A process for the preparation of 4-bromo-6-chloronicotinic acid methyl ester

Abstract

The application provides a preparation method of a medical intermediate 4-bromo-6-chloronicotinic acid methyl ester. The method takes 4,6-dichloronicotinic acid methyl ester as a starting material, reacts with an alkali salt to obtain 6-chloro-4-hydroxynicotinic acid methyl ester; then the 6-chloro-4-hydroxynicotinic acid methyl ester reacts with a bromination reagent under the action of an acid binding agent to obtain the target product 4-bromo-6-chloronicotinic acid methyl ester. The preparation method has short steps, the raw material is easy to obtain and low in price, the reaction conditions are mild, easy to purify, and simple to operate; meanwhile, the product has high yield, high purity, low production cost, is convenient for industrialized production, has a good application prospect, and plays a positive role in the research and development of downstream products of 4-bromo-6-chloronicotinic acid methyl ester.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a method for preparing methyl 4-bromo-6-chloronicotinic acid. Background Technology

[0002] 4-Bromo-6-chloronicotinic acid methyl ester is an important pharmaceutical intermediate with wide applications in drug preparation. For example, patent WO2022129281A1 reports that 4-bromo-6-chloronicotinic acid methyl ester is commonly used to prepare Nav1.8 inhibitor compounds (II) that can treat pain and pain-related diseases, disorders and symptoms, as well as cardiovascular diseases, disorders and symptoms. The specific synthetic route is shown below:

[0003]

[0004] Patent CN19651241A reports that 4-bromo-6-chloronicotinic acid methyl ester derivative 4-bromo-6-chloronicotinic acid aldehyde is an important intermediate in the preparation of selective inhibitors of FGFR4 enzyme (tyrosine kinase). Selective inhibitors of FGFR4 enzyme can be used to treat diseases caused by FGFR4 or FGF19, and have broad application prospects in the treatment of liver cancer, gastric cancer, renal cell carcinoma, sarcoma, cholangiocarcinoma, colon cancer, prostate cancer, ovarian cancer, and breast cancer.

[0005] Currently, there are few publicly disclosed synthetic routes for the preparation of 4-bromo-6-chloronicotinic acid ester. The main synthetic routes are those provided in CN19651241A and WO20243773A1, which prepare 4-bromo-6-chloronicotinic acid ethyl ester, an analogue of 4-bromo-6-chloronicotinic acid methyl ester. This route uses 4,6-dichloronicotinic acid ethyl ester (III) as the starting material, slowly adding a substituted benzylamine (IV) to react and obtain compound 6-chloro-4-((4-R-benzyl)amino)nicotinic acid ethyl ester (V); compound (V) then reacts with a strong acid to obtain compound 4-amino-6-chloronicotinic acid ethyl ester (VI); finally, compound (VI) is completely dissolved in dichloromethane and then reacted with tert-butyl nitrite and benzylethylammonium bromide to obtain the target compound 4-bromo-6-chloronicotinic acid ethyl ester (VII). The specific synthetic route is shown below:

[0006]

[0007] This route involves a long reaction process and a low overall yield of only 43%, which significantly increases production costs. Furthermore, the post-processing of this route is complex and results in high production costs.

[0008] There are relatively few publicly disclosed synthetic routes for the preparation of methyl 6-chloro-4-hydroxynicotinic acid, an intermediate of methyl 4-bromo-6-chloronicotinic acid. The main synthetic route is the one provided in WO2022253327A1. This route uses methyl 6-chloro-4-methoxynicotinic acid (VIII) as the starting material. Compound (VIII) is dissolved in toluene, and anhydrous aluminum trichloride is added to react and generate the target compound, methyl 6-chloro-4-hydroxynicotinic acid (IX). The specific synthetic route is shown below:

[0009]

[0010] The yield of this route is low, only 52.3%, and the purity of the product is also low, with a purity of only 90% after column chromatography. The toluene and aluminum trichloride required for the reaction are flammable and explosive, and the amount of aluminum trichloride required is more than three times the amount of the raw materials, resulting in a high risk factor, difficult operation, and complex post-processing, which is not conducive to industrial production. Summary of the Invention

[0011] In view of the shortcomings of the prior art, the technical problem to be solved by the present invention is to provide a method for preparing methyl 4-bromo-6-chloronicotinic acid with a shorter step, milder reaction conditions, lower production cost, higher product yield and purity, and easier industrial production.

