Synthesis method and application of 2-chloro-4-(1h-pyrazol-3-yl)benzonitrile

Abstract

This invention relates to the field of organic synthesis technology, specifically a method for synthesizing 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile and its application, comprising the following steps: S1. Compound 1a is added to a first organic solvent under inert gas protection and reacted with vinyl isobutyl ether under the conditions of a catalyst and potassium carbonate to obtain a system containing compound 2a; S2. The pH of the system containing compound 2a obtained in step S1 is adjusted to 2-3, and after reaction, compound 1 is obtained through post-treatment; S3. Compound 1 is added to a second organic solvent, and ethyl formate and sodium ethoxide are added to react and obtain a system containing compound 4a; S4. Acetic acid is added to the system containing compound 4a obtained in step S3 for neutralization, and under inert gas protection, hydrazine hydrate is added dropwise to react and the product is obtained through post-treatment. The synthesis method provided by this invention uses readily available raw materials, has a simple processing procedure, does not require column chromatography, simplifies the operation, and facilitates industrial-scale production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically a method for synthesizing 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile and its application. Background Technology

[0002] 2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile is an important intermediate used in the production of anticancer drugs, such as the anticancer drug Darolutamide (translated as: dalolutamide, dalolutamide, or dalamidamide, etc.) or the pyrazolamide derivatives disclosed in Chinese patent document CN113861115 A (application number 202111060328.9).

[0003] The existing synthetic routes for 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile include the following:

[0004] 1) Chinese patent document CN 110590668 A (application number 201910646622.4) discloses the following synthetic route,

[0005]

[0006] 5-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole was subjected to a carbon-carbon coupling reaction with potassium carbonate and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)benzonitrile in acetonitrile and aqueous solvent under the catalysis of palladium acetate and triphenylphosphine. After the reaction was completed, ammonia was added, and the mixture was filtered and dried to obtain a second intermediate. The second intermediate was subjected to a hydrolysis protection reaction with hydrochloric acid in methanol. After the reaction was completed, ammonia was added, water was added, and the mixture was filtered. The solid was washed with water and methanol and dried to obtain the product.

[0007] This route uses 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoron-2-yl)benzonitrile, both of which are difficult to obtain and expensive, resulting in high product costs.

[0008] 2) Chinese patent document CN 111087324 A (application number 201911422567.7) discloses the following synthetic route,

[0009]

[0010] 4-Acetyl-2-chlorobenzyl nitrile and DMF·DMA were heated to 100-110℃ for 10-16 hours, water was slowly added and the mixture was stirred, filtered, recrystallized with water and methanol, filtered and dried to obtain an intermediate. The intermediate was added with ethanol, hydrazine hydrate and acetic acid and refluxed for 6-8 hours. The mixture was concentrated, neutralized with sodium hydroxide, cooled and stirred, filtered and dried to obtain the product.

[0011] This synthetic route is simpler to operate than other routes, but the market supply of the raw material 4-acetyl-2-chlorobenzyl nitrile is relatively limited and the price is expensive, resulting in high raw material costs, long reaction time, and high reaction temperature, making it unsuitable for industrial-scale production.

[0012] 3) Chinese patent document CN 116444437 A (application number 202310218479.5) discloses the following synthetic route,

[0013]

[0014] Using 4-bromo-2-chlorobenzonitrile as a raw material, it was dissolved in tetrahydrofuran and reacted with isopropyl magnesium chloride and formylpiperidine under nitrogen protection. After post-treatment, column chromatography was used to obtain the first intermediate. The first intermediate and phosphorus reagent were reacted in tetrahydrofuran and column chromatography was used to obtain the second intermediate. The second intermediate and p-methylbenzenesulfonylhydrazine were reacted in acetonitrile. After treatment with sodium hydroxide, the mixture was concentrated under reduced pressure and separated by column chromatography to obtain the product.

[0015] This route requires multiple column chromatography steps, making the operation cumbersome and difficult to scale up for industrial production. In addition, both the first and second intermediates contain aldehyde groups, which are unstable during the reaction, resulting in low product yields. The yields of the three steps are 72%, 70%, and 65%, respectively.

