Preparation method of 4-bromine-6-chloronicotinic acid methyl ester

Abstract

The invention provides a preparation method of a medical intermediate 4-bromine-6-chloronicotinic acid methyl ester. The method comprises the following steps: by taking 4, 6-dichloro methyl nicotinate as an initial raw material, reacting with alkali salt to obtain 6-chloro-4-hydroxy methyl nicotinate; and reacting the 6-chloro-4-hydroxy methyl nicotinate with a bromination reagent under the action of an acid-binding agent to obtain the target product 4-bromo-6-chloronicotinate. The preparation method provided by the invention has the advantages of short steps, easily available and cheap raw materials, mild reaction conditions in each step, easy purification and simple operation; meanwhile, the product yield is high, the purity is high, the production cost is low, industrial production is facilitated, the application prospect is good, and the method plays a positive role in research and development of a 4-bromo-6-chloronicotinic acid methyl ester downstream product.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis, and specifically relates to a method for preparing 4-bromo-6-chloronicotinic acid methyl ester. Background Art

[0002] As an important pharmaceutical intermediate, 4-bromo-6-chloronicotinate methyl ester is widely used in the preparation of drugs. For example, patent WO2022129281A1 reports that 4-bromo-6-chloronicotinate methyl ester is often used to prepare Nav1.8 inhibitor compound (II) that can treat pain and pain-related diseases, disorders and symptoms, as well as cardiovascular diseases, disorders and symptoms. The specific synthesis route is as follows:

[0003]

[0004] Patent CN19651241A reports that 4-bromo-6-chloronicotinaldehyde, a derivative of 4-bromo-6-chloronicotinic acid methyl ester, is an important intermediate for preparing FGFR4 enzyme (tyrosine kinase) selective inhibitors. FGFR4 enzyme selective inhibitors 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, bile duct cancer, colon cancer, prostate cancer, ovarian cancer and breast cancer.

[0005] At present, there are few published synthetic routes for the preparation of 4-bromo-6-chloronicotinate. The main synthetic routes are provided in CN19651241A and WO20243773A1 to prepare 4-bromo-6-chloronicotinate ethyl analogue 4-bromo-6-chloronicotinate methyl ester. This route uses 4,6-dichloronicotinate ethyl ester (III) as the starting material, slowly adds substituted benzylamine (IV) to react, and the reaction obtains compound 6-chloro-4-((4-R-benzyl)amino)nicotinate ethyl ester (V); compound (V) is then reacted with a strong acid to obtain compound 4-amino-6-chloronicotinate 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-chloronicotinate ethyl ester (VII). The specific synthetic route is as follows:

[0006]

[0007] This route has a long reaction step and a low total yield of only 43%, which greatly increases the production cost. In addition, the post-processing of this route is complex and the production cost is high.

[0008] Regarding the preparation method of 6-chloro-4-hydroxynicotinic acid methyl ester, an intermediate of 4-bromo-6-chloronicotinic acid methyl ester, there are also few disclosed synthetic routes. The main synthetic route is the method provided in WO2022253327A1 to prepare 6-chloro-4-hydroxynicotinic acid methyl ester. This route uses 6-chloro-4-methoxynicotinic acid methyl ester (VIII) as the starting material, dissolves compound (VIII) in toluene solvent, adds anhydrous aluminum chloride to react, and generates the target compound 6-chloro-4-hydroxy-nicotinic acid methyl ester (IX). The specific synthetic route is as follows:

[0009]

[0010] The yield of this route is low, only 52.3%, and the purity of the product is not high, with the purity after column passing being only 90%; the toluene and aluminum chloride required for the reaction are flammable and explosive, and the amount of aluminum chloride required is more than three times the amount of the raw material, which has a high risk factor, is difficult to operate, and has complex post-processing, which is not conducive to industrial production. Summary of the invention

[0011] In view of the deficiencies in the prior art, the technical problem to be solved by the present invention is to provide a method for preparing 4-bromo-6-chloronicotinic acid methyl ester with shorter steps, mild reaction conditions, low production cost, high product yield and high purity, and convenient for industrial production.