[0012] To achieve the objectives of this invention, the following technical solution is adopted:

[0013] This invention provides a method for preparing methyl 4-bromo-6-chloronicotinate, the method comprising:

[0014]

[0015] Step 1:

[0016] 4,6-dichloronicotinic acid methyl ester (1) was reacted with an alkaline salt to obtain 6-chloro-4-hydroxynicotinic acid methyl ester (2);

[0017] Step 2:

[0018] 6-Chloro-4-hydroxynicotinic acid methyl ester (2) was reacted with a brominating agent under the action of an acid-binding agent to obtain the target product 4-bromo-6-chloronicotinic acid methyl ester (3).

[0019] In one embodiment, step 1 includes: slowly adding 4,6-dichloronicotinic acid methyl ester (1) to an organic solvent, stirring at room temperature for a period of time after the addition is complete, adding an alkaline salt after the addition is complete, controlling the reaction temperature, stirring until the reaction is complete, cooling the reaction mixture to room temperature, then pouring it into ice water, stirring, adjusting the pH to acidic, extracting with dichloromethane multiple times, and obtaining a white solid 6-chloro-4-hydroxynicotinic acid methyl ester (2) after concentration and recrystallization.

[0020] Preferably, in step 1:

[0021] The reaction temperature is 0–100°C, preferably 20–80°C, and more preferably 55°C.

[0022] The reaction time is 2 to 8 hours, preferably 3 to 6 hours.

[0023] The molar ratio of methyl 4,6-dichloronicotinic acid to the alkali salt is 1:(1-9), preferably 1:(1-4), and more preferably 1:(1-3).

[0024] The alkaline salt is selected from at least one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, sodium acetate, and potassium acetate, preferably sodium acetate.

[0025] The organic solvent is selected from at least one of dichloromethane, tetrahydrofuran, acetonitrile, methanol, 1,4-dioxane, DMF, and DMSO, preferably methanol.

[0026] In one embodiment, step 2 includes: slowly adding methyl 6-chloro-4-hydroxynicotinic acid (2) to an organic solvent. After the addition is complete, the temperature is controlled at -10 to 40°C and stirred at this temperature for a period of time. After the raw material is completely dissolved, an acid-binding agent is added and the temperature is controlled at -10 to 50°C. After the addition is complete, the mixture is stirred at this temperature for a period of time, and then a brominating agent is added and the reaction is carried out at a temperature controlled at -10 to 60°C. After the reaction is complete as detected by TLC, the reaction mixture is poured into ice water and the pH is adjusted to 7. After post-treatment, a white solid is obtained, which is the target product methyl 4-bromo-6-chloronicotinic acid (3).

[0027] Preferably, in step 2:

[0028] The organic solvent is selected from at least one of dichloromethane, tetrahydrofuran, acetonitrile, methanol, 1,4-dioxane, DMF, and DMSO, preferably dichloromethane or acetonitrile.

[0029] The molar ratio of methyl 6-chloro-4-hydroxynicotinic acid (2) to the acid-binding agent is 1:(1-7), preferably 1:(1-3).

[0030] The molar ratio of methyl 6-chloro-4-hydroxynicotinic acid (2) to the bromide reagent is 1:(1-7), preferably 1:(1-3).

[0031] The acid-binding agent is selected from at least one of triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, N,N-diethylethylamine, and N,N-diisopropylethylamine, preferably N,N-diisopropylethylamine.

[0032] The brominating agent is selected from at least one of bromine, N-bromosuccinimide, phosphorus tribromide, phosphorus tribromooxy, and phosphorus pentabromide, preferably phosphorus tribromooxy.

[0033] Compared with the prior art, the present invention has the following advantages:

[0034] This invention provides a method for preparing the pharmaceutical intermediate methyl 4-bromo-6-chloronicotinic acid. The preparation method of this invention has a short procedure, uses readily available and inexpensive raw materials, employs mild reaction conditions in each step, is easy to purify, and is simple to operate. Simultaneously, it yields high-purity products with low production costs. Therefore, this method is an economical and effective preparation method with good application prospects and plays a positive role in the research and development of downstream products of methyl 4-bromo-6-chloronicotinic acid. Attached Figure Description

[0035] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention and do not constitute a limitation thereof. In the drawings:

[0036] Figure 1 The LC-MS spectrum of methyl 6-chloro-4-hydroxynicotinic acid prepared in Example 1 of this invention;

[0037] Figure 2 6-Chloro-4-hydroxynicotinic acid methyl ester prepared in Example 1 of this invention 1 H NMR spectrum;

[0038] Figure 3 The GC-MS spectrum of methyl 4-bromo-6-chloronicotinic acid prepared in Example 1 of this invention;

