adjustment is completed.

[0023] Preferably, in step (5), the amount of methanol is 3-5 times the mass of 2,6-dichloro-4-trifluoromethylnicotinamide, the acid binding agent is selected from triethylamine, diisopropylethylamine, tripropylamine, the molar amount of the acid binding agent is 2-2.5 times that of 2,6-dichloro-4-trifluoromethylnicotinamide, and the mass amount of palladium carbon is 1%-5% of 2,6-dichloro-4-trifluoromethylnicotinamide.

[0024] Preferably, in step (5), the hydrogen flux is 300-400 L / min.

[0025] Preferably, in step (6), the amount of water added during the distillation recovery of methanol is 4-6 times that of 2,6-dichloro-4-trifluoromethylnicotinamide, and the methanol is distilled to recover the system temperature to 98° C.; the temperature is lowered to about 35° C. and filtered.

[0026] Preferably, the tertiary amine in step (1) and step (3) is selected from triethylamine, diisopropylethylamine and tripropylamine.

[0027] The beneficial effects of the present invention are:

[0028] (1) An alkaline hydrolysis step is added between the cyclization reaction and the chlorination reaction step to directly hydrolyze the cyanide group into a carboxyl group, thereby avoiding the use of concentrated sulfuric acid to hydrolyze the cyanide group. This is more advantageous in terms of safety, process stability and industrial operability.

[0029] (2) Using the chlorination process, both the phenolic hydroxyl group and the carboxyl hydroxyl group undergo chlorination reaction. In the subsequent treatment process, the acyl chloride reacts with ammonia water to form amide. By controlling the reaction temperature, the byproduct phosphorus oxychloride generated by the reaction of the chlorination system substrate with phosphorus oxychloride and ammonia is prevented from reacting. Subsequently, sodium hydroxide aqueous solution is added and the temperature is increased to destroy the phosphorus oxychloride.

[0030] (3) This process combines the advantages of process 1 and process 2, that is, the cyano group with strong electron-withdrawing ability is converted into amide before reduction, so that the activity of position 2 of the reduction reaction substrate is weakened, the reduction reaction selectivity is better, and good quality 4-trifluoromethylnicotinamide is obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 Example 1 Cyclization reaction tracking spectrum: 7.483min 3-cyano-2,6-dihydroxy-4-trifluoromethylpyridine, 12.607min 4,4,4-trifluoroacetoacetic acid ethyl ester.

[0032] Figure 2 Example 1 Alkaline hydrolysis reaction tracking spectrum: 2.384min is 2,6-dihydroxy-4-trifluoromethylnicotinic acid, 4.225min is 3-cyano-2,6-dihydroxy-4-trifluoromethylpyridine.

[0033] Figure 3 Example 1 Chlorination reaction tracking spectrum: 3.454min is 2,6-dihydroxy-4-trifluoromethylnicotinic acid, 26.981 is the derivative peak of 2,6-dichloro-4-trifluoromethylnicotinyl chloride.

[0034] Figure 4 Example 1 Amidation reaction tracking spectrum: 3.371min is the derivative peak of 2,6-dichloro-4-trifluoromethylnicotinyl chloride, 5.02min is 2,6-dichloro-4-trifluoromethylnicotinamide.

[0035] Figure 5 Example 1 Reduction reaction tracking spectrum: 1.394min is 4-trifluoromethylnicotinamide, 2.536min is 2-chloro-4-trifluoromethylnicotinamide.

[0036] Figure 6 Tracking spectrum of reduction reaction of Comparative Example 1: 0.529min and 0.945min are cyano reduction impurity peaks, 1.199min is 3-cyano-4-trifluoromethylpyridine peak, 2.130min is 2-chloro-3-cyano-4-trifluoromethylpyridine, and 3.351-4.480min are coupling impurity peaks.