[0016] 4) Chinese patent document CN 116444437 A (application number 202310218479.5) also discloses the following synthetic route,

[0017]

[0018] Using 4-formaldehyde-2-chlorobenzonitrile as raw material, potassium carbonate and anhydrous methanol were added, followed by slow addition of dimethyl (1-diazo-2-oxopropyl)phosphonate and column chromatography to obtain an intermediate. The intermediate was then subjected to column chromatography with the addition of trimethylsilyl diazomethane in tetrahydrofuran to obtain the product.

[0019] This route requires multiple column chromatography steps, making the operation cumbersome and difficult. The use of trimethylsilyldiazomethane is also quite dangerous. Furthermore, because the first intermediate contains an aldehyde group, the yield of the first step reaction is only 45%, making this route unsuitable for industrial-scale production.

[0020] Therefore, there is an urgent need for a synthetic route that uses readily available raw materials and is easy to operate to prepare 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile in order to meet market demand. Summary of the Invention

[0021] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile and its application. The raw materials used in the synthesis method are readily available, and the intermediate products have good stability, which effectively ensures the product yield and facilitates industrial-scale production.

[0022] To achieve the above-mentioned technical effects, the present invention adopts the following technical solution:

[0023] A synthetic method for 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile, the synthetic route is as follows:

[0024]

[0025] The synthetic route includes the following steps:

[0026] S1. Compound 1a is added to a first organic solvent under inert gas protection and reacted with vinyl isobutyl ether under the conditions of a catalyst and potassium carbonate to give a system containing compound 2a.

[0027] S2. After adjusting the pH of the system containing compound 2a obtained in step S1 to 2-3 and reacting, compound 1 is obtained through post-treatment;

[0028] S3. Compound 1 is added to a second organic solvent, followed by the addition of ethyl formate and sodium ethoxide. The reaction yields a system containing compound 4a.

[0029] S4. After neutralizing the system containing compound 4a obtained in step S3 with acetic acid, under inert gas protection, hydrazine hydrate is added dropwise for reaction, and the product is obtained after post-treatment.

[0030] Preferably, in step S1, the ratio of compound 1a to the first organic solvent is 1g:(4-6)mL; more preferably, the first organic solvent is selected from dioxane, tetrahydrofuran or acetonitrile; more preferably, the first organic solvent is dioxane.

[0031] Preferably, in step S1, the catalyst includes a palladium catalyst and triphenylphosphine, and the palladium catalyst is selected from palladium acetate or palladium chloride; the inert gas is selected from nitrogen or argon; more preferably, the equivalent ratio of compound 1a to palladium catalyst, triphenylphosphine, potassium carbonate and vinyl isobutyl ether is 1:(0.3%-5%):(0.4%-5%):(1.1-1.4%):(1.1-1.5); more preferably, the equivalent ratio of compound 1a to palladium catalyst, triphenylphosphine, potassium carbonate and vinyl isobutyl ether is 1:(0.4%-1%):(0.5%-1%):(1.2-1.3%):(1.2-1.4); most preferably, the equivalent ratio of compound 1a to palladium catalyst, triphenylphosphine, potassium carbonate and vinyl isobutyl ether is 1:0.5%:1%:1.2:1.3.

[0032] Preferably, in step S1, the reaction temperature is 70℃-80℃ and the reaction time is 6h-10h; more preferably, the reaction temperature is 73℃-77℃ and the reaction time is 7h-9h; even more preferably, the reaction temperature is 75℃ and the reaction time is 8h. Even more preferably, after the reaction is completed, the mixture is cooled and filtered to obtain a system containing compound 2a.

[0033] Preferably, in step S2, hydrochloric acid is used to adjust the pH, the reaction temperature is 40℃-50℃, and the reaction time is 10h-14h; more preferably, the reaction temperature is 43℃-47℃, and the reaction time is 11h-13h. More preferably, the reaction temperature is 45℃, and the reaction time is 12h.

