Synthesis method of 5-halogenated-2-methyl nicotinic acid

Abstract

The invention provides a synthetic method of a medicine intermediate 5-halogenated-2-methyl nicotinic acid. The method comprises the following steps: by taking 2-methyl-6-hydroxynicotinonitrile as a starting raw material, carrying out halogenation reaction to obtain 5-halogenated-2-methyl-6-hydroxynicotinonitrile, then carrying out chlorination reaction to obtain 5-halogenated-2-methyl-6-chloronicotinonitrile, then carrying out reductive dechlorination to obtain 5-halogenated-2-methyl nicotinonitrile, and finally, carrying out alkaline hydrolysis to obtain the target product 5-halogenated-2-methyl nicotinic acid. The synthesis method provided by the invention has the advantages of simple process route, easily available raw materials, avoidance of use of a noble metal catalyst, low production cost, mild reaction conditions in each step, easiness in purification, high product yield, high purity and better application prospect, and plays a positive role in research and development of downstream products of 5-halo-2-methyl nicotinic acid.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical intermediate synthesis, and particularly relates to a method for synthesizing 5-halo-2-methylnicotinic acid. Background Art

[0002] As an important pharmaceutical intermediate, 5-halo-2-methylnicotinic acid has a wide range of applications in the preparation of drugs and is often used to prepare a series of drugs with breakthrough therapeutic effects. For example, 5-chloro-2-methylnicotinic acid can be used to prepare c-Met kinase inhibitor (A), NMDA / NR2B antagonist (B), etc., while 5-bromo-2-methylnicotinic acid can be used to prepare active MET inhibitor (C), etc. The specific preparation routes are as follows:

[0003]

[0004]

[0005] Currently, there are relatively few reports on the direct synthesis of 5-halo-2-methylnicotinic acid in the prior art. Starting from the molecular structure, 5-halo-2-methylnicotinic acid can be obtained by hydrolysis of 5-halo-2-methylnicotinic acid methyl ester or ethyl ester, and the synthesis route is as follows:

[0006]

[0007] Therefore, in the molecular route design, these ester compounds are usually used as precursors for further processing to obtain the target product. The following will briefly introduce the related synthesis research of its precursor 5-halo-2-methylnicotinic acid ester in recent years.

[0008] In 2002, Ohkura Naoto et al. reported a method for synthesizing ethyl 5-bromo-2-methylnicotinate from nitropropanedial and ethyl aminocrotonate through three-step reactions. The specific synthesis route is as follows:

[0009]

[0010] However, the above method has certain limitations: firstly, the yield of the first cyclization reaction is relatively low, only 30%; secondly, nitropropanedial, as an explosive compound, has a high safety risk during storage and use. Therefore, the applicability of this synthesis route in large-scale industrial production is limited.

[0011] In 2005, Audoly et al. used ethyl 2,5-dichloropyridinecarboxylate and trimethylcyclotriboroxane as raw materials to react under alkaline conditions to synthesize ethyl 5-chloro-2-methylnicotinate. The specific synthesis route is as follows:

[0012]

[0013] Although the above method has relatively mild reaction conditions, it also has obvious limitations. First, the yield of the target product is relatively low, only 38%. Second, the raw materials used in this method are costly, especially the catalyst tetrakis(triphenylphosphine)palladium, whose molar mass is as high as 1155.56 g / mol, and the usage amount needs to reach 10% of the molar amount of the substrate, resulting in a large amount of catalyst used and high cost, thus significantly increasing the overall production cost. Therefore, this synthesis method is greatly limited in practical applications and has poor economic benefits.

[0014] In 2016, Zhang Guoliang et al. reported a new synthesis method for ethyl 5-chloro-2-methylnicotinate, and the specific synthesis route is as follows:

[0015]

[0016] Although the above method has mild reaction conditions and has been successfully scaled up to the kilogram level, showing certain industrialization potential. However, potassium tert-butoxide used in the process of scaling up the reaction is prone to violent reactions when encountering water or acid, causing fires and posing great safety hazards. At the same time, the stability of the raw materials required for the reaction is poor and they are prone to decomposition under strong acid, strong base and high temperature conditions. Therefore, this method is also not suitable for large-scale industrial production.

