A preparation method of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester

Abstract

The present invention belongs to the technical field of drug synthesis, and in particular to a preparation method of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl esters. The present invention provides a preparation method of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl esters, comprising the following steps: 3-picoline-2-carboxylic acid ethyl ester, meta-chloroperbenzoic acid and a first organic solvent are mixed, and an oxidation reaction is performed to obtain 3-picoline-2-carboxylic acid ethyl ester oxide; the 3-picoline-2-carboxylic acid ethyl ester oxide, a chlorinating agent, a catalyst and a second organic solvent are mixed, and a chlorination reaction is performed to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl esters. 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl esters can be prepared according to the preparation method provided by the present invention, and the preparation raw materials are easy to obtain, and the operation is simple and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester. Background Art

[0002] Arthritis refers to inflammatory diseases that occur in the joints and surrounding tissues of the human body. Arthritis is a major cause of disability. Drugs used to treat arthritis usually include NSAIDs (nonsteroidal anti-inflammatory drugs) or COX-2 inhibitors, but the use of NSAIDs or COX-2 inhibitors can cause side effects and adversely affect the cardiovascular system. Therefore, patients with poor cardiovascular conditions (such as high blood pressure) cannot use NSAIDs or COX-2 inhibitors.

[0003] Studies have shown that EP4 of the prostaglandin E2 (PGE2) receptor subtype is the main receptor involved in arthritic pain in rodent models of rheumatoid arthritis and osteoarthritis. Selective EP4 receptor antagonists can be used to treat arthritis. The structural formula of the selective EP4 receptor antagonist is Since selective EP4 receptor antagonists do not interfere with the biosynthesis of prostaglandins (such as PGU and TxA2), they do not have the cardiovascular side effects of NSAIDs and COX-2 inhibitors.

[0004] 6-Chloro-3-methyl-2-pyridinecarboxylic acid methyl ester (C8H8ClNO2) is an intermediate for the synthesis of selective EP4 receptor antagonists. However, there are few reports on the synthesis of 3-methyl-6-chloropyridinecarboxylic acid methyl ester. Summary of the invention

[0005] In view of this, the present invention provides a method for preparing 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester. According to the preparation method provided by the present invention, 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester can be prepared for synthesizing a selective EP4 receptor antagonist.

[0006] In order to solve the above technical problems, the present invention provides a method for preparing 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester, comprising the following steps:

[0007] Mixing ethyl 3-methylpyridine-2-carboxylate, m-chloroperbenzoic acid and a first organic solvent, and performing an oxidation reaction to obtain ethyl 3-methylpyridine-2-carboxylate oxide;

[0008] The 3-methylpyridine-2-carboxylic acid ethyl ester oxide, a chlorinating agent, a catalyst and a second organic solvent are mixed and subjected to a chlorination reaction to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.

[0009] Preferably, the molar ratio of ethyl 3-methylpyridine-2-carboxylate to m-chloroperbenzoic acid is 1:(2-7).

[0010] Preferably, the mass ratio of the ethyl 3-methylpyridine-2-carboxylate to the volume ratio of the first organic solvent is 1 g: (8-15) mL.

[0011] Preferably, the oxidation reaction is carried out at a temperature of 20 to 40° C. and for a time of 10 to 20 hours.

[0012] Preferably, the temperature of the chlorination reaction is 20-40° C. and the time is 8-15 hours.

[0013] Preferably, the chlorinating agent includes phosphorus trichloride, phosphorus pentachloride, thionyl chloride, carbon tetrachloride or oxalyl chloride.

[0014] Preferably, the catalyst comprises N,N-dimethylformamide, palladium chloride, ferric chloride or aluminum chloride.

[0015] Preferably, the molar ratio of the 3-methylpyridine-2-carboxylic acid ethyl ester oxide to the chlorinating agent is 1:(3-7);

[0016] The molar ratio of the catalyst to the chlorinating agent is 1:(1-5).

[0017] Preferably, the mass ratio of the 3-methylpyridine-2-carboxylic acid ethyl ester oxide to the volume ratio of the second organic solvent is 1 g: (8-15) mL.

[0018] Preferably, the first organic solvent and the second organic solvent independently include dichloromethane, chloroform, acetone, acetonitrile or tetrahydrofuran.