[0034] Preferably, in step S2, the post-processing method is as follows: the reaction system is concentrated under vacuum at 50℃-60℃, washed with water after adding a third organic reagent, concentrated at 40℃-50℃, and then crystallized by adding a fourth organic reagent. After filtration and drying, compound 1 is obtained. More preferably, the ratio of the third organic reagent to compound 1a is (10-30) mL:1g, and the ratio of the fourth organic reagent to compound 1a is (1-4)g:1g. The third organic reagent is selected from dichloromethane, trichloromethane, toluene, or tetrahydrofuran, and the fourth organic reagent is selected from isohexane, cyclohexane, or petroleum ether. The crystallization temperature is 0℃-5℃, and the crystallization time is 3h-7h. More preferably, the third organic reagent is dichloromethane, and the fourth organic reagent is isohexane. The crystallization temperature is 0℃-2℃, and the crystallization time is 4h-6h. Most preferably, the crystallization temperature is 0℃, and the crystallization time is 5h.

[0035] Preferably, in step S3, the ratio of compound 1 to the second organic solvent is 1 g:(4-8) mL; more preferably, the second organic solvent is selected from dioxane, tetrahydrofuran or acetonitrile; more preferably, the second organic solvent is tetrahydrofuran.

[0036] Preferably, in step S3, the equivalence ratio of compound 1 to ethyl formate and sodium ethoxide is 1:(1.1-1.4):(1.0-1.4); more preferably, the equivalence ratio of compound 1 to ethyl formate and sodium ethoxide is 1:(1.1-1.3):(1.0-1.2); and even more preferably, the equivalence ratio of compound 1 to ethyl formate and sodium ethoxide is 1:1.2:1.1.

[0037] Preferably, in step S3, the reaction temperature is 30℃-50℃ and the reaction time is 4h-6h; more preferably, the reaction temperature is 35℃-45℃ and the reaction time is 4.5h-5.5h; even more preferably, the reaction temperature is 40℃ and the reaction time is 5h.

[0038] Preferably, in step S4, the inert gas is nitrogen or argon, and the equivalence ratio of compound 4a to acetic acid and hydrazine hydrate is 1:(1.1-1.4):(1.1-1.4); more preferably, the equivalence ratio of compound 4a to acetic acid and hydrazine hydrate is 1:(1.2-1.3):(1.2-1.3); preferably, the equivalence ratio of compound 4a to acetic acid and hydrazine hydrate is 1:1.2:1.2.

[0039] Preferably, in step S4, the reaction temperature is 50℃-70℃ and the reaction time is 3h-5h; more preferably, the reaction temperature is 55℃-65℃ and the reaction time is 3.5h-4.5h; even more preferably, the reaction temperature is 60℃ and the reaction time is 4h.

[0040] Preferably, in step S4, the post-treatment specifically involves concentrating the product at 40℃-50℃, adding a third organic solvent, washing with water, washing with sodium bicarbonate solution, and washing with water again, concentrating again at 40℃-50℃, adding ethyl acetate and a fourth organic reagent for crystallization, filtering, and drying to obtain the product. More preferably, the ratio of the third organic reagent to compound 1 is (4-8) mL:1 g, and the ratio of the fourth organic reagent to compound 1 is (0.5-1.3) g:1 g. The third organic reagent is selected from dichloromethane, trichloromethane, toluene, or tetrahydrofuran, and the fourth organic reagent is selected from isohexane, cyclohexane, or petroleum ether. The crystallization temperature is 0℃-5℃, and the crystallization time is 2h-5h. Preferably, the third organic reagent is dichloromethane, the fourth organic reagent is isohexane, the crystallization temperature is 0℃-2℃, and the crystallization time is 4h-6h. Most preferably, the crystallization temperature is 0℃, and the crystallization time is 3h.

[0041] The present invention also provides 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile prepared by the above-described synthesis method.

[0042] This invention also provides the application of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile prepared by the above-described synthesis method as an intermediate in the preparation of dalolutamide.