[0037] Figure 7 Tracking spectrum of reduction reaction of Comparative Example 2: 1.388min is 4-trifluoromethylnicotinamide, 2.524min is 2-chloro-4-trifluoromethylnicotinamide, and 2.956min is 2,6-dichloro-4-trifluoromethylnicotinamide. DETAILED DESCRIPTION

[0038] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention are described clearly and completely below. 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 should fall within the scope of protection of the present invention.

[0039] Example 1

[0040] (1) 109.2 g of triethylamine and 51.4 g (0.6 mol) of cyanoacetamide were mixed, the temperature was raised to 90-92° C., 93.9 g (0.5 mol) of ethyl 4,4,4-trifluoroacetoacetate was added dropwise, and the dropping period was 5 h. After the dropping was completed, the reaction was kept warm for 4 h. The residual ethyl 4,4,4-trifluoroacetoacetate was 0.142% by high performance liquid chromatography, and the reaction was qualified.

[0041] (2) Add 350 g of a 20% sodium hydroxide aqueous solution, heat the system at normal pressure to remove and recover triethylamine, and keep the system at 95-96° C. for 12 h. Follow the HPLC method to find that the residual 3-cyano-2,6-dihydroxy-4-trifluoromethylpyridine is 0.148%. Use hydrochloric acid to adjust the pH of the system to 1.5-2, using 225 g of hydrochloric acid. Cool the system to 6° C. and filter. Dry at 70° C. for more than 8 h to constant weight. Dry to obtain 108.2 g of 2,6-dihydroxy-4-trifluoromethylnicotinic acid. The quantitative content is 98.4% by external standard method, and the yield is 95.4%.

[0042] (3) 100 g of 2,6-dihydroxy-4-trifluoromethylnicotinic acid and 500 g of phosphorus oxychloride were heated to 65° C., 94.5 g of triethylamine was added dropwise, and the temperature was continued to rise to 90-92° C. and kept for 12 h. The system gradually became clear, and the residual 2,6-dihydroxy-4-trifluoromethylnicotinic acid was detected to be 0.282%, indicating a qualified reaction.

[0043] (4) The vacuum degree was set to about -0.097 MPa, and the phosphorus oxychloride was recovered by desolventizing and dissolving to 135°C in the system. The chlorinated solution after desolventizing was added dropwise to 78.8 g of ammonia water (10% mass concentration). The ammonia water was kept at -10-0°C during the addition process. After the addition was completed, the temperature was kept at -10-0°C for 0.5 h. The residual 2,6-dichloro-4-trifluoromethylnicotinyl chloride was detected to be 1.663%. Sodium hydroxide solution (mass concentration 20%) was used to adjust the pH of the system to 8-9, and 550 g of liquid caustic soda was consumed. The pH was maintained at 20-30°C during the pH adjustment process. After the adjustment was completed, stirring was continued for 0.5 h. Filtering and drying were performed to obtain 107.8 g of 2,6-dichloro-4-trifluoromethylnicotinamide. The quantitative content was 96.8% by external standard method, and the yield was 91.4%.

[0044] (5) 100 g of 2,6-dichloro-4-trifluoromethylnicotinamide was dissolved in 400 g of methanol, 86.8 g of triethylamine and 2.0 g of palladium carbon were added, and hydrogen reduction was carried out at 25-27° C. for 4 h. The ultra-high performance liquid chromatography detected 2-chloro-4-trifluoromethylnicotinamide at 0.45%, indicating a qualified reaction.

[0045] (6) After filtration to recover palladium on carbon, 400 g of water was added, and the system was distilled to 98° C. under normal pressure, maintained for 10 min, cooled to 35° C., filtered, and the filter cake was rinsed with 100 g of water. After drying, 69.2 g of 4-trifluoromethylnicotinamide was obtained. The quantitative content was 98.2% by external standard method, and the yield was 94.6%.

[0046] Example 2

[0047] (1) 98.6 g of triethylamine and 49.3 g (0.58 mol) of cyanoacetamide were mixed, the temperature was raised to 90-92° C., and 93.9 g (0.5 mol) of ethyl 4,4,4-trifluoroacetoacetate was added dropwise for 5 h. After the addition was completed, the mixture was kept warm for 4 h. The residual ethyl 4,4,4-trifluoroacetoacetate was 0.435% by high performance liquid chromatography, indicating that the reaction was qualified.