[0019] The present invention provides a method for preparing 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester, comprising the following steps: mixing 3-methylpyridine-2-carboxylic acid ethyl ester, meta-chloroperbenzoic acid and a first organic solvent, performing an oxidation reaction, and obtaining 3-methylpyridine-2-carboxylic acid ethyl ester oxide; mixing the 3-methylpyridine-2-carboxylic acid ethyl ester oxide, a chlorinating agent, a catalyst and a second organic solvent, and performing a chlorination reaction to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester. According to the preparation method provided by the present invention, 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester can be prepared, and the prepared 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester has a high yield and purity; the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester prepared according to the preparation method provided by the present invention has a yield of more than 63% and a purity of more than 96%. The preparation raw materials of the preparation method provided by the present invention are easy to obtain, the operation is simple, and it is suitable for industrial production. DETAILED DESCRIPTION

[0020] The present invention provides a method for preparing 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester, comprising the following steps:

[0021] Mixing ethyl 3-methylpyridine-2-carboxylate, m-chloroperbenzoic acid and a first organic solvent, and performing an oxidation reaction to obtain ethyl 3-methylpyridine-2-carboxylate oxide;

[0022] The 3-methylpyridine-2-carboxylic acid ethyl ester oxide, a chlorinating agent, a catalyst and a second organic solvent are mixed and subjected to a chlorination reaction to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.

[0023] In the present invention, unless otherwise specified, the raw materials used are commercially available products well known to those skilled in the art.

[0024] The present invention mixes ethyl 3-methylpyridine-2-carboxylate, m-chloroperbenzoic acid and a first organic solvent, and performs an oxidation reaction to obtain ethyl 3-methylpyridine-2-carboxylate oxide. In the present invention, the mixing preferably includes the following steps:

[0025] dissolving ethyl 3-methylpyridine-2-carboxylate in a first organic solvent to obtain ethyl 3-methylpyridine-2-carboxylate solution;

[0026] The ethyl 3-methylpyridine-2-carboxylate solution and m-chloroperbenzoic acid are first mixed to obtain a solution to be reacted.

[0027] The present invention dissolves 3-methylpyridine-2-carboxylic acid ethyl ester in a first organic solvent to obtain a 3-methylpyridine-2-carboxylic acid ethyl ester solution. In the present invention, the 3-methylpyridine-2-carboxylic acid ethyl ester is purchased from Anaiji Chemical. In the present invention, the first organic solvent preferably includes dichloromethane, chloroform, acetone, acetonitrile or tetrahydrofuran, more preferably dichloromethane, acetone or acetonitrile. In the present invention, the mass of the 3-methylpyridine-2-carboxylic acid ethyl ester and the volume ratio of the first organic solvent are preferably 1g: (8-15) mL, more preferably 1g: (9-12) mL. In the present invention, the dissolution temperature is preferably -1 to 1°C, more preferably 0°C. The present invention dissolves at low temperatures to avoid violent reactions and explosions. The present invention has no special requirements for the dissolution method, as long as it can be completely dissolved.

[0028] After obtaining the 3-methylpyridine-2-carboxylic acid ethyl ester solution, the present invention first mixes the 3-methylpyridine-2-carboxylic acid ethyl ester solution and meta-chloroperbenzoic acid to obtain a solution to be reacted. In the present invention, the molar ratio of the 3-methylpyridine-2-carboxylic acid ethyl ester and meta-chloroperbenzoic acid is preferably 1: (2 to 7), more preferably 1: (3 to 6.5). In the present invention, the first mixing is preferably carried out under stirring, and the stirring speed is preferably 800 to 1000 r / min, more preferably 850 to 950 r / min; the stirring time is preferably 10 to 20 min, more preferably 15 to 18 min.

[0029] In the present invention, the meta-chloroperbenzoic acid is used as an oxidant, and the meta-chloroperbenzoic acid has both oxidizing and acidic properties and is an organic reagent.

[0030] In the present invention, the temperature of the oxidation reaction is preferably 20-40°C, more preferably 15-30°C; the heating rate to the temperature required for the oxidation reaction is preferably 2-10°C / min, more preferably 4-6°C / min; the time of the oxidation reaction is preferably 10-20h, more preferably 13-17h.