[0043] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0044] 1. The synthesis method provided by this invention uses readily available raw materials, has a simple processing procedure, does not require chromatography, simplifies the operation, and facilitates industrial-scale production;

[0045] 2. In the synthesis method provided by the present invention, the yield of compound 1 prepared from compound 1a can reach 82%-90%, and the yield of compound 3 prepared from compound 1 can reach 81%-85%, which significantly improves the yield compared with the prior art. Attached Figure Description

[0046] Figure 1 The nuclear magnetic resonance (NMR) of 4-acetyl-2-chlorobenzyl nitrile prepared in Example 1 1 H NMR spectrum;

[0047] Figure 2 This is the liquid chromatogram of 4-acetyl-2-chlorobenzyl nitrile obtained in Example 1;

[0048] Figure 3 The nuclear magnetic resonance (NMR) of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile prepared in Example 1 1 H NMR spectrum;

[0049] Figure 4 This is a liquid chromatogram of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile prepared in Example 1. Detailed Implementation

[0050] The present invention will be further described below with reference to the embodiments and accompanying drawings.

[0051] The raw materials and experimental equipment used in each embodiment and comparative example are all commercially available raw materials and commonly used experimental equipment in the field, and their specific sources will not be repeated here.

[0052] Example 1

[0053] The synthetic route for a 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile is as follows:

[0054]

[0055] The synthetic route includes the following steps:

[0056] S1. Take 20g of compound 1a and put it into a three-necked flask containing 100mL of dioxane. Purge with nitrogen gas, add 15.3g of potassium carbonate, 0.1g of palladium acetate, 0.24g of triphenylphosphine and 12g of vinyl isobutyl ether, heat to 75℃ and react for 8h. After cooling and filtration, obtain a system containing compound 2a.

[0057] S2. The system containing compound 2a obtained in step S1 was added to 11g of 30% hydrochloric acid, the pH was adjusted to 2, and the reaction was carried out at 45°C for 12h. Then, it was concentrated under vacuum at 40°C until it became viscous. After adding 200mL of dichloromethane, it was washed twice with 100mL of water each time. The mixture was concentrated at 45°C until it became viscous. Then, 20g of isohexane was added, and the mixture was crystallized at 0°C for 5h. After filtration, it was dried at 40°C to obtain 15.1g of compound 1, with a yield of 90%.

[0058] like Figure 1 As shown, the NMR data for compound 1 are: NMR (400 MHz; CDCl3): δ 2.63 (s, 3H) 7.80 (d, 1H) 7.89 (d, 1H) 8.05 (s, 1H); Figure 2 As shown, the purity of compound 1 is 99.2%;

[0059] S3. Add 15.1g of compound 1 obtained in step S2 to 100mL of tetrahydrofuran, add 7.5g of ethyl formate, add a total of 6.3g of sodium ethoxide in 10 batches, and react at 40℃ for 5h to obtain a system containing compound 4a.

[0060] S4. After neutralizing the system containing compound 4a obtained in step S3 with 6g of acetic acid, nitrogen gas was introduced for protection. 3.2g of hydrazine hydrate was added dropwise and reacted at 60℃ for 4h. The mixture was then concentrated under vacuum at 40℃ until viscous. 200mL of dichloromethane was added, and the mixture was washed twice with 100mL of water each time. After washing with 100mL of 5% sodium bicarbonate solution, the mixture was washed once with 100mL of water. The mixture was concentrated at 50℃ until viscous. 10mL of ethyl acetate and 15mL of isohexane were added, and the mixture was crystallized at 0℃ for 3h. The mixture was filtered and dried to obtain 14.5g of compound 3, with a yield of 85%.

[0061] like Figure 3 As shown, the NMR data for compound 3 are: NMR (400 MHz; d6-DMSO): δ 6.99 (t, 1H), 7.62 (m, 1H), 7.89 (d, 2H), 8.15 (s, 1H), 13.29 (s, 1H); Figure 4 As shown, the purity of compound 3 is 99.8%.