[0048] (2) Add 350 g of a 20% sodium hydroxide aqueous solution, heat the system to 95-96° C. at normal pressure, and heat for 12 h. Follow the HPLC method to find that the residual 3-cyano-2,6-dihydroxy-4-trifluoromethylpyridine is 0.253%. Use hydrochloric acid to adjust the pH of the system to 1.5-2, using 220 g of hydrochloric acid. Cool the system to 5° C. and filter. Dry at 70° C. for more than 8 h to constant weight. Dry to obtain 106.9 g of 2,6-dihydroxy-4-trifluoromethylnicotinic acid. The quantitative content is 98.3% by external standard method, and the yield is 94.1%.

[0049] (3) 100 g of 2,6-dihydroxy-4-trifluoromethylnicotinic acid and 500 g of phosphorus oxychloride were heated to 65° C., 94.4 g of triethylamine was added dropwise, and the temperature was continued to rise to 90-92° C. and kept for 12 h. The system gradually became clear, and the residual 2,6-dihydroxy-4-trifluoromethylnicotinic acid was detected to be 0.225%, indicating a qualified reaction.

[0050] (4) The vacuum degree was set to -0.095 MPa, and the phosphorus oxychloride was recovered by desolventizing and dissolving to 132°C in the system. The chlorinated solution after desolventizing was added dropwise to 78.7 g of ammonia water (10% mass concentration). The ammonia water was kept at -10-0°C during the addition process. After the addition was completed, the temperature was kept at -10-0°C for 0.5 h. The residual 2,6-dichloro-4-trifluoromethylnicotinyl chloride was detected to be 1.540%. Sodium hydroxide solution (mass concentration 20%) was used to adjust the pH of the system to 8-9. 559 g of liquid caustic soda was consumed. The pH was maintained at 20-30°C during the pH adjustment process. After the adjustment was completed, stirring was continued for 0.5 h. Filtering and drying were performed to obtain 108.5 g of 2,6-dichloro-4-trifluoromethylnicotinamide. The quantitative content was 95.9% by external standard method, and the yield was 91.1%.

[0051] (5) 100 g of 2,6-dichloro-4-trifluoromethylnicotinamide was dissolved in 500 g of methanol, 86.8 g of triethylamine and 1.5 g of palladium carbon were added, and hydrogen reduction was carried out at 25-27° C. for 6 h. The ultra-high performance liquid chromatography detected 2-chloro-4-trifluoromethylnicotinamide at 0.65%, indicating a qualified reaction.

[0052] (6) After filtering the palladium carbon, 400 g of water was added, and the system was distilled to 98° C. under normal pressure, maintained for 10 min, cooled to 35° C., filtered, and the filter cake was rinsed with 100 g of water. After drying, 67.2 g of 4-trifluoromethylnicotinamide was obtained. The quantitative content was 97.8% by external standard method, and the yield was 92.3%.

[0053] Example 3

[0054] (1) 128.6 g of triethylamine and 51.4 g (0.6 mol) of cyanoacetamide were mixed, the temperature was raised to 90-92° C., 93.9 g (0.5 mol) of ethyl 4,4,4-trifluoroacetoacetate was added dropwise, and the dropping period was 4.5 h. After the dropping was completed, the temperature was kept for 4 h. The residual ethyl 4,4,4-trifluoroacetoacetate was 0.164% by high performance liquid chromatography, and the reaction was qualified.

[0055] (2) 467 g of a 15% sodium hydroxide aqueous solution was added, and the temperature was raised at normal pressure to desolventize and recover triethylamine. The system was kept at 95-96° C. for 12 h. The 3-cyano-2,6-dihydroxy-4-trifluoromethylpyridine remained at 0.356% by high performance liquid chromatography tracking. The pH of the system was adjusted to 1.5-2 with hydrochloric acid, consuming 231 g of hydrochloric acid. The temperature was lowered to 5° C. and filtered. The drying temperature was 70° C. and the drying time was more than 8 h to constant weight. 109 g of 2,6-dihydroxy-4-trifluoromethylnicotinic acid was obtained by drying. The quantitative content was 98.2% by external standard method and the yield was 96.0%.