[0017] In 2017, Akira et al. used acrolein as the starting material, underwent an elimination reaction after bromination to obtain 2-bromopropenal, and further carried out a condensation reaction with ethyl 2-chloroacetoacetate to synthesize ethyl 5-bromo-2-methylnicotinate. The specific synthesis route is as follows:

[0018]

[0019] However, the final yield of the above method is only 7%. Analyzing the reasons, it may be that 2-bromopropenal is extremely prone to polymerization, and the condensation reaction has a low yield, many types of impurities and is difficult to purify. Therefore, this method is also difficult to achieve industrial scale-up production.

[0020] In 2020, Zhang et al. used the nucleophilic addition reaction of 5-bromo-1,2,3-triazine and ethyl acetoacetate to synthesize ethyl 5-bromo-2-methylnicotinate. The specific synthesis route is as follows:

[0021]

[0022] In the above method, the yield of the target product can reach 84%. However, the main limitation of this method lies in the high price of 5-bromo-1,2,3-triazine, which makes the production cost very high, thus limiting the practical application of this method in industrial production.

[0023] In summary, the current synthesis methods of 5-halo-2-methylnicotinic acid have the following problems: First, the starting materials are expensive, resulting in relatively high overall production costs; second, the process is relatively complex, and some methods have problems such as low yield, difficulty in scaling up, and purification difficulties. These factors jointly restrict the industrial production of 5-halo-2-methylnicotinic acid and are also one of the main reasons for its long-term high market price. Summary of the Invention

[0024] In view of the deficiencies of the prior art, the technical problem to be solved by the present invention is to provide a synthesis method of 5-halo-2-methylnicotinic acid with a simple process route, mild reaction conditions, low production cost, high product yield and high purity, which is convenient for industrial production.

[0025] To achieve the object of the present invention, the following technical solutions are adopted:

[0026] The present invention provides a synthesis method of 5-halo-2-methylnicotinic acid, and its synthesis route is as follows:

[0027]

[0028] Among them, X is selected from halogen;

[0029] The synthesis method includes the following steps:

[0030] 1. React 2-methyl-6-hydroxynicotinonitrile (1) with a halogenating reagent to obtain 5-halo-2-methyl-6-hydroxynicotinonitrile (2);

[0031] 2. React 5-halo-2-methyl-6-hydroxynicotinonitrile (2) with a chlorinating reagent under the action of an acid-binding agent to obtain 5-halo-2-methyl-6-chloronicotinonitrile (3);

[0032] 3. React 5-halo-2-methyl-6-chloronicotinonitrile (3) with a reducing reagent to obtain 5-halo-2-methylnicotinonitrile (4);

[0033] 4. Hydrolyze 5-halo-2-methylnicotinonitrile (4) under alkaline conditions to obtain the target compound 5-halo-2-methylnicotinic acid (5).

[0034] In one embodiment, the specific steps of Step 1 include: slowly adding 2-methyl-6-hydroxynicotinonitrile (1) into a reaction solvent. After addition, start adding an alkali salt. After addition, stir at room temperature. After all the raw materials are dissolved, start slowly adding a halogenating reagent in multiple portions. After addition, stir at room temperature. After the reactants are fully mixed, start heating up, control the reaction temperature at 25 °C to 100 °C, stir until the reaction is complete, stop heating, cool to room temperature, then pour the reaction solution into ice water, adjust the pH to 6, filter, and dry to obtain the white solid 5-halo-2-methyl-6-hydroxynicotinonitrile (2).

[0035] Preferably, in Step 1:

[0036] The reaction solvent is selected from at least one of water, tetrahydrofuran, acetonitrile, methanol, and 1,4-dioxane, and preferably water.

[0037] The alkali salt is selected from at least one of sodium hydroxide, potassium hydroxide, and lithium hydroxide, and preferably sodium hydroxide or potassium hydroxide.

[0038] The halogenating reagent is selected from at least one of dibromohydantoin, N-bromosuccinimide, dichlorohydantoin, and N-chlorosuccinimide, and preferably dibromohydantoin or dichlorohydantoin.

[0039] The molar ratio of the 2-methyl-6-hydroxynicotinonitrile (1) to the alkali salt is 1:(0.5 - 3).

[0040] The molar ratio of the 2-methyl-6-hydroxynicotinonitrile (1) to the halogenating reagent is 1:(0.2 - 5).