[0062] The preparation process of Examples 2-13 is the same as that of Example 1. For specific parameter settings and yield data of Compound 1 and Compound 3, please refer to Table 1 and Table 2.

[0063] Table 1 Summary of preparation data for Compound 1

[0064]

[0065]

[0066] In Table 1, the feed amounts of potassium carbonate, palladium acetate, triphenylphosphine, and vinyl isobutyl ether are all equivalent ratios based on the equivalent of compound 1a being 1.

[0067] In Table 1, compared with Example 1, Example 2 and Example 11 show a decrease in the content of palladium acetate in the catalyst, resulting in a lower yield. This indicates that the catalyst directly affects the reaction rate and the progress of the reaction in the coupling reaction. Example 12 shows an increase in the amount of palladium acetate compared to Example 1, but the yield remains unchanged. This proves that increasing the catalyst will increase the reaction rate but has no significant impact on the yield. However, increasing the amount of catalyst will directly affect the cost of the entire process. Therefore, 0.3%-5% is selected, with 0.5% being preferred.

[0068] Compared with the reactant in Example 1, the amounts of vinyl isobutyl ether in Examples 3, 4, 9, and 10 increase the amount of reactant, leading to side reactions, while decreasing the amount of reactant results in incomplete reaction. Therefore, the equivalent ratio of vinyl isobutyl ether to compound 1a is selected as (1.1-1.5), preferably 1.3.

[0069] In Example 5, compared to Example 1, the effect of triphenylphosphine as a palladium acetate ligand in the range of 0.4%-5% was minimal.

[0070] Comparing Examples 6 and 7: Although the solvents tetrahydrofuran and acetonitrile in Example 1 can produce the product, the yield is low. Therefore, dioxane is preferred in this reaction.

[0071] Compared with Example 1, Example 8 showed a lower yield due to a slower reaction caused by a lower temperature. Compared with Example 1, Example 13 showed a lower yield due to a faster reaction caused by a higher temperature that was difficult to control. The boiling point of vinyl isobutyl ether is 83°C, and the reaction temperature is 70°C-80°C, with 75°C being the preferred reaction temperature.

[0072] Table 2 Summary of preparation data for compound 3

[0073] Group Ethyl formate Sodium ethoxide Acetic acid hydrazine hydrate S3 reaction temperature S3 reaction solvent yield Example 1 1.2 1.1 1.2 1.2 40℃ Tetrahydrofuran 85％ Example 2 1.1 1.1 1.2 1.2 40℃ Tetrahydrofuran 82％ Example 3 1.2 1.4 1.2 1.2 40℃ Tetrahydrofuran 83％ Example 4 1.2 1.1 1.2 1.4 40℃ Tetrahydrofuran 83％ Example 5 1.2 1.1 1.3 1.2 40℃ Tetrahydrofuran 84％ Example 6 1.2 1.1 1.2 1.2 40℃ Dioxane 81％ Example 7 1.2 1.1 1.2 1.2 40℃ Acetonitrile 81％ Example 8 1.2 1.1 1.2 1.2 50℃ Tetrahydrofuran 83％ Example 9 1.3 1.1 1.2 1.2 40℃ Tetrahydrofuran 82％ Example 10 1.4 1.1 1.2 1.2 40℃ Tetrahydrofuran 81％ Example 11 1.2 1.1 1.2 1.1 40℃ Tetrahydrofuran 83％ Example 12 1.2 1.1 1.2 1.3 40℃ Tetrahydrofuran 84％ Example 13 1.2 1.1 1.2 1.2 30℃ Tetrahydrofuran 81％

[0074] In Table 2, the amounts of ethyl formate, sodium ethoxide, acetic acid, and hydrazine hydrate are all equivalent ratios based on the equivalent of compound 1 being 1.

[0075] In Table 2, the amount of ethyl formate in Example 2 was reduced compared to Example 1, resulting in a lower yield; while the amount of ethyl formate in Examples 9 and 10 was increased compared to Example 1, resulting in a lower yield. This indicates that the amount of ethyl formate reactant in the condensation reaction affects the degree of reaction. Therefore, the amount of ethyl formate to be fed should be selected as 1.1-1.4, preferably 1.2.

