Process for the synthesis of 5-bromo-6-methylnicotinic acid

Abstract

The application discloses a synthesis method of 5-bromo-6-methylnicotinic acid. Compared with 5-bromo-6-methylnicotinic acid ethyl ester, the raw material 5-bromo-6-chloronicotinic acid methyl ester used in the method is cheaper and easier to obtain, so that the cost of industrial scale production is greatly reduced; in addition, the yield and the purity of the product are both high, the yield reaches more than 99%, and the purity of the product is close to 98%.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic chemistry, in particular to a method for synthesizing 5-bromo-6-methylnicotinic acid. BACKGROUND

[0002] 5-bromo-6-methylnicotinic acid is an intermediate for synthesizing various specific drugs. For example, it can be used as a selective inhibitor of protein kinase II for treating chronic myeloid leukemia, and its derivatives can also be used as vaccine adjuvants. In the prior art, the method for preparing 5-bromo-6-methylnicotinic acid mostly uses 5-bromo-6-methylnicotinate as a raw material. However, 5-bromo-6-methylnicotinate is expensive and has a low reaction yield, resulting in a high industrialization cost. For example, patent CN104341425B discloses a method for preparing 5-bromo-6-methylnicotinic acid. First, 5-bromo-6-methylnicotinate is dissolved in heavy water, then deuterated sodium hydroxide is added, and the mixture is reacted at 140℃ for 12 hours under nitrogen protection. After cooling to room temperature, concentrated hydrochloric acid is added to adjust the pH to be acidic, and 5-bromo-6-methylnicotinic acid is obtained by filtration. This method has a very low yield of only 43%, and heavy water and deuterated sodium hydroxide are used as raw materials, which increases the cost and makes the post-treatment complicated and unsuitable for industrial production. There is an urgent need in the field to develop a 5-bromo-6-methylnicotinic acid production process with low cost to meet the current market demand. SUMMARY

[0003] The present application aims to provide a method for synthesizing 5-bromo-6-methylnicotinic acid.

[0004] To solve the above technical problems, the present application provides, in a first aspect, a method for synthesizing 5-bromo-6-methylnicotinic acid, which comprises the following steps:

[0005] S1, contacting and reacting 5-bromo-6-chloronicotinic acid methyl ester and a compound of formula I in the presence of a base to obtain a compound of formula II; and

[0006] S2, hydrolyzing the compound of formula II in the presence of an acid to obtain 5-bromo-6-methylnicotinic acid.

[0007]

[0008] In formula I, R 1 and R 2 are each independently selected from C 1-4 alkyl.

[0009] In some preferred embodiments, the C 1-4 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; more preferably, the C 1-4 alkyl is methyl or ethyl.

[0010] In some preferred embodiments, the compound of formula I is dimethyl malonate, diethyl malonate, or dibutyl malonate; more preferably, the compound of formula I is diethyl malonate.

[0011] In some preferred embodiments, the molar ratio of the methyl 5-bromo-6-chloronicotinic acid ester to the base is 1:(1-3), for example 1:2.

[0012] In some preferred embodiments, the molar ratio of the methyl 5-bromo-6-chloronicotinic acid ester to the compound of formula I is 1:(1-5), for example 1:2 or 1:3.5.

[0013] In some preferred embodiments, in step S1, the reaction is carried out in an aprotic polar solvent.

[0014] In some preferred embodiments, in step S1, the alkali is an alkali metal carbonate; more preferably, the alkali is selected from at least one of sodium carbonate, potassium carbonate, and cesium carbonate; even more preferably, the alkali is cesium carbonate.

[0015] In some preferred embodiments, in step S1, the aprotic polar solvent is selected from at least one of dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolinone (DMI), N,N-dimethylformamide (DMF), and hexamethylphosphoric triamine (HMPA); more preferably, the aprotic polar solvent is dimethyl sulfoxide.

[0016] In some preferred embodiments, the reaction temperature in step S1 is 100-150°C.

[0017] In some preferred embodiments, in step S1, the reaction time is not less than 1 hour, preferably not less than 2 hours, for example 2-4 hours.

[0018] In some preferred embodiments, the reaction in step S1 is carried out in an inert atmosphere.

[0019] In some preferred embodiments, step S1, after reacting methyl 5-bromo-6-chloronicotinate with the compound of formula I, further includes the steps of extraction and rotary evaporation of the product. Preferably, the extractant used in the extraction step is ethyl acetate.