[0012] To achieve the purpose of the present invention, the present invention adopts the following technical solutions:

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

[0014]

[0015] Step 1:

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

[0017] Step 2:

[0018] 6-chloro-4-hydroxynicotinate methyl ester (2) is reacted with a brominating agent under the action of an acid binding agent to obtain the target product 4-bromo-6-chloronicotinate methyl ester (3).

[0019] In one embodiment, step 1 comprises: slowly adding 4,6-dichloronicotinate methyl ester (1) to an organic solvent, stirring at room temperature for a period of time after the addition is completed, adding an alkali salt after all the raw materials are dissolved, controlling the reaction temperature after the addition is completed, 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 for multiple times, concentrating, and recrystallizing to obtain a white solid 6-chloro-4-hydroxynicotinate methyl ester (2).

[0020] Preferably, in step 1:

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

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

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

[0024] The alkali 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 comprises: slowly adding 6-chloro-4-hydroxynicotinate methyl ester (2) to an organic solvent, controlling the temperature at -10 to 40°C after the addition, stirring at the temperature for a period of time, and after all the raw materials are dissolved, starting to add an acid binding agent, controlling the temperature at -10 to 50°C, and stirring at the temperature for a period of time after the addition, then adding a bromination reagent, controlling the temperature at -10 to 60°C for reaction, and after TLC detection of the completion of the reaction, pouring the reaction mixture into ice water, adjusting the pH to 7, and post-treating to obtain a white solid, namely the target product 4-bromo-6-chloronicotinate methyl ester (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 the 6-chloro-4-hydroxynicotinate methyl ester (2) to the acid-binding agent is 1:(1-7), preferably 1:(1-3).

[0030] The molar ratio of the 6-chloro-4-hydroxynicotinate methyl ester (2) to the bromination 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 bromination reagent is selected from at least one of bromine, N-bromosuccinimide, phosphorus tribromide, phosphorus oxybromide, and phosphorus pentabromide, preferably phosphorus oxybromide.

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

[0034] The present invention provides a preparation method of a pharmaceutical intermediate 4-bromo-6-chloronicotinate methyl ester. The preparation method of the present invention has short steps, its raw materials are easily available and inexpensive, the reaction conditions of each step are mild, it is easy to purify, and the operation is simple; at the same time, the product yield is high, the purity is high, and the production cost is low. Therefore, the method of the present invention is an economical and effective preparation method, has a good application prospect, and plays a positive role in the research and development of downstream products of 4-bromo-6-chloronicotinate methyl ester. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The accompanying drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation of the present invention. In the accompanying drawings:

[0036] Figure 1 LC-MS spectrum of 6-chloro-4-hydroxynicotinate methyl ester prepared in Example 1 of the present invention;

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

[0038] Figure 3 The GC-MS spectrum of methyl 4-bromo-6-chloronicotinate prepared in Example 1 of the present invention;

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

[0040] Figure 5 The GC-MS spectrum of methyl 4-bromo-6-chloronicotinate prepared in Example 2 of the present invention;

[0041] Figure 6 This is the GC-MS spectrum of methyl 4-bromo-6-chloronicotinate prepared in Example 3 of the present invention. DETAILED DESCRIPTION

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

[0043] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0044] Example 1

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

[0046] In a 2L reaction bottle, add 500mL of methanol solvent, add 4,6-dichloronicotinate methyl ester (100g, 0.485mol) under stirring, after addition, stir at room temperature for 30 minutes, after all the raw materials are dissolved, slowly add sodium acetate (99.5g, 1.21mol), after addition, start to heat to 55℃, keep the temperature at this temperature for 5 hours, after TLC detection reaction is complete, cool the reaction mixture to room temperature, then pour into ice water, stir for 1 hour, slowly add dilute hydrochloric acid, adjust pH to 5-6, and stir for 30 minutes. The mixture was stirred for 30 minutes, and the aqueous phase was extracted with dichloromethane three times (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 rinsed 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 obtain 82.4 g of white solid 6-chloro-4-hydroxynicotinate methyl ester with a yield of 90.5% and a purity of 100% (LC-MS purity, as shown in FIG. 5 ). Figure 1 shown), 1 H NMR spectrum Figure 2 shown.