[0041] In one embodiment, the specific steps of Step 2 include: slowly adding 5-halo-2-methyl-6-hydroxynicotinonitrile (2) into a reaction solvent. After addition, cool the reaction solution to -20 °C to 20 °C, stir at this temperature, then add an acid-binding agent, control the temperature at -20 °C to 60 °C. After addition, stir at this temperature, then add a chlorinating reagent, control the temperature at -5 °C to 100 °C, and keep warm until the reaction is complete. After detecting the completion of the reaction by TLC, pour the reaction solution into ice water, adjust the pH to 7 with an alkali, and perform post-treatment to obtain the white solid 5-halo-2-methyl-6-chloronicotinonitrile (3).

[0042] Preferably, in Step 2:

[0043] The reaction solvent is selected from at least one of dichloroethane, tetrahydrofuran, acetonitrile, and 1,4-dioxane, and preferably dichloroethane.

[0044] The acid-binding agent is selected from at least one of triethylamine, N,N-dimethylaniline, N,N-diethylaniline, and N,N-diisopropylethylamine, and preferably N,N-diisopropylethylamine.

[0045] The chlorinating reagent is selected from at least one of phosphorus oxychloride and thionyl chloride, and preferably is phosphorus oxychloride.

[0046] The molar ratio of the 5-halo-2-methyl-6-hydroxynicotinonitrile (2) to the acid-binding agent is 1:(0.2 - 5).

[0047] The molar ratio of the 5-halo-2-methyl-6-hydroxynicotinonitrile (2) to the chlorinating reagent is 1:(1 - 9).

[0048] In one embodiment, the specific steps of step 3 include: slowly adding 5-halo-2-methyl-6-chloronicotinonitrile (3) into a reaction solvent. After adding, start adding a reducing reagent, control the temperature at -5°C to 60°C. After adding, stir. After the reactants are fully mixed, control the temperature at -20°C to 100°C, stir at this temperature until the reaction is complete, then cool the reaction solution, pour it into ice water, adjust the pH to 7, and perform post-treatment to obtain the white solid 5-halo-2-methylnicotinonitrile (4).

[0049] Preferably, in step 3:

[0050] The reaction solvent is selected from at least one of water, tetrahydrofuran, acetonitrile, methanol, ethanol, acetic acid, and 1,4-dioxane, and preferably is a mixed solvent of acetic acid and methanol.

[0051] The reducing reagent is selected from at least one of zinc powder, iron powder, and copper powder, and preferably is zinc powder.

[0052] The molar ratio of the 5-halo-2-methyl-6-chloronicotinonitrile (3) to the reducing reagent is 1:(1 - 9).

[0053] In one embodiment, the specific steps of step 4 include: slowly adding 5-halo-2-methylnicotinonitrile (4) into a reaction solvent. After adding, start adding an alkali salt, control the temperature at -5°C to 80°C. After adding, stir. After the reactants are fully mixed, control the temperature at -20°C to 120°C, stir at this temperature until the reaction is complete, then cool the reaction solution, pour it into ice water, adjust the pH to 3, and perform post-treatment to obtain the white solid, i.e., the target compound 5-halo-2-methylnicotinic acid (5).

[0054] Preferably, in step 4:

[0055] The reaction solvent is selected from at least one of water, tetrahydrofuran, acetonitrile, methanol, and 1,4-dioxane, and preferably is water.

[0056] The alkali salt is selected from at least one of sodium hydroxide, potassium hydroxide, and lithium hydroxide, and preferably is sodium hydroxide or potassium hydroxide.

[0057] The molar ratio of the 5-halo-2-methylnicotinonitrile (4) to the alkali salt is 1:(1-9).

[0058] The present invention has the following beneficial effects compared with the prior art:

[0059] The present invention provides a method for synthesizing a pharmaceutical intermediate 5-halo-2-methylnicotinic acid. The synthesis method of the present invention has a simple process route, readily available raw materials, avoids the use of precious metal catalysts, has a low production cost, and the reaction conditions of each step are mild, easy to purify, and the product has a high yield and high purity. Therefore, the method of the present invention is an economical and effective synthesis method, has good application prospects, and plays a positive role in the research and development of downstream products of 5-halo-2-methylnicotinic acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] The drawings are used to provide a further understanding of the present invention, and constitute a part of the specification, and are used to explain the present invention together with the embodiments of the present invention, and do not constitute a limitation to the present invention. In the drawings:

[0061] Figure 1 is the 1 H NMR spectrum of 5-bromo-2-methylnicotinic acid synthesized in Example 1 of the present invention;