[0020] In some preferred embodiments, in step S2, the acid is hydrochloric acid or sulfuric acid, more preferably hydrochloric acid, and even more preferably hydrochloric acid with a mass percentage of 20-40%.

[0021] In some preferred embodiments, in step S2, the reaction temperature is 90-120°C, more preferably 100-110°C, and even more preferably 103-110°C.

[0022] In some preferred embodiments, the reaction time in step S2 is at least 1 hour, preferably 1-2 hours, for example 1.5 hours.

[0023] In some preferred embodiments, after the hydrolysis of the compound of formula II in step S2, the method further comprises the following steps in sequence: adjusting the pH of the reaction system to alkaline (preferably pH 7-8), filtering to obtain a filtrate, and adjusting the pH of the filtrate to acidic (preferably pH 3-4).

[0024] Compared with the prior art, the present application has at least the following advantages:

[0025] (1) The method provided by the present application uses 5-bromo-6-chloronicotinic acid methyl ester as raw material, which is cheaper and more readily available than 5-bromo-6-methylnicotinic acid ethyl ester, thereby greatly reducing the cost of industrial scale production.

[0026] (2) The method provided by the present application has high yield and high product purity. In some preferred embodiments, the yield is more than 99% and the product purity is close to 98%.

[0027] It should be understood that, within the scope of the present application, each of the technical features described above and in the following (e.g., in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0028] One or more embodiments are illustrated by way of example in the drawings corresponding to the present application, and these example illustrations do not constitute a limitation on the embodiments.

[0029] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of the 5-bromo-6-methylnicotinic acid product prepared according to the embodiments of the present application. DETAILED DESCRIPTION

[0030] The present inventors have developed a low-cost 5-bromo-6-methylnicotinic acid production method suitable for industrial production through extensive and in-depth research, and have significantly improved the yield and product purity through reaction condition optimization.

[0031] Synthesis method of 5-bromo-6-methylnicotinic acid

[0032] The present application relates to a synthesis method of 5-bromo-6-methylnicotinic acid, comprising steps S1 and S2.

[0033] In step S1, the following nucleophilic substitution reaction occurs:

[0034]

[0035] The compound of formula II is obtained by contacting 5-bromo-6-chloronicotinic acid methyl ester with a compound of formula I in the presence of a base.

[0036] In the above nucleophilic substitution reaction, the reactant "5-bromo-6-chloronicotinic acid methyl ester" and "5-bromo-6-chloronicotinic acid methyl ester" can be used interchangeably, and the CAS number is 78686-77-8. 5-bromo-6-chloronicotinic acid methyl ester is commercially available, and the 5-bromo-6-chloronicotinic acid methyl ester used in the present application is purchased from Shanghai Baiyi Biotechnology Co., Ltd. The reactant of formula I is a malonic acid diester nucleophile, and in formula I, R 1 and R 2 are each independently selected from C 1-4 alkyl; C 1-4 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; more preferably methyl or ethyl. In some embodiments of the present application, the compound of formula I is dimethyl malonate, diethyl malonate or dibutyl malonate. Under the same reaction conditions, the reaction yield is higher when the compound of formula I is diethyl malonate. 5-bromo-6-chloronicotinic acid methyl ester and the compound of formula I

[0037] The above nucleophilic substitution reaction must be carried out in the presence of a base, which is used as an acid-binding agent to neutralize the acid generated in the reaction, and also provides the basic atmosphere required for the nucleophilic substitution reaction. As an acid-binding agent, the base can be an organic weak base or an inorganic strong base weak acid salt. Examples of organic bases include triethylamine, DIEA or pyridine, etc. Examples of inorganic bases include sodium acetate, potassium acetate, sodium carbonate, potassium carbonate or cesium carbonate, etc. The base used in the present application is preferably an inorganic strong base weak acid salt, more preferably an alkali metal carbonate, such as at least one of sodium carbonate, potassium carbonate and cesium carbonate. In a preferred embodiment of the present application, cesium carbonate is used as the base, and the reaction yield is higher under the same conditions. The amount of base added in the above nucleophilic substitution reaction is usually excessive, and in some embodiments of the present application, the molar ratio of the reactant 5-bromo-6-chloronicotinic acid methyl ester to the base is 1:(1-3), for example 1:2.