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

[0048] In a 2L reaction bottle, add 500mL of dichloromethane solvent, add 6-chloro-4-hydroxynicotinate methyl ester (100g, 0.533mol) under stirring, after the addition is completed, cool the reaction solution to -5℃, stir at this temperature for 30 minutes, after the raw materials are completely dissolved, start to dropwise add N,N-diisopropylethylamine (68.9g, 0.533moL), control the temperature not to exceed 0℃, after the addition is completed, stir well at this temperature for 30 minutes, then slowly add phosphorus oxybromide (152.8g, 0.533mol), control the temperature not to exceed -2℃, after the addition is completed, control the reaction temperature to -5℃~-2℃, and keep the reaction at this temperature overnight. The next day, after TLC detection of the reaction was complete, the reaction mixture was poured into ice water, adjusted to pH = 7 with saturated sodium bicarbonate aqueous solution, extracted three times with dichloromethane (500mL×3), the organic phases were combined, washed once with saturated brine (500mL×1), washed once with water (500mL×1), decolorized with activated carbon, dried over anhydrous sodium sulfate, filtered, the filter cake was rinsed twice with dichloromethane (100mL×2), the organic phases were combined, and concentrated to dryness to obtain 125.0 g of white solid 4-bromo-6-chloronicotinate methyl ester, with a yield of 93.6% and a purity of 100% (GC-MS purity, as Figure 3 Its NMR spectrum is shown in Figure 4 shown.

[0049] Example 2

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

[0051] In a 2L reaction bottle, add 500mL of methanol solvent, add 4,6-dichloronicotinate methyl ester (100g, 0.485mol) under stirring, after the addition is completed, stir at room temperature for 30 minutes, after the raw materials are completely dissolved, slowly add sodium acetate (99.5g, 1.21mol), after the addition is completed, start to heat to 65℃, keep the temperature at this temperature for 3 hours, after TLC detection, the reaction mixture is cooled to room temperature, then poured into ice water, stirred for 1 hour, slowly added dilute hydrochloric acid, adjusted pH = 5- 6. Stir for another 30 minutes, extract the aqueous phase with dichloromethane solvent 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, rinse the filter cake with dichloromethane twice (100 mL × 2), combine the organic phases, concentrate to dryness, and recrystallize with a mixed solvent of ethyl acetate: n-heptane = 1:5 to obtain 81.2 g of white solid 6-chloro-4-hydroxynicotinate methyl ester with a yield of 89.2%.

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

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

[0054] Example 3

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

[0056] In a 2L reaction bottle, add 500mL of methanol solvent, add 4,6-dichloronicotinate methyl ester (100g, 0.485mol) under stirring, after addition, stir at room temperature for 30 minutes, after all the raw materials are dissolved, start to add sodium acetate (120.0g, 1.46mol) in small amounts and multiple times, after addition, start to heat to 55℃, keep the temperature at this temperature for 5 hours, after TLC detection, the reaction mixture is cooled to room temperature, then poured into ice water, stirred for 1 hour, slowly added dilute hydrochloric acid, adjusted pH= 5-6, after stirring for another 30 minutes, the aqueous phase was extracted with dichloromethane three times (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, the filter cake was rinsed 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 obtain 80.1 g of 6-chloro-4-hydroxynicotinate as a white solid with a yield of 88.0%.