[0076] Compared to Example 1, Example 3 uses a higher amount of sodium ethoxide. From the perspective of reaction yield, increasing the amount of sodium ethoxide leads to side reactions, while decreasing it results in incomplete reaction of the raw materials. Therefore, the amount of sodium ethoxide to be added is selected as (1.0-1.4), preferably 1.1.

[0077] In Example 4 and Example 12, the increased amount of hydrazine hydrate added compared to Example 1 led to the formation of side reactions, thus affecting the yield. In Example 11, the amount of hydrazine hydrate added was less than that in Example 1, so the yield was also lower than that in Example 1. It can be seen that the amount of hydrazine hydrate added affects the degree of reaction. Therefore, the equivalent ratio of hydrazine hydrate added was selected as (1.1-1.4), preferably 1.2.

[0078] As can be seen from Example 5 compared with Example 1, the amount of acetic acid added has little effect on the reaction.

[0079] Compared with Example 1, Examples 6 and 7 used dioxane and acetonitrile as solvents, respectively. Although products could be obtained, the yields were low. Therefore, tetrahydrofuran is preferred as the solvent for the reaction.

[0080] The reaction temperature in Example 8 was higher than that in Example 1, resulting in a slight decrease in the reaction yield of Example 8 compared to Example 1, but still within an acceptable range. In Example 13, the reaction temperature was lower than that in Example 1, the reaction was slower, and the yield was lower. Therefore, the reaction temperature in step S3 is preferably 40°C.

[0081] Example 14

[0082] This embodiment provides the application of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile obtained in any one of Examples 1 to 13 as an intermediate in the preparation of dalolutamide.

[0083] Comparative Example 1

[0084] This comparative example uses the synthetic route provided in Chinese patent document CN111087324A.

[0085]

[0086] Compound 1 (20 g) was added to a three-necked flask, followed by DMF·DMA (39.8 g). The mixture was heated to 100-110 °C and reacted for 10-16 hours. 200 g of water was slowly added and the mixture was stirred into a slurry. The slurry was filtered, and the crude product was crystallized from methanol and water. After filtration and drying, compound 222.2 g was obtained.

[0087] In a three-necked flask, 22.2 g of compound 2 was added, along with 120 ml of ethanol, 11.8 g of 80% hydrazine hydrate, and 5.7 g of acetic acid. The mixture was heated to reflux for 6-8 hours. Part of the ethanol was concentrated, and then slowly neutralized with 3% sodium hydroxide solution. After cooling, the mixture was pulped, filtered, and dried to obtain 17.5 g of compound 3. The overall yield of the two-step synthesis from compound 1 to compound 3 was 77%.

[0088] Comparative Examples 2-9

[0089] Comparative Examples 2-9 used the preparation method provided in Example 1. In Comparative Examples 2-5, the conditions for compound 1 differed from those in Example 1, while the conditions for compound 3 were the same as in Example 1. In Comparative Examples 6-9, the preparation process for compound 1 was the same as in Example 1 and is therefore not shown in Table 3. The conditions for compound 3 differed from those in Example 1. Specific feed parameters and reaction parameters are shown in Tables 3 and 4.

[0090] Table 3 Summary of preparation data for Compound 1

[0091] Group Potassium carbonate Palladium acetate Triphenylphosphine Vinyl isobutyl ether S1 reaction temperature S1 reaction solvent yield Comparative Example 2 1.2 0.5％ 1％ 1.3 50℃ Dioxane 52％ Comparative Example 3 1.2 0.5％ 1％ 1.3 75℃ DMF 35％ Comparative Example 4 0.5 0.5％ 1％ 1.3 75℃ Dioxane 37％ Comparative Example 5 1.2 0.1％ 1％ 1.3 75℃ Dioxane 60％

[0092] In Table 3, the feed amounts of potassium carbonate, palladium acetate, triphenylphosphine, and vinyl isobutyl ether are all equivalent ratios based on the equivalent of compound 1a being 1.