[0038] The above-mentioned nucleophilic substitution reaction is preferably carried out in a non-protic polar solvent as a reaction medium. In the present application, the term "non-protic polar solvent" means a solvent which is both a non-protic solvent and a polar solvent, and which has extremely weak or no tendency of self-transfer of protons, and has a weak tendency of accepting protons, because the centers of gravity of positive and negative charges in the solvent molecule do not coincide (the dipole moment is not zero). Exemplary non-protic polar solvents include amides, ketones, nitrile solvents, pyridine, dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI), N,N-dimethylformamide (DMF), hexamethylphosphoric triamide (HMPA), and the like. In a preferred embodiment of the present application, the non-protic polar solvent is at least one selected from the group consisting of dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI), N,N-dimethylformamide (DMF), and hexamethylphosphoric triamide (HMPA). In a more preferred embodiment, the non-protic polar solvent is dimethyl sulfoxide or 1,3-dimethyl-2-imidazolidinone, and a higher yield can be obtained under the same conditions.

[0039] The above-mentioned nucleophilic substitution reaction is carried out in an inert atmosphere,

[0040] The temperature for the above-mentioned nucleophilic substitution reaction is not particularly limited as long as the reaction proceeds, and is preferably in the range of 100 to 150°C, for example, 110°C. The reaction time for the above-mentioned nucleophilic substitution reaction is not particularly limited as long as the reaction proceeds, and is preferably not less than 1 hour.

[0041] After the completion of the nucleophilic substitution reaction, the intermediate compound of formula II and other impurities in the reaction system can be separated by sequentially carrying out extraction and spin-drying. The specific method of extraction and spin-drying is well known to those skilled in the art, and the extraction solvent is preferably ethyl acetate.

[0042] In step S2, the hydrolysis reaction shown below is carried out:

[0043]

[0044] The compound of formula II is hydrolyzed in the presence of an acid to obtain 5-bromo-6-methylnicotinic acid.

[0045] In the above-mentioned hydrolysis reaction, the acid used is preferably an inorganic acid such as hydrochloric acid, sulfuric acid, or nitric acid. In some preferred embodiments of the present application, the acid used is hydrochloric acid, and a higher yield can be obtained under the same conditions when a hydrochloric acid having a mass percentage of 20 to 40% (for example, 36%) is used.

[0046] The reaction temperature in the above hydrolysis reaction affects the yield and purity of the reaction product. The reaction temperature in the hydrolysis reaction of the present application can be 90-120°C, preferably 100-110°C. The optimal reaction temperature in the hydrolysis reaction of the present application is 110°C, at which the reaction yield is higher under the same conditions. The reaction time in the hydrolysis reaction of the present application is not limited as long as the reaction proceeds sufficiently.

[0047] After the above hydrolysis reaction, a post-treatment step for purifying the target product is further included. The post-treatment step after the hydrolysis reaction of the present application includes a step of dissolving the product in the form of a salt in water and separating it from an organic phase and other impurities; and a step of recovering the salt of the product to the form of an acid from water; and a step of washing the precipitated product until it becomes close to neutral. When the above purification step is performed, the purity of the product can be improved to 97% or more under the same conditions. More specifically, the post-treatment steps include a step of adjusting the pH of the reaction system to be alkaline (preferably, pH 7-8), filtering the filtrate, and adjusting the pH of the filtrate to be acidic to precipitate a solid (preferably, pH 3-4); and a step of washing the solid with water until it becomes close to neutral (preferably, pH 6-7).

[0048] In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the present application will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate but not to limit the scope of the present application. The experimental methods in the following examples, for which no specific conditions are indicated, are generally performed under conventional conditions or under the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are weight percentages and weight parts. The experimental materials and reagents used in the following examples are commercially available unless otherwise specified.

[0049] Unless otherwise indicated, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It should be noted that the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the exemplary embodiments of the present application.