[0056] (3) 100 g of 2,6-dihydroxy-4-trifluoromethylnicotinic acid and 600 g of phosphorus oxychloride were heated to 65° C., 94.5 g of triethylamine was added dropwise, and the temperature was continued to rise to 90-92° C. and kept for 12 h. The system gradually became clear, and the residual 2,6-dihydroxy-4-trifluoromethylnicotinic acid was detected to be 0.085%, indicating a qualified reaction.

[0057] (4) The vacuum degree was set to about -0.095 MPa, and the phosphorus oxychloride was recovered by desolventizing and dissolving to 138°C in the system. The chlorinated solution after desolventizing was added dropwise to 77.0 g of ammonia water (10% mass concentration). The ammonia water was kept at -10-0°C during the addition process. After the addition was completed, the temperature was kept at -10-0°C for 0.5 h. The residual 2,6-dichloro-4-trifluoromethylnicotinyl chloride was detected to be 1.826%. After the reaction was completed, sodium hydroxide solution (mass concentration 20%) was used to adjust the pH of the system to 8-9, and 570 g of liquid caustic soda was consumed. The pH was maintained at 20-30°C during the pH adjustment process. After the adjustment was completed, stirring was continued for 0.5 h. Filtering and drying were performed to obtain 106.8 g of 2,6-dichloro-4-trifluoromethylnicotinamide. The quantitative content was 97.1% by external standard method, and the yield was 90.9%.

[0058] (5) 100 g of 2,6-dichloro-4-trifluoromethylnicotinamide was dissolved in 400 g of methanol, 8.32 g of triethylamine and 2.0 g of palladium carbon were added, and hydrogen reduction was carried out at 25-27° C. for 5 h. The ultra-high performance liquid chromatography detected 0.52% of 2-chloro-4-trifluoromethylnicotinamide, indicating that the reaction was qualified.

[0059] (6) After filtering the palladium carbon, 400 g of water was added, and the system was distilled to 98° C. under normal pressure, maintained for 10 min, cooled to 35° C., filtered, and the filter cake was rinsed with 100 g of water. After drying, 68.5 g of 4-trifluoromethylnicotinamide was obtained. The quantitative content was 98.4% by external standard method, and the yield was 93.4%.

[0060] Comparative Example 1

[0061] (1) 109.2 g of triethylamine and 51.4 g (0.6 mol) of cyanoacetamide were mixed, the temperature was raised to 90-92° C., 93.9 g (0.5 mol) of ethyl 4,4,4-trifluoroacetoacetate was added dropwise, and the dropping period was 5 h. After the dropping was completed, the reaction was kept warm for 4 h. The residual ethyl 4,4,4-trifluoroacetoacetate was 0.152% by high performance liquid chromatography, and the reaction was qualified.

[0062] (2) Add 350 g of water, heat the mixture to 95.5° C. at normal pressure to remove and recover triethylamine, adjust the pH value of the mixture to 1.5-2 with hydrochloric acid, consume 18 g of hydrochloric acid, cool the mixture to 6° C., filter and dry the mixture to obtain 99.4 g of 3-cyano-2,6-dihydroxy-4-trifluoromethylpyridine. The quantitative content of the mixture was 98.5% by external standard method, and the yield was 96.0%.

[0063] (3) 95 g of 3-cyano-2,6-dihydroxy-4-trifluoromethylpyridine and 475 g of phosphorus oxychloride were heated to 65° C., 98.3 g of triethylamine was added dropwise, and the temperature was continued to rise to 90-92° C. for 12 h. The system gradually became clear, and 0.367% of 3-cyano-2,6-dihydroxy-4-trifluoromethylpyridine was detected, indicating a qualified reaction.