[0039] Figure 4 4-Bromo-6-chloronicotinic acid methyl ester prepared in Example 1 of this invention 1 H NMR spectrum;

[0040] Figure 5 The GC-MS spectrum of methyl 4-bromo-6-chloronicotinic acid prepared in Example 2 of this invention;

[0041] Figure 6 The GC-MS spectrum of methyl 4-bromo-6-chloronicotinic acid prepared in Example 3 of this invention. Detailed Implementation

[0042] The embodiments of the present invention are described in detail below. The embodiments are provided to better illustrate the content of the present invention and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0043] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0044] Example 1

[0045] 1. Synthesis of methyl 6-chloro-4-hydroxynicotinic acid ester

[0046] In a 2L reaction flask, add 500mL of methanol solvent, and while stirring, add methyl 4,6-dichloronicotinic acid (100g, 0.485mol). After the addition is complete, stir at room temperature for 30 minutes until all the raw materials are dissolved. Then, slowly add sodium acetate (99.5g, 1.21mol). After the addition is complete, raise the temperature to 55℃ and maintain the reaction at this temperature for 5 hours. After the reaction is confirmed to be complete by TLC, cool the reaction mixture to room temperature, then pour it into ice water and stir for 1 hour. Slowly add dilute hydrochloric acid to adjust the pH to 5-6, and stir for another 30 minutes. The aqueous phase was extracted three times with dichloromethane (500 mL × 3), the organic phases were combined, washed once with saturated brine (500 mL × 1), washed once with water (500 mL × 1), decolorized with activated carbon, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed twice with dichloromethane (100 mL × 2). The organic phases were combined, concentrated to dryness, and recrystallized with a mixed solvent of ethyl acetate:n-heptane = 1:5 to give 82.4 g of white solid methyl 6-chloro-4-hydroxynicotinic acid, yield 90.5%, purity 100% (LC-MS purity, as shown). Figure 1 As shown), its 1 H NMR spectrum as follows Figure 2 As shown.

[0047] 2. Synthesis of methyl 4-bromo-6-chloronicotinate

[0048] In a 2L reaction flask, add 500mL of dichloromethane solvent and add methyl 6-chloro-4-hydroxynicotinic acid (100g, 0.533mol) with stirring. After the addition is complete, cool the reaction solution to -5℃ and stir at this temperature for 30 minutes. After the raw materials are completely dissolved, start adding N,N-diisopropylethylamine (68.9g, 0.533mol) dropwise, controlling the temperature not to exceed 0℃. After the addition is complete, stir thoroughly at this temperature for 30 minutes. Then slowly add phosphorus tribromooxyphosphorus (152.8g, 0.533mol), controlling the temperature not to exceed -2℃. After the addition is complete, control the reaction temperature at -5℃ to -2℃ and keep the reaction at this temperature overnight. The following day, after TLC detection showed the reaction was complete, the reaction mixture was poured into ice water, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and extracted three times with dichloromethane (500 mL × 3). The organic phases were combined, washed once with saturated brine (500 mL × 1), washed once with water (500 mL × 1), decolorized with activated carbon, dried with anhydrous sodium sulfate, filtered, and the filter cake was washed twice with dichloromethane (100 mL × 2). The organic phases were combined and concentrated to dryness to obtain 125.0 g of white solid methyl 4-bromo-6-chloronicotinate, yield 93.6%, purity 100% (GC-MS purity, as shown). Figure 3 As shown), its nuclear magnetic resonance spectrum is as follows. Figure 4 As shown.

[0049] Example 2

[0050] 1. Synthesis of methyl 6-chloro-4-hydroxynicotinic acid ester

[0051] In a 2L reaction flask, add 500mL of methanol solvent, and while stirring, add methyl 4,6-dichloronicotinic acid (100g, 0.485mol). After the addition is complete, stir at room temperature for 30 minutes until all the raw materials are dissolved. Then, slowly add sodium acetate (99.5g, 1.21mol). After the addition is complete, raise the temperature to 65℃ and maintain the reaction at this temperature for 3 hours. After the reaction is confirmed to be complete by TLC, cool the reaction mixture to room temperature, then pour it into ice water and stir for 1 hour. Slowly add dilute hydrochloric acid to adjust the pH to 5. 6. Stir for another 30 minutes, extract the aqueous phase three times with dichloromethane solvent (500mL×3), combine the organic phases, wash once with saturated brine (500mL×1), wash once with water (500mL×1), decolorize with activated carbon, dry with anhydrous sodium sulfate, filter, wash the filter cake twice with dichloromethane (100mL×2), combine the organic phases, concentrate to dryness, recrystallize with a mixed solvent of ethyl acetate:n-heptane = 1:5 to give 81.2g of white solid methyl 6-chloro-4-hydroxynicotinic acid, yield 89.2%.