[0050] Example 1

[0051] 1) Preparation of Compound 1

[0052] Into a 250 ml three-necked flask, 5-bromo-6-chloromethyl acetate 10 g, DMSO 100 ml, malonic acid diethyl ester 14 g, cesium carbonate 28.8 g were added at room temperature under stirring, and the mixture was heated to 110°C under nitrogen protection for 3 h. The reaction mixture was poured into 300 ml ice water, and extracted with 70 ml EA for 3 times. The organic phase was combined and washed with 100 ml water once. The organic phase was concentrated to dryness to give a yellow liquid 14.84 g. (LC purity: 98.87%; yield: 99.37%)

[0053] 2) Preparation of compound 2

[0054] Into a 250ml flask, compound 1 17.4g, concentrated hydrochloric acid 160ml were added at room temperature, and the mixture was stirred and heated to 110°C for 1.5h. The reaction solution was cooled, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The aqueous phase was washed twice with DCM. The pH of the aqueous phase was adjusted to 3-4 with hydrochloric acid, and a solid was precipitated. The solid was filtered, washed with water until the pH was 6-7, and dried to obtain compound 2 8.27g. (LC purity: 97.93%, yield: 82.31%) Figure 1 .

[0055] Example 2

[0056] In this example, 5-bromo-6-methylnicotinic acid was prepared by substantially the same method as in Example 1, except that a different solvent was used in step (1). The specific preparation method is as follows:

[0057] 1) Preparation of compound 1

[0058] Into a 250ml flask, 5-bromo-6-chloromethyl acetate 10g, DMF 100ml were added at room temperature, and diethyl malonate 14g, cesium carbonate 28.8g were added with stirring. The mixture was heated to 110°C under nitrogen protection for 3h. The reaction solution was poured into 300ml ice water, and extracted with 70ml EA three times. The organic phase was combined, and washed with 100ml water once. The organic phase was concentrated to obtain a yellow liquid 12.03g. (LC purity: 99.03%, yield: 80.51%)

[0059] 2) Preparation of compound 2

[0060] Into a 250ml flask, compound 1 17.4g, concentrated hydrochloric acid 160ml were added at room temperature, and the mixture was stirred and heated to 110°C for 1.5h. The reaction solution was cooled, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The aqueous phase was washed twice with DCM. The pH of the aqueous phase was adjusted to 3-4 with hydrochloric acid, and a solid was precipitated. The solid was filtered, washed with water until the pH was 6-7, and dried to obtain compound 2 8.27g. (LC purity: 97.93%, yield: 82.31%)

[0061] Example 3

[0062] In this example, 5-bromo-6-methylnicotinic acid was prepared by substantially the same method as in Example 1, except that a different solvent was used in step (1). The specific preparation method is as follows:

[0063] 1) Preparation of compound 1

[0064] 250ml three-necked flask, 5-bromo-6-chloromethyl acetate 10g, DMI 100ml, diethyl malonate 14g, cesium carbonate 28.8g were added under stirring, and the mixture was heated to 110°C under nitrogen protection for 3h. The reaction solution was poured into 300ml ice water, and extracted with 70ml EA for 3 times. The organic phase was combined and washed with 100ml water for once. The organic phase was concentrated to dryness to obtain yellow liquid 14.74g. (LC purity: 99.03%; yield: 98.67%)

[0065] 2) Preparation of compound 2

[0066] 250ml three-necked flask, compound 1 17.4g, concentrated hydrochloric acid 160ml, and the mixture was heated to 110°C under stirring for 1.5h. The reaction solution was cooled, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The water phase was washed with DCM for twice. The pH of the water phase was adjusted to 3-4 with hydrochloric acid, and the solid was precipitated. The solid was filtered, and the filter cake was washed with water until the pH was 6-7. The filter cake was dried to obtain compound 2 8.23g. (LC purity: 98.77%, yield: 81.85%)

[0067] Example 4

[0068] In this example, 5-bromo-6-methylnicotinic acid was prepared by using the same method as in Example 1, except that the solvent used in step (1) was different. The specific preparation method is as follows:

[0069] 1) Preparation of compound 1

[0070] 250ml three-necked flask, 5-bromo-6-chloromethyl acetate 10g, HMPA 100ml, diethyl malonate 14g, cesium carbonate 28.8g were added under stirring, and the mixture was heated to 110°C under nitrogen protection for 3h. The reaction solution was poured into 300ml ice water, and extracted with 70ml EA for 3 times. The organic phase was combined and washed with 100ml water for once. The organic phase was concentrated to dryness to obtain yellow liquid 14.74g. (LC purity: 99.03%; yield: 98.67%)