[0064] (4) The vacuum degree was set to about -0.097 MPa, and the phosphorus oxychloride was recovered by desolventizing and desolventizing to 135° C. The chlorinated solution after desolventizing was added dropwise to 300 g of liquid caustic soda (mass concentration 20%), and the dropping process was maintained at 20-30° C. After the dropwise addition was completed, the pH of the system was adjusted to 8-9 using liquid caustic soda (mass concentration 20%), and 87 g of liquid caustic soda was consumed. After the adjustment was completed, stirring was continued for 0.5 h, 380 g of dichloroethane was added, and the mixture was allowed to stand for 0.5 h and separated. The aqueous phase was extracted once with 190 g of dichloroethane, the dichloroethane phases were combined, and washed once with 190 g of water. After separation, the dichloroethane phase was distilled under reduced pressure to 120° C. to obtain 106.7 g of 3-cyano-2,6-dichloro-4-trifluoromethylpyridine. The quantitative content was 95.5% and the yield was 92.2% when detected by external standard method.

[0065] (5) 100 g of 3-cyano-2,6-dichloro-4-trifluoromethylpyridine was dissolved in 400 g of methanol, 91 g of triethylamine and 2.0 g of palladium carbon were added, and hydrogen reduction was carried out at 25-27° C. for 4 h. The ultra-high performance liquid chromatography detection showed that 3-cyano-2-chloro-4-trifluoromethylpyridine was 0.98%, and the reaction was qualified.

[0066] (6) After filtering the palladium carbon, the mixture was distilled at normal pressure to 98° C., and then distilled at reduced pressure to 140° C. to obtain 64.3 g of 3-cyano-4-trifluoromethylpyridine. The quantitative content was 92.7% by external standard method, and the yield was 87.5%.

[0067] (7) 60 g of 3-cyano-4-trifluoromethylpyridine and 180 g of concentrated sulfuric acid with a content of 95.0% were heated to 90° C. and kept warm for 8 h. The residual 3-cyano-4-trifluoromethylpyridine was 1.0% by high performance liquid chromatography detection. The reaction was qualified. 300 g of water was weighed and the qualified liquid was slowly added dropwise to the water. The temperature was controlled at 30-50° C. After the addition was completed, it was stirred for 0.5 h and filtered. The filter cake was washed 3 times with 300 g of water and dried to obtain 60.6 g of 4-trifluoromethylnicotinamide. The quantitative content was 94.5% by external standard method and the yield was 93.2%.

[0068] Compared with Example 1, the hydrolysis step is placed at the end. During the reduction of 3-cyano-2,6-dichloro-4-trifluoromethylpyridine, more impurities are generated, including cyano reduction impurities and coupling impurities, resulting in a low yield of the reduction reaction product. The coupling impurities, due to their structural characteristics, have a certain passivation effect on the reduction reaction catalyst. In order to avoid the generation of carboxylic acid during the hydrolysis of the cyano group, acid hydrolysis is adopted, using a concentrated sulfuric acid system, and the conditions are harsh and have safety risks.

[0069] Comparative Example 2

[0070] (1) 109.2 g of triethylamine and 51.4 g (0.6 mol) of cyanoacetamide were mixed, the temperature was raised to 90-92° C., 93.9 g (0.5 mol) of ethyl 4,4,4-trifluoroacetoacetate was added dropwise, and the dropping period was 5 h. After the dropping was completed, the temperature was kept for 4 h. The residual ethyl 4,4,4-trifluoroacetoacetate was 0.134% by high performance liquid chromatography, and the reaction was qualified.

[0071] (2) Add 350 g of water, heat the mixture to 95.5° C. at normal pressure to remove and recover triethylamine, adjust the pH value of the mixture to 1.5-2 with hydrochloric acid, consume 18.3 g of hydrochloric acid, cool the mixture to 6° C., filter and dry the mixture to obtain 100.3 g of 3-cyano-2,6-dihydroxy-4-trifluoromethylpyridine. The quantitative content of the mixture was 0.982% by external standard method, and the yield was 96.6%.