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

[0058] In a 2L reaction bottle, add 500mL of acetonitrile solvent, add 6-chloro-4-hydroxy-nicotinic acid methyl ester (100g, 0.533mol) with stirring, after the addition is complete, stir at room temperature for 30 minutes, after the raw materials are completely dissolved, start to dropwise add N,N-diisopropylethylamine (137.8g, 1.066mol), after the addition is complete, stir well for 30 minutes, start to add phosphorus oxybromide (305.7g, 1.066mol) in small amounts and multiple times, after the addition is complete, raise the temperature to 40°C, and keep the reaction at this temperature overnight. The next day, after TLC detected that the reaction was complete, the reaction mixture was poured into ice water, adjusted to pH = 7 with saturated sodium bicarbonate aqueous solution, extracted three times with dichloromethane (500mL×3), the organic phases were combined, washed once with saturated brine (500mL×1), washed once with water (500mL×1), decolorized with activated carbon, dried over anhydrous sodium sulfate, filtered, the filter cake was rinsed twice with dichloromethane (100mL×2), the organic phases were combined, concentrated to dryness, and recrystallized with a mixed solvent of ethyl acetate: n-heptane = 1:10 to obtain 120.5 g of white solid 4-bromo-6-chloronicotinate methyl ester, with a yield of 90.3% and a purity of 96.28% (GC-MS purity, as Figure 6 shown).

[0059] Obviously, the above embodiments are only examples for clearly explaining the present invention, and are not intended to limit the implementation methods of the present invention. Those skilled in the art may 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 their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A method for preparing methyl 4-bromo-6-chloronicotinate, characterized in that: The method comprises: Step 1: Reacting 4,6-dichloronicotinic acid methyl ester (1) with an alkali salt to obtain 6-chloro-4-hydroxynicotinic acid methyl ester (2); Step 2: 6-Chloro-4-hydroxynicotinate methyl ester (2) is reacted with a brominating agent under the action of an acid binding agent to obtain the target product 4-bromo-6-chloronicotinate methyl ester (3).

2. The preparation method according to claim 1, characterized in that: Step 1 comprises: slowly adding 4,6-dichloronicotinate methyl ester (1) to an organic solvent, stirring at room temperature for a period of time after the addition is completed, adding an alkali salt after the raw materials are completely dissolved, controlling the reaction temperature after the addition is completed, 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 for multiple times, concentrating, and recrystallizing to obtain a white solid 6-chloro-4-hydroxynicotinate methyl ester (2).

3. The preparation method according to claim 1 or 2, characterized in that: In step 1, the reaction temperature is 0 to 100°C, preferably 20 to 80°C; and / or The reaction time is 2 to 8 hours, preferably 3 to 6 hours.

4. The preparation method according to claim 1 or 2, characterized in that: In step 1, the alkali salt is selected from at least one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, sodium acetate, and potassium acetate, preferably sodium acetate.

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

6. The preparation method according to claim 1 or 2, characterized in that: In step 1, the molar ratio of 4,6-dichloronicotinic acid methyl ester to the alkali salt is 1:(1-9), preferably 1:(1-4).

7. The preparation method according to claim 1, characterized in that: Step 2 comprises: slowly adding 6-chloro-4-hydroxynicotinate methyl ester (2) to an organic solvent, controlling the temperature at -10 to 40°C after the addition, stirring at the temperature for a period of time, adding an acid binding agent after all the raw materials are dissolved, controlling the temperature at -10 to 50°C, stirring at the temperature for a period of time after the addition, then adding a bromination reagent, controlling the temperature at -10 to 60°C for reaction, and after TLC detection of the completion of the reaction, pouring the reaction mixture into ice water, adjusting the pH to 7, and post-treating to obtain a white solid, namely the target product 4-bromo-6-chloronicotinate methyl ester (3).

8. The preparation method according to claim 1 or 7, characterized in that: In step 2, 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; and / or The bromination reagent is selected from at least one of bromine, N-bromosuccinimide, phosphorus tribromide, phosphorus oxybromide, and phosphorus pentabromide, preferably phosphorus oxybromide; and / or The organic solvent is selected from at least one of dichloromethane, tetrahydrofuran, acetonitrile, methanol, 1,4-dioxane, DMF, and DMSO, preferably dichloromethane or acetonitrile.

9. The preparation method according to claim 1 or 7, characterized in that: In step 2, the molar ratio of the 6-chloro-4-hydroxynicotinate (2) to the acid-binding agent is 1:(1-7), preferably 1:(1-3); and / or The molar ratio of the 6-chloro-4-hydroxynicotinate methyl ester (2) to the bromination reagent is 1:(1-7), preferably 1:(1-3).

Images