[0071] 2) Preparation of compound 2

[0072] 250ml three-necked flask, compound 1 17.4g, concentrated hydrochloric acid 160ml, and the mixture was heated to 110°C under stirring for 1.5h. The reaction solution was cooled, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The water phase was washed with DCM for twice. The pH of the water phase was adjusted to 3-4 with hydrochloric acid, and the solid was precipitated. The solid was filtered, and the filter cake was washed with water until the pH was 6-7. The filter cake was dried to obtain compound 2 8.23g. (LC purity: 98.77%, yield: 81.85%)

[0073] Example 5

[0074] In this example, 5-bromo-6-methylnicotinic acid is prepared by substantially the same method as in Example 1, except that in step (1), a different nucleophile is used. In this example, the specific preparation method is as follows:

[0075] 1) Preparation of compound 1

[0076] Into a 250 ml three-necked flask, 5-bromo-6-chloromethyl acetate 10 g, HMPA 100 ml, dimethyl malonate 11.63 g, cesium carbonate 28.8 g were added at room temperature under stirring, and the mixture was heated to 110°C under nitrogen protection and kept for 3 h. The reaction solution was poured into 300 ml ice water, and extracted with 70 ml EA for 3 times. The organic phase was combined and washed with 100 ml water once. The organic phase was concentrated to dryness to give yellow liquid 10.52 g. (LC purity: 98.98%; yield: 70.44%)

[0077] 2) Preparation of compound 2

[0078] Into a 250 ml three-necked flask, compound 1 17.4 g, concentrated hydrochloric acid 160 ml were added at room temperature under stirring, and the mixture was heated to 110°C and kept for 1.5 h. The reaction solution was cooled, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The aqueous phase was washed with DCM twice. The pH of the aqueous phase was adjusted to 3-4 with hydrochloric acid, and a solid was precipitated. The solid was filtered, washed with water until the pH was 6-7, and dried to give compound 2 8.32 g. (LC purity: 98.58%, yield: 82.79%)

[0079] Example 6

[0080] In this example, 5-bromo-6-methylnicotinic acid is prepared by substantially the same method as in Example 1, except that in step (1), a different nucleophile is used. In this example, the specific preparation method is as follows:

[0081] 1) Preparation of compound 1

[0082] Into a 250 ml three-necked flask, 5-bromo-6-chloromethyl acetate 10 g, HMPA 100 ml, dibutyl malonate 19.03 g, cesium carbonate 28.8 g were added at room temperature under stirring, and the mixture was heated to 110°C under nitrogen protection and kept for 3 h. The reaction solution was poured into 300 ml ice water, and extracted with 70 ml EA for 3 times. The organic phase was combined and washed with 100 ml water once. The organic phase was concentrated to dryness to give yellow liquid 9.84 g. (LC purity: 99.88%; yield: 65.88%)

[0083] 2) Preparation of compound 2

[0084] 250ml three-port bottle at room temperature, add compound 1 17.4g, concentrated hydrochloric acid 160ml, stir to warm to 110°C, keep warm for 1.5h; cool down, adjust the pH of the reaction solution to 7-8 with saturated sodium bicarbonate solution; wash the aqueous phase with DCM twice; adjust the pH of the aqueous phase to 3-4 with hydrochloric acid, precipitate the solid, filter, wash the filter cake with water until the pH is 6-7, and dry to obtain compound 2 8.34g.(LC purity: 98.66%, yield: 83.00%)

[0085] Example 7

[0086] In this example, 5-bromo-6-methylnicotinic acid is prepared by using the substantially same method as in Example 1, except that a different acid-binding agent is used in step (1). The specific preparation method is as follows:

[0087] 1) Preparation of compound 1

[0088] 250ml three-port bottle at room temperature, add compound 1 17.4g, concentrated hydrochloric acid 160ml, stir to warm to 110°C, keep warm for 1.5h; cool down, adjust the pH of the reaction solution to 7-8 with saturated sodium bicarbonate solution; wash the aqueous phase with DCM twice; adjust the pH of the aqueous phase to 3-4 with hydrochloric acid, precipitate the solid, filter, wash the filter cake with water until the pH is 6-7, and dry to obtain compound 2 8.34g.(LC purity: 98.66%, yield: 83.00%)