[0052] 2. Synthesis of methyl 4-bromo-6-chloronicotinate

[0053] In a 2L reaction flask, add 500mL of dichloromethane solvent and add methyl 6-chloro-4-hydroxynicotinic acid (100g, 0.533mol) with stirring. After the addition is complete, cool the reaction solution to 0℃ and stir at this temperature for 30 minutes. After the raw materials are completely dissolved, start adding N,N-diisopropylethylamine (68.9g, 0.533mol) dropwise, controlling the temperature not to exceed 5℃. After the addition is complete, stir thoroughly at this temperature for 30 minutes. Then, slowly add phosphorus tribromooxyphosphorus (152.8g, 0.533mol) while controlling the temperature not to exceed 5℃. After the addition is complete, control the reaction temperature at 0℃~5℃ and keep the reaction at this temperature overnight. The following day, after TLC detection showed the reaction was complete, the reaction mixture was poured into ice water, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and extracted three times with dichloromethane (500 mL × 3). The organic phases were combined, washed once with saturated brine (500 mL × 1), washed once with water (500 mL × 1), decolorized with activated carbon, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed twice with dichloromethane (100 mL × 2). The organic phases were combined, concentrated to dryness, and recrystallized with a mixed solvent of ethyl acetate:n-heptane = 1:10 to give 122.0 g of white solid methyl 4-bromo-6-chloronicotinate, yield 91.4%, purity 100% (GC-MS purity, as shown). Figure 5 (As shown).

[0054] Example 3

[0055] 1. Synthesis of methyl 6-chloro-4-hydroxynicotinic acid ester

[0056] In a 2L reaction flask, add 500mL of methanol solvent, and while stirring, add methyl 4,6-dichloronicotinic acid (100g, 0.485mol). After the addition is complete, stir at room temperature for 30 minutes until all the raw materials are dissolved. Then, add sodium acetate (120.0g, 1.46mol) in small amounts several times. After the addition is complete, raise the temperature to 55℃ and maintain the reaction at this temperature for 5 hours. After the reaction is confirmed to be complete by TLC, cool the reaction mixture to room temperature, then pour it into ice water and stir for 1 hour. Slowly add dilute hydrochloric acid to adjust the pH to 0.5. 5-6. After stirring for another 30 minutes, the aqueous phase was extracted three times with dichloromethane (500 mL × 3). The organic phases were combined, washed once with saturated brine (500 mL × 1), washed once with water (500 mL × 1), decolorized with activated carbon, dried with anhydrous sodium sulfate, filtered, and the filter cake was washed twice with dichloromethane (100 mL × 2). The organic phases were combined, concentrated to dryness, and recrystallized with a mixed solvent of ethyl acetate:n-heptane = 1:5 to give 80.1 g of white solid methyl 6-chloro-4-hydroxynicotinic acid, with a yield of 88.0%.

[0057] 2. Synthesis of methyl 4-bromo-6-chloronicotinate

[0058] In a 2L reaction flask, 500mL of acetonitrile solvent was added, and methyl 6-chloro-4-hydroxy-nicotinic acid (100g, 0.533mol) was added with stirring. After the addition was complete, the mixture was stirred at room temperature for 30 minutes until all the raw materials were dissolved. Then, N,N-diisopropylethylamine (137.8g, 1.066mol) was added dropwise. After the addition was complete, the mixture was stirred thoroughly for 30 minutes. Then, phosphorus tribromooxyphosphate (305.7g, 1.066mol) was added in small amounts several times. After the addition was complete, the temperature was raised to 40℃ and the reaction was maintained at this temperature overnight. The following day, after TLC detection showed the reaction was complete, the reaction mixture was poured into ice water, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and extracted three times with dichloromethane (500 mL × 3). The organic phases were combined, washed once with saturated brine (500 mL × 1), washed once with water (500 mL × 1), decolorized with activated carbon, dried with anhydrous sodium sulfate, filtered, and the filter cake was washed twice with dichloromethane (100 mL × 2). The organic phases were combined, concentrated to dryness, and recrystallized with a mixed solvent of ethyl acetate:n-heptane = 1:10 to give 120.5 g of white solid methyl 4-bromo-6-chloronicotinate, yield 90.3%, purity 96.28% (GC-MS purity, as shown). Figure 6 (As shown).