[0062] Figure 2 is the 13 C NMR spectrum of 5-bromo-2-methylnicotinic acid synthesized in Example 1 of the present invention;

[0063] Figure 3 is the LC-MS spectrum of 5-bromo-2-methylnicotinic acid synthesized in Example 1 of the present invention;

[0064] Figure 4 is the 1 H NMR spectrum of 5-chloro-2-methylnicotinic acid synthesized in Example 2 of the present invention;

[0065] Figure 5 is the 13 C NMR spectrum of 5-chloro-2-methylnicotinic acid synthesized in Example 2 of the present invention;

[0066] Figure 6 is the LC-MS spectrum of 5-chloro-2-methylnicotinic acid synthesized in Example 2 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0067] The embodiments of the present invention will be described in detail below. The examples are given to better illustrate the content of the present invention and are only used to explain the present invention, and should not be construed as a limitation to the present invention.

[0068] For those without specific technologies or conditions noted in the examples, follow the technologies or conditions described in the literature in this field or the product specifications. For reagents or instruments without the manufacturer noted, they are all conventional products that can be obtained through regular channels.

[0069] Example 1

[0070] 1. Synthesis of 5-bromo-2-methyl-6-hydroxynicotinonitrile

[0071] In a 2 L reaction flask, add 500 mL of water. While stirring, add 2-methyl-6-hydroxynicotinonitrile (100 g, 0.745 mol). After addition, slowly add sodium hydroxide (29.8 g, 0.745 mol). After addition, stir at room temperature for 30 minutes. After all the raw materials are dissolved, slowly add dibromohydantoin (105.8 g, 0.373 mol) in multiple portions. After addition, stir at room temperature for 30 minutes. After the reactants are fully mixed, start heating to 50 °C and hold the reaction at this temperature with stirring until the reaction is complete. After detecting the completion of the reaction by TLC, cool the reaction mixture to room temperature, then pour it into ice water, adjust the pH to 6 with 6 N hydrochloric acid, stir to precipitate a large amount of solid, filter, wash the solid with water three times (500 mL × 3), dry, and obtain 146.9 g of white solid 5-bromo-2-methyl-6-hydroxynicotinonitrile with a yield of 92.5%.

[0072] 2. Synthesis of 5-bromo-2-methyl-6-chloronicotinonitrile

[0073] In a 2 L reaction flask, add 500 mL of dichloroethane. While stirring, add 5-bromo-2-methyl-6-hydroxynicotinonitrile (100 g, 0.469 mol). After addition, cool the reaction solution to -5 °C and stir at this temperature for 30 minutes. Then add N,N-diisopropylethylamine (60.7 g, 0.469 mol) dropwise, controlling the temperature not to exceed 0 °C. After addition, stir thoroughly at this temperature for 30 minutes, then slowly add phosphorus oxychloride (86.4 g, 0.563 mol), controlling the temperature not to exceed -2 °C. After addition, start heating to 45 °C and hold the reaction at this temperature overnight. The next day, after detecting the completion of the reaction by TLC, pour the reaction mixture into ice water, adjust the pH to 7 with saturated sodium bicarbonate aqueous solution, extract with dichloroethane three times (500 mL × 3), combine the organic phases, wash once with saturated brine (500 mL × 1), wash once with water (500 mL × 1), decolorize with activated carbon, dry with anhydrous sodium sulfate, filter, wash the filter cake with dichloroethane twice (100 mL × 2), combine the organic phases, concentrate to dryness, and obtain 99.5 g of white solid 5-bromo-2-methyl-6-chloronicotinonitrile with a yield of 91.6%.

[0074] 3. Synthesis of 5-bromo-2-methylnicotinonitrile

[0075] In a 2L reaction flask, add 100 mL of acetic acid and 500 mL of methanol. While stirring, add 5-bromo-2-methyl-6-chloronicotinonitrile (100 g, 0.535 mol). After addition, stir at room temperature. After all the raw materials are dissolved, start to slowly add zinc powder (28.3 g, 0.535 mol), control the temperature not to exceed 20 °C, stir at room temperature. After the reactants are fully mixed, start to heat up to 50 °C and keep the reaction at this temperature. After TLC detects that the reaction is complete, cool the reaction mixture to room temperature, then pour it into ice water, stir for 1 hour, adjust the pH to 7 with saturated sodium bicarbonate aqueous solution, and then extract three times with ethyl acetate (500 mL × 3). Combine the organic phases, rotary evaporate the solvent under reduced pressure. Wash the crude product three times with a mixed solvent of ethyl acetate:n-heptane = 1:10 (500 mL × 3), dry it, and obtain 82.1 g of white solid 5-bromo-2-methylnicotinonitrile, with a yield of 96.5%.