[0089] 2) Preparation of compound 2

[0090] 250ml three-port bottle at room temperature, add compound 1 17.4g, concentrated hydrochloric acid 160ml, stir to warm to 110°C, keep warm for 1.5h; cool down, adjust the pH of the reaction solution to 7-8 with saturated sodium bicarbonate solution; wash the aqueous phase with DCM twice; adjust the pH of the aqueous phase to 3-4 with hydrochloric acid, precipitate the solid, filter, wash the filter cake with water until the pH is 6-7, and dry to obtain compound 2 8.34g.(LC purity: 98.66%, yield: 83.00%)

[0091] Example 8

[0092] In this example, 5-bromo-6-methylnicotinic acid is prepared by using the substantially same method as in Example 1, except that a different acid-binding agent is used in step (1). The specific preparation method is as follows:

[0093] 1) Preparation of compound 1

[0094] Into a 250ml flask, add compound 1 17.4g, concentrated hydrochloric acid 160ml, stir and heat to 110°C, keep for 1.5h; cool down, adjust the pH of the reaction solution to 7-8 with saturated sodium bicarbonate solution; wash the aqueous phase with DCM twice; adjust the pH of the aqueous phase to 3-4 with hydrochloric acid, precipitate the solid, filter, wash the filter cake with water until the pH is 6-7, and dry to obtain compound 2 8.26g. (LC purity: 98.78%, yield: 82.18%)

[0095] 2) Preparation of compound 2

[0096] Into a 250ml flask, add compound 1 17.4g, concentrated hydrochloric acid 160ml, stir and heat to 110°C, keep for 1.5h; cool down, adjust the pH of the reaction solution to 7-8 with saturated sodium bicarbonate solution; wash the aqueous phase with DCM twice; adjust the pH of the aqueous phase to 3-4 with hydrochloric acid, precipitate the solid, filter, wash the filter cake with water until the pH is 6-7, and dry to obtain compound 2 8.26g. (LC purity: 98.78%, yield: 82.18%)

[0097] Table 1 below shows the effect of changes in each factor on the yield of the nucleophilic substitution reaction in step (1). It can be seen that when the solvent used is DMSO / DMI, the nucleophilic reagent is diethyl malonate, and the acid binding agent is cesium carbonate, the yield is significantly improved.

[0098] Table 1

[0099] Group Solvent Nucleophile Acid scavenger Reaction yield Example 1 DMSO diethyl malonate cesium carbonate 99.37％ Example 2 DMF diethyl malonate cesium carbonate 80.51％ Example 3 DMI diethyl malonate cesium carbonate 98.67％ Example 4 HMPA diethyl malonate cesium carbonate 78.93％ Example 5 DMSO dimethyl malonate cesium carbonate 70.44％ Example 6 DMSO dibutyl malonate cesium carbonate 65.88％ Example 7 DMSO dimethyl malonate sodium carbonate 47.31％ Example 8 DMSO dimethyl malonate potassium carbonate 55.86％

[0100] The inventors found that in step (2), the solvent used, the acid concentration of the solvent, the reaction temperature and the post-reaction treatment step all have an effect on the reaction results. In the following Examples 9-14, the solvent used, the acid concentration of the solvent, the reaction temperature and the post-reaction treatment step were changed to explore their effects on the yield and purity of 5-bromo-6-methyl nicotinic acid.

[0101] Example 9

[0102] In this example, 5-bromo-6-methyl nicotinic acid was prepared using a method substantially the same as that of Example 1, except that in step (2), a different solvent was used. The specific preparation method is as follows:

[0103] 1) Preparation of compound 1

[0104] 250ml three-necked flask, compound 1 17.4g, 20%~30% hydrochloric acid 200ml, stirring, heating to reflux (about 103°C), 1.5h; cooling, the reaction solution pH adjusted to 7~8 with saturated sodium bicarbonate solution; DCM washing water twice; water with hydrochloric acid to adjust the pH to 3~4, precipitate, filtration, filter cake washed with water to pH 6~7, drying to obtain compound 2 4.20g. (LC purity: 98.78%, yield: 41.77%)

[0105] 2) Preparation of compound 2

[0106] 250ml three-necked flask, compound 1 17.4g, 20%~30% hydrochloric acid 200ml, stirring, heating to reflux (about 103°C), 1.5h; cooling, the reaction solution pH adjusted to 7~8 with saturated sodium bicarbonate solution; DCM washing water twice; water with hydrochloric acid to adjust the pH to 3~4, precipitate, filtration, filter cake washed with water to pH 6~7, drying to obtain compound 2 4.20g. (LC purity: 98.78%, yield: 41.77%)