[0059] Obviously, the above embodiments are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art can make various modifications and variations to the present invention without departing from the spirit and scope of the invention. Therefore, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention also intends to include these modifications and variations.

Claims

1. A method for preparing methyl 4-bromo-6-chloronicotinic acid, characterized in that, The method includes: ， Step 1: 4,6-dichloronicotinic acid methyl ester (1) was reacted with an alkaline salt to obtain 6-chloro-4-hydroxynicotinic acid methyl ester (2). Step 2: 6-Chloro-4-hydroxynicotinic acid methyl ester (2) was reacted with a brominating agent under the action of an acid-binding agent to obtain the target product 4-bromo-6-chloronicotinic acid methyl ester (3). In step 1, the alkaline salt is selected from at least one of potassium carbonate, sodium bicarbonate, sodium acetate, and potassium acetate; In step 1, the reaction time is 3-6 hours; In step 2, the acid-binding agent is selected from at least one of N,N-diethylethylamine and N,N-diisopropylethylamine; and / or The brominating reagent is selected from at least one of bromine, N-bromosuccinimide, phosphorus tribromide, phosphorus tribromooxyphosphorus, and phosphorus pentabromide.

2. The preparation method according to claim 1, characterized in that, Step 1 includes: slowly adding 4,6-dichloronicotinic acid methyl ester (1) to an organic solvent. After the addition is complete, stir at room temperature for a period of time. After the raw materials are completely dissolved, add an alkaline salt. After the addition is complete, control the reaction temperature and stir until the reaction is complete. Cool the reaction mixture to room temperature, then pour it into ice water, stir, adjust the pH to acidic, extract with dichloromethane multiple times, concentrate and recrystallize to obtain white solid 6-chloro-4-hydroxynicotinic acid methyl ester (2).

3. The preparation method according to claim 2, characterized in that, In step 1, the organic solvent is selected from at least one of dichloromethane, tetrahydrofuran, acetonitrile, methanol, 1,4-dioxane, and DMF.

4. The preparation method according to claim 1, characterized in that, In step 1, the reaction temperature is 0~100°C.

5. The preparation method according to claim 1, characterized in that, In step 1, the molar ratio of methyl 4,6-dichloronicotinate to the alkaline salt is 1:(1~9).

6. The preparation method according to claim 2 or 3, characterized in that, In step 1, the reaction temperature is 20~80°C; and / or The alkaline salt is sodium acetate; and / or The organic solvent is methanol; and / or The molar ratio of methyl 4,6-dichloronicotinic acid to the alkali salt is 1:(1~4).

7. The preparation method according to claim 1, characterized in that, Step 2 includes: slowly adding methyl 6-chloro-4-hydroxynicotinic acid (2) to an organic solvent. After the addition is complete, the temperature is controlled at -10~40°C. The mixture is stirred at this temperature for a period of time until all the raw materials are dissolved. Then, an acid-binding agent is added, and the temperature is controlled at -10~50°C. After the addition is complete, the mixture is stirred at this temperature for a period of time. Then, a brominating reagent is added, and the temperature is controlled at -10~60°C for the reaction. After the reaction is complete as detected by TLC, the reaction mixture is poured into ice water and the pH is adjusted to 7. After post-treatment, a white solid is obtained, which is the target product methyl 4-bromo-6-chloronicotinic acid (3).

8. The preparation method according to claim 7, characterized in that, In step 2, the organic solvent is selected from at least one of dichloromethane, tetrahydrofuran, acetonitrile, methanol, 1,4-dioxane, and DMF.

9. The preparation method according to claim 1, characterized in that, In step 2, the molar ratio of methyl 6-chloro-4-hydroxynicotinic acid (2) to the acid-binding agent is 1:(1~7); and / or The molar ratio of methyl 6-chloro-4-hydroxynicotinic acid (2) to the bromide reagent is 1:(1~7).

10. The preparation method according to claim 7 or 8, characterized in that, In step 2, the acid-binding agent is N,N-diisopropylethylamine; and / or The brominating agent is phosphorus tribromooxyphos; and / or The organic solvent is dichloromethane, acetonitrile; and / or The molar ratio of methyl 6-chloro-4-hydroxynicotinic acid (2) to the acid-binding agent is 1:(1~3); and / or The molar ratio of methyl 6-chloro-4-hydroxynicotinic acid (2) to the bromide reagent is 1:(1~3).

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