[0076] 4. Synthesis of 5-bromo-2-methylnicotinic acid

[0077] In a 2L reaction flask, add 500 mL of water. While stirring, add 5-bromo-2-methylnicotinonitrile (100 g, 0.508 mol). After addition, slowly add sodium hydroxide (30.5 g, 0.761 mol) while stirring at room temperature, control the temperature not to exceed 30 °C. After addition, stir at room temperature. After the reactants are fully mixed, start to heat up to 80 °C and keep the reaction at this temperature. After TLC detects that the reaction is complete, cool the reaction mixture to room temperature, then pour it into ice water, adjust the pH to 3 with 6N HCl, stir for 1 hour, a large amount of solid precipitates, filter, and then wash three times with a mixed solvent of ethyl acetate:n-heptane = 1:3 (500 mL × 3), dry it, and obtain 104.0 g of white solid 5-bromo-2-methylnicotinic acid, with a yield of 94.9%.

[0078] 1 H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 2.63 (s, 3H), as Figure 1 shown.

[0079] 13 C NMR (101 MHz, DMSO-d6) δ 166.87 (s), 157.75 (s), 152.42 (s), 140.36 (s), 128.04 (s), 117.44 (s), 24.29 (s), as Figure 2 shown.

[0080] LC-MS (ESI): m / z calcd for C7H6BrNO2 [M + H] + : 217.9, asFigure 3 as shown

[0081] Example 2

[0082] 1. Synthesis of 5-chloro-2-methyl-6-hydroxynicotinonitrile

[0083] In a 2 L reaction flask, 500 mL of water was added. While stirring, 2-methyl-6-hydroxynicotinonitrile (100 g, 0.745 mol) was added. After addition, sodium hydroxide (29.8 g, 0.745 mol) was slowly added. After addition, the mixture was stirred at room temperature. After all the raw materials were dissolved, dichlorohydantoin (73.4 g, 0.373 mol) was slowly added. After addition, the mixture was stirred at room temperature for 30 minutes. After the reactants were fully mixed, the temperature was raised to 50 °C and the reaction was carried out under insulation at this temperature. After the reaction was completed as detected by TLC, the reaction mixture was cooled to room temperature, then poured into ice water, and the pH was adjusted to 6 with 6N hydrochloric acid. A large amount of solid was precipitated by stirring, filtered, washed three times with water (500 mL × 3), and dried to obtain 120.3 g of white solid 5-chloro-2-methyl-6-hydroxynicotinonitrile, with a yield of 95.7%.

[0084] 2. Synthesis of 5,6-dichloro-2-methylnicotinonitrile

[0085] In a 2 L reaction flask, 500 mL of dichloroethane was added. While stirring, 5-chloro-2-methyl-6-hydroxynicotinonitrile (100 g, 0.593 mol) was added. After addition, the reaction solution was cooled to -5 °C and stirred at this temperature for 30 minutes. Then N,N-diisopropylethylamine (76.7 g, 0.593 moL) was added dropwise, controlling the temperature not to exceed 0 °C. After addition, the mixture was stirred at this temperature for 30 minutes. Then phosphorus oxychloride (109.1 g, 0.712 mol) was slowly added, controlling the temperature not to exceed -2 °C. After addition, the temperature was raised to 45 °C and the reaction was carried out under insulation overnight. The next day, after the reaction was completed as detected by TLC, the reaction mixture was poured into ice water, the pH was adjusted to 7 with saturated sodium bicarbonate aqueous solution, and extracted three times with dichloroethane (500 mL × 3). The organic phases were combined, washed once with saturated brine (500 mL × 1) and once with water (500 mL × 1), decolorized with activated carbon, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed twice with dichloroethane (100 mL × 2). The organic phases were combined and concentrated to dryness to obtain 105.6 g of white solid 5,6-dichloro-2-methylnicotinonitrile, with a yield of 95.2%.