[0107] Example 10

[0108] In this example, the same method as in example 1 is used to prepare 5-bromo-6-methyl nicotinic acid, except that the solvent acid concentration is different in step (2). In this example, the specific preparation method is as follows:

[0109] 1) Preparation of compound 1

[0110] 250ml three-necked flask, compound 1 17.4g, 20%~30% hydrochloric acid 200ml, stirring, heating to reflux (about 103°C), 1.5h; cooling, the reaction solution pH adjusted to 7~8 with saturated sodium bicarbonate solution; DCM washing water twice; water with hydrochloric acid to adjust the pH to 3~4, precipitate, filtration, filter cake washed with water to pH 6~7, drying to obtain compound 2 4.20g. (LC purity: 98.78%, yield: 41.77%)

[0111] 2) Preparation of compound 2

[0112] 250ml three-necked flask, compound 1 17.4g, 20%~30% hydrochloric acid 200ml, stirring, heating to reflux (about 103°C), 1.5h; cooling, the reaction solution pH adjusted to 7~8 with saturated sodium bicarbonate solution; DCM washing water twice; water with hydrochloric acid to adjust the pH to 3~4, precipitate, filtration, filter cake washed with water to pH 6~7, drying to obtain compound 2 4.20g. (LC purity: 98.78%, yield: 41.77%)

[0113] Example 11

[0114] In this embodiment, 5-bromo-6-methylnicotinic acid is prepared by using the substantially same method as that in Embodiment 1, except that the reaction temperature in step (2) is different. In this embodiment, the specific preparation method is as follows:

[0115] 1) Preparation of compound 1

[0116] Into a 250 ml three-necked flask, 5-bromo-6-chloromethyl acetate 10 g and DMSO 100 ml were added at room temperature, and then malonic acid diethyl ester 14 g and cesium carbonate 28.8 g were added under stirring. The reaction was carried out under nitrogen protection at 110°C for 3 h. The reaction solution was poured into 300 ml ice water, and then extracted with 70 ml EA for 3 times. The organic phase was combined, and then washed with 100 ml water once. The organic phase was concentrated to dryness to obtain a yellow liquid 14.81 g. (LC purity: 98.88%; yield: 99.15%)

[0117] 2) Preparation of compound 2

[0118] Into a 250 ml three-necked flask, compound 1 17.4 g and concentrated hydrochloric acid 160 ml were added at room temperature, and then the reaction was carried out under stirring at 100°C for 1.5 h. The reaction solution was cooled, and then the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The water phase was washed with DCM twice. The pH of the water phase was adjusted to 3-4 with hydrochloric acid, and then a solid was precipitated. The solid was filtered, and then washed with water until the pH was 6-7. The filter cake was dried to obtain compound 2 6.10 g. (LC purity: 99.01%, yield: 60.65%)

[0119] Embodiment 12

[0120] In this embodiment, 5-bromo-6-methylnicotinic acid is prepared by using the substantially same method as that in Embodiment 1, except that the post-reaction treatment step in step (2) is different. In this embodiment, the specific preparation method is as follows:

[0121] 1) Preparation of compound 1

[0122] Into a 250 ml three-necked flask, 5-bromo-6-chloromethyl acetate 10 g and DMSO 100 ml were added at room temperature, and then malonic acid diethyl ester 14 g and cesium carbonate 28.8 g were added under stirring. The reaction was carried out under nitrogen protection at 110°C for 3 h. The reaction solution was poured into 300 ml ice water, and then extracted with 70 ml EA for 3 times. The organic phase was combined, and then washed with 100 ml water once. The organic phase was concentrated to dryness to obtain a yellow liquid 14.81 g. (LC purity: 98.88%; yield: 99.15%)

[0123] 2) Preparation of compound 2

[0124] 250ml three-port bottle at room temperature, add compound 1 17.4g, concentrated hydrochloric acid 160ml, stir to warm to 110°C, keep warm for 1.5h; cool down, do not adjust pH, directly wash the aqueous phase with DCM twice; adjust the pH of the aqueous phase to 3-4 with hydrochloric acid, precipitate the solid, filter, wash the filter cake with water until the pH is 6-7, and dry to obtain compound 2 7.11g. (LC purity: 85.71%, yield: 70.73%)