[0093] The reaction temperature of Comparative Example 2 was 50℃, and the reaction effect was not ideal. A large amount of raw materials did not react completely, which affected the product yield.

[0094] In Comparative Example 3, the reaction solvent was changed to DMF, but the reaction effect was not ideal, and a large number of impurities were generated, which affected the product yield and purity.

[0095] In Comparative Example 4, the amount of potassium carbonate added was 0.5, and the reaction effect was not ideal. A large amount of raw materials did not react completely, which affected the product yield and purity.

[0096] Comparative Example 5 had a palladium acetate feed amount of 0.1, but the reaction effect was not ideal, with a large amount of raw materials not reacting completely, which affected the product yield.

[0097] Table 4 Summary of preparation data for compound 3

[0098] Group Ethyl formate Sodium ethoxide Acetic acid hydrazine hydrate S3 reaction temperature S3 reaction solvent yield Comparative Example 6 1.2 1.1 1.2 0.8 40℃ Tetrahydrofuran 73％ Comparative Example 7 0.8 1.1 1.2 1.2 40℃ Tetrahydrofuran 71％ Comparative Example 8 1.2 1.1 1.2 1.2 40℃ DMF 68％ Comparative Example 9 1.2 1.1 1.2 1.2 60℃ Tetrahydrofuran 67％

[0099] In Table 4, the amounts of ethyl formate, sodium ethoxide, acetic acid, and hydrazine hydrate are all equivalent ratios based on the equivalent of compound 1 being 1.

[0100] In Comparative Example 6, the feed amount of hydrazine hydrate was 0.8, and the intermediate reaction was incomplete, resulting in a decrease in yield.

[0101] In Comparative Example 7, the amount of ethyl formate fed was 0.8, and the intermediate reaction was incomplete, resulting in a reduced yield.

[0102] Replacing the solvent in Comparative Example 8 with DMF will result in more reaction byproducts, which in turn will lead to a decrease in yield.

[0103] In Comparative Example 9, the reaction temperature was set at 60℃. Higher temperatures resulted in more reaction byproducts, which in turn led to a decrease in yield.

Claims

1. A process for the synthesis of 2-chloro-4-(lH-pyrazol-3-yl)benzonitrile, characterized in that, The synthetic route is as follows: ， The synthetic route comprises the following steps: S1. Compound 1a is put into a first organic solvent, protected by inert gas, reacted with vinyl n-butyl ether under the condition of a catalyst and potassium carbonate to obtain a system containing compound 2a; S2. The pH of the system containing compound 2a obtained in step S1 is adjusted to 2-3, reacted, and then treated to obtain compound 1; S3. Compound 1 is put into a second organic solvent, ethyl formate and sodium ethoxide are added, and reacted to obtain a system containing compound 4a, S4. After neutralization by adding acetic acid to the system containing compound 4a obtained in step S3, the system is protected by inert gas, hydrazine hydrate is added dropwise, and then treated to obtain the product; In step S3, the equivalent ratio of compound 1 to ethyl formate and sodium ethoxide is 1:(1.1-1.3):(1.0-1.2); the reaction temperature is 30-50℃, and the reaction time is 4-6h; In step S4, the equivalent ratio of compound 4a to acetic acid and hydrazine hydrate is 1:(1.1-1.4):(1.1-1.4).

2. The method of synthesis of claim 1, wherein, In step S1, the ratio of compound 1a to the first organic solvent is 1g:(4-6)mL.

3. The method of synthesis of claim 2, wherein, The first organic solvent is selected from one of dioxane, tetrahydrofuran or acetonitrile.

4. The method of synthesis of claim 3, wherein, The first organic solvent is dioxane.

5. The method of synthesis of claim 1, wherein, In step S1, the catalyst comprises a palladium catalyst and triphenylphosphine, the palladium catalyst is selected from palladium acetate or palladium chloride; the inert gas is selected from nitrogen or argon; and the equivalent ratio of compound 1a to the palladium catalyst, triphenylphosphine, potassium carbonate and vinyl n-butyl ether is 1:(0.3%-5%):(0.4%-5%):(1.1-1.4):(1.1-1.5). The reaction temperature is 70-80℃, and the reaction time is 6-10h.