[0086] 3. Synthesis of 5-chloro-2-methylnicotinonitrile

[0087] In a 2 L reaction flask, add 100 mL of acetic acid and 500 mL of methanol. While stirring, add 5,6-dichloro-2-methylnicotinonitrile (100 g, 0.535 mol). After addition, stir at room temperature. Once all the raw materials are dissolved, slowly add zinc powder (35.0 g, 0.535 mol), controlling the temperature not to exceed 20 °C. Stir at room temperature for 30 minutes. After the reactants are fully mixed, start heating to 50 °C and hold the reaction at this temperature. After TLC detects that the reaction is complete, cool the reaction mixture to room temperature, then pour it into ice water, stir for 1 hour, adjust the pH to 7 with saturated sodium bicarbonate aqueous solution, extract three times with ethyl acetate (500 mL × 3), combine the organic phases, rotary evaporate the solvent under reduced pressure, wash the crude product three times with a mixed solvent of ethyl acetate:n-heptane = 1:10 (500 mL × 3), and dry to obtain 79.5 g of white solid 5-chloro-2-methylnicotinonitrile with a yield of 97.5%.

[0088] 4. Synthesis of 5-chloro-2-methylnicotinic acid

[0089] In a 2 L reaction flask, add 500 mL of water. While stirring, add 5-chloro-2-methylnicotinonitrile (100 g, 0.655 mol). After addition, slowly add sodium hydroxide (39.3 g, 0.983 mol) while stirring at room temperature, controlling the temperature not to exceed 30 °C. Stir at room temperature. After the reactants are fully mixed, start heating to 80 °C and hold the reaction at this temperature, stirring until the reaction is complete. After TLC detects that the reaction is complete, cool the reaction mixture to room temperature, then pour it into ice water, adjust the pH to 3 with 6N HCl, stir for 1 hour, a large amount of solid precipitates, filter, and then wash three times with a mixed solvent of ethyl acetate:n-heptane = 1:3 (500 mL × 3), and dry to obtain 109.2 g of white solid 5-chloro-2-methylnicotinic acid with a yield of 97.1%.

[0090] 1 H NMR (400 MHz, DMSO-d6) δ 13.52 (s, 1H), 8.57 (s, 1H), 8.10 (s, 1H), 2.64 (s, 3H), as Figure 4 shown

[0091] 13 C NMR (101 MHz, DMSO-d6) δ 166.88 (s), 157.49 (s), 150.16 (s), 137.58 (s), 128.72 (s), 127.54 (s), 24.22 (s), as Figure 5 shown.

[0092] LC-MS (ESI): m / z calcd for C7H6ClNO2 [M + H] + : 172.0, as Figure 6as shown

[0093] Obviously, the above embodiments are only examples given to clearly illustrate the present invention, and are not intended to limit the implementation manners of the present invention. Those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and its equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims

1. A method for synthesizing 5-halo-2-methylnicotinic acid, characterized in that, The synthetic route is as follows: Wherein, X is selected from halogen; The synthetic method comprises the following steps:

1. React 2-methyl-6-hydroxynicotinonitrile (1) with a halogenating reagent to obtain 5-halo-2-methyl-6-hydroxynicotinonitrile (2); 2. React 5-halo-2-methyl-6-hydroxynicotinonitrile (2) with a chlorinating reagent under the action of a deacidifying agent to obtain 5-halo-2-methyl-6-chloronicotinonitrile (3); 3. React 5-halo-2-methyl-6-chloronicotinonitrile (3) with a reducing reagent to obtain 5-halo-2-methylnicotinonitrile (4); 4. Hydrolyze 5-halo-2-methylnicotinonitrile (4) under alkaline conditions to obtain the target compound 5-halo-2-methylnicotinic acid (5).

2. The synthesis method according to claim 1, wherein The specific steps of step 1 include: slowly adding 2-methyl-6-hydroxynicotinonitrile (1) into a reaction solvent, and after addition, starting to add an alkali salt. After addition, stir at room temperature. After all the raw materials are dissolved, slowly add the halogenating reagent in multiple portions. After addition, stir at room temperature. After the reactants are fully mixed, start to raise the temperature, control the reaction temperature at 25°C to 100°C, stir until the reaction is complete, stop heating, cool to room temperature, then pour the reaction solution into ice water, adjust the pH to 6, filter, and dry to obtain the white solid 5-halo-2-methyl-6-hydroxynicotinonitrile (2).