[0125] Example 13

[0126] In this example, 5-bromo-6-methylnicotinic acid is prepared by using the method substantially the same as that of Example 1, except that the post-reaction treatment step in step (2) is different. In this example, the specific preparation method is as follows:

[0127] 1) Preparation of compound 1

[0128] 250ml three-port bottle at room temperature, add compound 1 17.4g, concentrated hydrochloric acid 160ml, stir to warm to 110°C, keep warm for 1.5h; cool down, do not adjust pH, directly wash the aqueous phase with DCM twice; adjust the pH of the aqueous phase to 3-4 with hydrochloric acid, precipitate the solid, filter, wash the filter cake with water until the pH is 6-7, and dry to obtain compound 2 7.11g. (LC purity: 85.71%, yield: 70.73%)

[0129] 2) Preparation of compound 2

[0130] 250ml three-port bottle at room temperature, add compound 1 17.4g, concentrated hydrochloric acid 160ml, stir to warm to 110°C, keep warm for 1.5h; cool down, do not adjust pH, directly wash the aqueous phase with DCM twice; adjust the pH of the aqueous phase to 3-4 with hydrochloric acid, precipitate the solid, filter, wash the filter cake with water until the pH is 6-7, and dry to obtain compound 2 7.11g. (LC purity: 85.71%, yield: 70.73%)

[0131] Example 14

[0132] In this example, 5-bromo-6-methylnicotinic acid is prepared by using the method substantially the same as that of Example 1, except that the post-reaction treatment step in step (2) is different. In this example, the specific preparation method is as follows:

[0133] 1) Preparation of compound 1

[0134] 250ml three-port bottle at room temperature, add 5-bromo-6-chloro methyl formate 10g, DMSO 100ml, add malonic acid diethyl ester 14g, cesium carbonate 28.8g under stirring, nitrogen protection, temperature to 110℃, keep 3h; pour the liquid into 300ml ice water, 70ml EA extraction 3 times; combined organic phase, 100ml water wash organic phase once; organic phase concentrated to dry yellow liquid 14.77g.(LC purity: 98.97%; yield: 98.87%)

[0135] 2) Preparation of compound 2

[0136] 250ml three-port bottle at room temperature, add compound 1 17.4g, concentrated hydrochloric acid 160ml, stirring to 110℃, keep 1.5h; cooling, adjust the pH of the reaction solution to 7-8 with saturated sodium bicarbonate solution; DCM wash the aqueous phase twice; aqueous phase with hydrochloric acid to adjust the pH to 3-4, precipitate solid, filter, filter cake water wash to pH 5-6, dry to get compound 2 7.61g.(LC purity: 94.18%, yield: 75.73%)

[0137] The following table 2 shows the effect of each factor change on the yield and purity of the reaction in step (2).

[0138] Table 2

[0139]

[0140] Those skilled in the art can understand that the above embodiments are specific examples for implementing the present application, and in actual application, various changes can be made in form and details without departing from the spirit and scope of the present application.

Claims

1. A method for synthesizing 5-bromo-6-methylnicotinic acid, characterized in that, The method includes the following steps: S1, In the presence of a base, methyl 5-bromo-6-chloronicotinate is reacted with compound I to give compound II; and S2, in the presence of an acid, the compound of formula II is hydrolyzed to give 5-bromo-6-methylnicotinic acid; In Formula I, the compound of Formula I is diethyl malonate; In step S1, the reaction is carried out in an aprotic polar solvent selected from at least one of dimethyl sulfoxide (DMSO) and 1,3-dimethyl-2-imidazolinone (DMI). The alkali is cesium carbonate.

2. The method according to claim 1, characterized in that, In step S2, the acid is hydrochloric acid or sulfuric acid.

3. The method as described in claim 2, characterized in that, The acid is hydrochloric acid.

4. The method according to claim 2, characterized in that, In step S2, the acid is hydrochloric acid with a mass percentage of 30-40%.

5. The method according to claim 1, characterized in that, In step S2, the reaction temperature is 90-120℃.

6. The method according to claim 5, characterized in that, The reaction temperature is 100-110℃.

7. The method according to claim 6, characterized in that, The reaction temperature is 103-110℃.

8. The method according to claim 1, characterized in that, In step S2, after the compound of formula II is hydrolyzed, the steps of adjusting the pH of the reaction system to alkaline, filtering and taking the filtrate, and adjusting the pH of the filtrate to acidic are also included in sequence.

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