[0072] (3) 95 g of 3-cyano-2,6-dihydroxy-4-trifluoromethylpyridine and 475 g of phosphorus oxychloride were heated to 60-70° C., 98.3 g of triethylamine was added dropwise, and the temperature was continued to be raised to 90-92° C. for 12 h. The system gradually became clear, and the residual 3-cyano-2,6-dihydroxy-4-trifluoromethylpyridine was detected to be 0.258%, indicating a qualified reaction;

[0073] (4) desolventizing and recovering phosphorus oxychloride to a temperature of 130-140° C., weighing 300 g of 20% liquid caustic soda, cooling to 20-30° C., adding dropwise the desolventized chlorination solution, and after the addition, continuing to use 20% liquid caustic soda to adjust the pH of the system to 8-9, consuming 97 g of liquid caustic soda, continuing to stir for 0.5 h after the adjustment, adding 380 g of dichloroethane, stirring for 0.5 h, and then standing for separation, extracting the aqueous phase once with 190 g of dichloroethane, combining the dichloroethane phases, and washing once with 190 g of water. After separation, the dichloroethane phases were decompressed and distilled to a temperature of 120° C. to obtain 105.8 g of 3-cyano-2,6-dichloro-4-trifluoromethylpyridine, and the quantitative content was 95.3% by external standard method, and the yield was 91.2%;

[0074] (5) 100 g of 3-cyano-2,6-dichloro-4-trifluoromethylpyridine and 300 g of concentrated sulfuric acid with a content of 96.0% were heated to 90° C. and kept warm for 8 h. The residual 3-cyano-2,6-dichloro-4-trifluoromethylpyridine was detected by high performance liquid chromatography (HPLC) and 1.0% was found. The reaction was qualified. 500 g of water was weighed and the qualified liquid was slowly added dropwise to the water. The temperature was controlled at 30-50° C. After the addition was completed, the mixture was stirred for 0.5 h and filtered. The filter cake was washed 3 times with 500 g of water and dried to obtain 98.5 g of 2,6-dichloro-4-trifluoromethylnicotinamide. The quantitative content was 97.5% by external standard method and the yield was 93.6%.

[0075] (6) Add 78 g of triethylamine and 1.9 g of palladium carbon to 95 g of 2,6-dichloro-4-trifluoromethylnicotinamide and 380 g of methanol, and reduce with hydrogen at 25-27 ° C for 4 h. Ultra-high performance liquid chromatography detected 2-chloro-4-trifluoromethylnicotinamide at 0.82%, indicating a qualified reaction;

[0076] (7) After filtering the palladium carbon, 400 g of water was added, and the system was distilled to 98° C. under normal pressure, cooled to 35° C., filtered, and the filter cake was rinsed with 100 g of water. After drying, 62.5 g of 4-trifluoromethylnicotinamide was obtained. The quantitative content was 97.3% by external standard method, and the yield was 94.1%.

[0077] Compared with Example 1, the same process of first hydrolyzing the cyano group to form an amide is adopted. The difference is that acid hydrolysis is adopted and a concentrated sulfuric acid system is used. The conditions are harsh and there are safety risks. In Example 1, the cyano group is first hydrolyzed to form a carboxyl group in the later stage of the cyclization reaction, and the carboxyl group is prepared as an acyl chloride through a chlorination reaction, and then reacted with ammonia water to form an amide. The process has high safety, mild conditions, high stability, and is more suitable for industrial production.