6. The method of synthesis of claim 5, wherein, In step S1, the equivalent ratio of compound 1a to the palladium catalyst, triphenylphosphine, potassium carbonate and vinyl n-butyl ether is 1:(0.4%-1%):(0.5%-1%):(1.2-1.3):(1.2-1.4); the reaction temperature is 73-77℃, and the reaction time is 7-9h; after the reaction is completed, the system is filtered by cooling to obtain a system containing compound 2a.

7. The method of synthesis of claim 1, wherein, In step S2, hydrochloric acid is used to adjust the pH, and the reaction temperature is 40-50℃, and the reaction time is 10-14h.

8. The method of synthesis of claim 7, wherein, In step S2, the reaction temperature is 43-47℃, and the reaction time is 11-13h.

9. The method of synthesis of claim 1, wherein, In step S2, the specific method of the post-treatment is that the system after the reaction is concentrated under vacuum at 50-60℃, water is washed after adding a third organic reagent, concentrated at 40-50℃, a fourth organic reagent is added for crystallization, and then filtered and dried to obtain compound 1.

10. The method of synthesis of claim 9, wherein, In step S2, the ratio of the third organic reagent to compound 1a is (10-30)mL:1g, and the ratio of the fourth organic reagent to compound 1a is (1-4)g:1g; the third organic reagent is selected from one of dichloromethane, trichloromethane, toluene or tetrahydrofuran, the fourth organic reagent is selected from isohexane, cyclohexane or petroleum ether, the crystallization temperature is 0-5℃, and the crystallization time is 3-7h.

11. The method of synthesis of claim 10, wherein, The third organic reagent is dichloromethane, the fourth organic reagent is isohexane, the crystallization temperature is 0-2℃, and the crystallization time is 4-6 hours.

12. The method of synthesis of claim 1, wherein, In step S3, the ratio of compound 1 to the second organic solvent is 1g:(4-8)mL.

13. The method of synthesis of claim 12, wherein, In step S3, the second organic solvent is selected from one of dioxane, tetrahydrofuran or acetonitrile; the reaction temperature is 35-45℃, and the reaction time is 4.5-5.5 hours.

14. The method of synthesis of claim 13, wherein, The second organic solvent is tetrahydrofuran.

15. The method of synthesis of claim 1, wherein, In step S4, the inert gas is nitrogen or argon, and the equivalent ratio of compound 4a to acetic acid and hydrazine hydrate is 1:(1.2-1.3):(1.2-1.3). In step S4, the reaction temperature is 50-70℃, and the reaction time is 3-5 hours.

16. The method of synthesis of claim 15, wherein, In step S4, the reaction temperature is 55-65℃, and the reaction time is 3.5-4.5 hours.

17. The method of synthesis of claim 1, wherein, In step S4, the post-treatment is as follows: after being concentrated at 40-50℃, the third organic reagent is added, and then the mixture is sequentially washed with water, sodium bicarbonate solution and water, concentrated again at 40-50℃, and then crystallized by adding ethyl acetate and the fourth organic reagent, and the product is obtained by filtration and drying.

18. The method of synthesis of claim 17, wherein, The ratio of the third organic reagent to compound 1 is (4-8)mL:1g, the ratio of the fourth organic reagent to compound 1 is (0.5-1.3)g:1g, the third organic reagent is selected from one of dichloromethane, chloroform, toluene or tetrahydrofuran, the fourth organic reagent is selected from isohexane, cyclohexane or petroleum ether, the crystallization temperature is 0-5℃, and the crystallization time is 2-5 hours.

19. The method of synthesis of claim 18, wherein, The third organic reagent is dichloromethane, the fourth organic reagent is isohexane, the crystallization temperature is 0-2℃, and the crystallization time is 4-6 hours.

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