3. The synthesis method according to claim 1 or 2, characterized in that, In step 1, the reaction solvent is selected from at least one of water, tetrahydrofuran, acetonitrile, methanol, and 1,4-dioxane, preferably water; The alkali salt is selected from at least one of sodium hydroxide, potassium hydroxide, and lithium hydroxide, preferably sodium hydroxide or potassium hydroxide; The halogenating reagent is selected from at least one of dibromohydantoin, N-bromosuccinimide, dichlorohydantoin, and N-chlorosuccinimide, preferably dibromohydantoin or dichlorohydantoin.

4. The synthesis method according to claim 1, wherein The specific steps of step 2 include: slowly adding 5-halo-2-methyl-6-hydroxynicotinonitrile (2) into a reaction solvent, and after addition, cooling the reaction solution to -20°C to 20°C, stirring at this temperature, then adding a deacidifying agent, controlling the temperature at -20°C to 60°C. After addition, stir at this temperature, then add a chlorinating reagent, control the temperature at -5°C to 100°C, and keep warm until the reaction is complete; after TLC detects that the reaction is complete, pour the reaction solution into ice water, adjust the pH to 7 with an alkali, and perform post-treatment to obtain the white solid 5-halo-2-methyl-6-chloronicotinonitrile (3).

5. The synthesis method according to claim 1 or 4, characterized in that, In step 2, the reaction solvent is selected from at least one of dichloroethane, tetrahydrofuran, acetonitrile, and 1,4-dioxane, preferably dichloroethane; The deacidifying agent is selected from at least one of triethylamine, N,N-dimethylaniline, N,N-diethylaniline, and N,N-diisopropylethylamine, preferably N,N-diisopropylethylamine; The chlorinating reagent is selected from at least one of phosphorus oxychloride and thionyl chloride, preferably phosphorus oxychloride.

6. The synthesis method according to claim 1, characterized in that, The specific steps of Step 3 include: slowly adding 5-halo-2-methyl-6-chloronicotinonitrile (3) into a reaction solvent. After addition, start adding a reducing agent, control the temperature at -5°C to 60°C. After addition, stir. After the reactants are fully mixed, control the temperature at -20°C to 100°C and stir at this temperature until the reaction is complete. Then cool the reaction solution, pour it into ice water, adjust the pH to 7, and perform post-treatment to obtain the white solid 5-halo-2-methylnicotinonitrile (4).

7. The synthesis method according to claim 1 or 6, characterized in that, In Step 3, the reaction solvent is selected from at least one of water, tetrahydrofuran, acetonitrile, methanol, ethanol, acetic acid, 1,4-dioxane, and is preferably a mixed solvent of acetic acid and methanol; The reducing agent is selected from at least one of zinc powder, iron powder, and copper powder, and is preferably zinc powder.

8. The synthesis method according to claim 1, characterized in that The specific steps of Step 4 include: slowly adding 5-halo-2-methylnicotinonitrile (4) into a reaction solvent. After addition, start adding an alkali salt, control the temperature at -5°C to 80°C. After addition, stir. After the reactants are fully mixed, control the temperature at -20°C to 120°C and stir at this temperature until the reaction is complete. Then cool the reaction solution, pour it into ice water, adjust the pH to 3, and perform post-treatment to obtain the white solid, i.e., the target compound 5-halo-2-methylnicotinic acid (5).

9. The synthesis method according to claim 1 or 8, characterized in that, In Step 4, the reaction solvent is selected from at least one of water, tetrahydrofuran, acetonitrile, methanol, 1,4-dioxane, and is preferably water; The alkali salt is selected from at least one of sodium hydroxide, potassium hydroxide, and lithium hydroxide, and is preferably sodium hydroxide or potassium hydroxide.

10. The synthesis method according to any one of claims 1-9, characterized in that, In Step 1, the molar ratio of 2-methyl-6-hydroxynicotinonitrile (1) to the alkali salt is 1:(0.5 - 3); the molar ratio of 2-methyl-6-hydroxynicotinonitrile (1) to the halogenating agent is 1:(0.2 - 5); In Step 2, the molar ratio of 5-halo-2-methyl-6-hydroxynicotinonitrile (2) to the acid-binding agent is 1:(0.2 - 5); the molar ratio of 5-halo-2-methyl-6-hydroxynicotinonitrile (2) to the chlorinating agent is 1:(1 - 9); In Step 3, the molar ratio of 5-halo-2-methyl-6-chloronicotinonitrile (3) to the reducing agent is 1:(1 - 9); In Step 4, the molar ratio of 5-halo-2-methylnicotinonitrile (4) to the alkali salt is 1:(1 - 9).

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