Claims

1. A method for synthesizing 4-trifluoromethylnicotinamide, characterized in that: The process route is as follows: ； The specific steps include: (1) Mix the tertiary amine and cyanoacetamide, raise the temperature to 90-92°C, and add ethyl 4,4,4-trifluoroacetoacetate dropwise; after the addition is complete, keep the temperature for reaction for 2-4 hours; (2) adding alkali solution, heating at normal pressure to desolventize and recover the tertiary amine, to a system temperature of 95-100°C, keeping the temperature for 10-12 hours, adjusting the pH of the system to 1.5-2 with hydrochloric acid, cooling to below 10°C, filtering, and drying to obtain 2,6-dihydroxy-4-trifluoromethylnicotinic acid; (3) Heat 2,6-dihydroxy-4-trifluoromethylnicotinic acid and phosphorus oxychloride to 60-70°C, add tertiary amine dropwise, and continue to heat to 90-100°C after the addition is complete and keep the temperature for reaction for 10-12 hours; (4) Recover phosphorus oxychloride by desolventizing and dissolving to a temperature of 130-140°C in the system, cool down to about 100°C, drop the desolventized chlorinated solution into an ammonia solution, keep the ammonia solution at -10-0°C during the addition process, and continue to keep the temperature at -10-0°C for reaction after the addition is completed. The residual 2,6-dihydroxy-4-trifluoromethylnicotinyl chloride to be detected is less than 2%, adjust the pH of the system to 8-9 with alkaline solution, maintain the temperature at 20-30°C during the pH adjustment process, filter and dry to obtain 2,6-dichloro-4-trifluoromethylnicotinamide; (5) Dissolve 2,6-dichloro-4-trifluoromethylnicotinamide in methanol, add an acid-binding agent, use palladium carbon as a catalyst, and reduce with hydrogen at 25-30°C. When the residual 2-chloro-4-trifluoromethylnicotinamide is less than 1%, the reaction is qualified; (6) Filter and recover the palladium-carbon catalyst, add water and heat to distill and recover methanol, then cool and filter, wash with water, and dry to obtain 4-trifluoromethylnicotinamide.

2. The method for synthesizing 4-trifluoromethylnicotinamide according to claim 1, characterized in that: In step (1), the mass of the tertiary amine is 2-3 times that of cyanoacetamide, and the molar amount of cyanoacetamide is 1.1-1.3 times that of ethyl 4,4,4-trifluoroacetoacetate.

3. The method for synthesizing 4-trifluoromethylnicotinamide according to claim 1, characterized in that: In step (2), the alkali solution is a sodium hydroxide solution, and the molar amount of sodium hydroxide is 3-5 times that of ethyl 4,4,4-trifluoroacetoacetate.

4. The method for synthesizing 4-trifluoromethylnicotinamide according to claim 1, characterized in that: In step (3), the mass of phosphorus oxychloride is 4-6 times that of 2,6-dihydroxy-4-trifluoromethylnicotinic acid; and the molar amount of the tertiary amine added dropwise is 2-2.5 times that of 2,6-dihydroxy-4-trifluoromethylnicotinic acid.

5. The method for synthesizing 4-trifluoromethylnicotinamide according to claim 1, characterized in that: The molar amount of ammonia in step (4) is 1-1.05 times that of 2,6-dihydroxy-4-trifluoromethylnicotinic acid.

6. The method for synthesizing 4-trifluoromethylnicotinamide according to claim 1, characterized in that: In step (5), the amount of methanol used is 3-5 times the mass of 2,6-dichloro-4-trifluoromethylnicotinamide, the acid binding agent is selected from triethylamine, diisopropylethylamine, and tripropylamine, the molar amount of the acid binding agent is 2-2.5 times the mass of 2,6-dichloro-4-trifluoromethylnicotinamide, and the mass amount of palladium carbon is 1%-5% of 2,6-dichloro-4-trifluoromethylnicotinamide.

7. The method for synthesizing 4-trifluoromethylnicotinamide according to claim 1, characterized in that: In step (6), when distilling and recovering methanol, the amount of water added is 4-6 times that of 2,6-dichloro-4-trifluoromethylnicotinamide, and the methanol is distilled and recovered until the system temperature reaches 98°C.

8. The method for synthesizing 4-trifluoromethylnicotinamide according to claim 1, characterized in that: The tertiary amine in step (1) and step (3) is selected from triethylamine, diisopropylethylamine and tripropylamine.

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