[0031] In the present invention, the structural formula of the 3-methylpyridine-2-carboxylic acid ethyl ester oxide is as shown in formula a:

[0032]

[0033] In the present invention, the oxidation reaction preferably further comprises:

[0034] The pH value of the system after the oxidation reaction is adjusted to 6.5-7.5;

[0035] Extracting the solution after adjusting the pH value, and taking the organic phase;

[0036] The organic phase is dehydrated, filtered and rotary evaporated in sequence to obtain 3-methylpyridine-2-carboxylic acid ethyl ester oxide.

[0037] The pH value of the system after the oxidation reaction is adjusted to 6.5 to 7.5. In the present invention, the pH value of the solution after the pH value is adjusted is preferably 7 to 7.3. In the present invention, the pH value adjusting agent for adjusting the pH value preferably includes sodium bicarbonate aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution or sodium hydroxide aqueous solution; the mass concentration of the pH value adjusting agent is preferably 10 to 20%, more preferably 15 to 18%. The present invention has no special limitation on the amount of the pH value adjusting agent, as long as the required pH value can be achieved. In the present invention, the pH value is preferably adjusted with stirring, and the stirring time is preferably 20 to 40 minutes, more preferably 25 to 30 minutes. The present invention has no special requirements on the stirring speed, and any speed can be used.

[0038] After adjusting the pH value, the present invention extracts the solution after adjusting the pH value to take the organic phase. In the present invention, the extractant for extraction preferably includes ethyl acetate. In the present invention, the volume ratio of the solution after adjusting the pH value to the extractant is preferably 1: (0.8 to 2), more preferably 1: (1 to 1.5). The present invention has no special limitation on the extraction method, and the conventional method in the art can be used.

[0039] After obtaining the organic phase, the present invention dehydrates the organic phase and then filters and rotary evaporates in sequence to obtain 3-methylpyridine-2-carboxylic acid ethyl ester oxide. In the present invention, the dehydrating agent for dehydration preferably includes anhydrous sodium sulfate. In the present invention, the mass ratio of the anhydrous sodium sulfate to the volume ratio of the organic phase is preferably (0.07-0.3) g:1 mL, and more preferably (0.071-0.12) g:1 mL. In the present invention, the filtration removes the dehydrating agent. The present invention has no special requirements for the filtration, and the conventional method in the art can be used. In the present invention, the temperature of the rotary evaporation is preferably 40-50°C, and more preferably 45-48°C. In the present invention, the volume ratio of the liquid after rotary evaporation and the organic phase after dehydration is preferably (0.2-0.5):1, and more preferably (0.2-0.5):1. The present invention has no special requirements for the time of the rotary evaporation as long as the volume ratio of the liquid after rotary evaporation and the organic phase after dehydration can be met.

[0040] In the present invention, 3-methylpyridine-2-carboxylic acid ethyl ester oxide is a yellow solution.

[0041] After obtaining 3-methylpyridine-2-carboxylic acid ethyl ester oxide, the present invention mixes the 3-methylpyridine-2-carboxylic acid ethyl ester oxide, a chlorinating agent, a catalyst and a second organic solvent to carry out a chlorination reaction to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester. In the present invention, the mixing preferably includes the following steps:

[0042] premixing a second organic solvent, a chlorinating agent and a catalyst to obtain a mixed solution;

[0043] The mixed solution and 3-methylpyridine-2-carboxylic acid ethyl ester oxide are mixed for a second time to obtain a reaction solution for chlorination reaction.

[0044] The present invention premixes a second organic solvent, a chlorinating agent and a catalyst to obtain a mixed solution. In the present invention, the second organic solvent preferably includes dichloromethane, chloroform, acetone, acetonitrile or tetrahydrofuran, more preferably dichloromethane, chloroform or acetone. In the present invention, the chlorinating agent preferably includes phosphorus trichloride, phosphorus pentachloride, thionyl chloride, carbon tetrachloride or oxalyl chloride, more preferably ferric chloride, thionyl chloride or carbon tetrachloride. In the present invention, the catalyst preferably includes N,N-dimethylformamide, palladium trichloride, ferric chloride or aluminum chloride, more preferably ferric chloride or aluminum chloride. The present invention can only be carried out under the action of the catalyst. In the present invention, the molar ratio of the catalyst to the chlorinating agent is preferably 1: (1 to 5), more preferably 1: (1.2 to 3.3).

[0045] In the present invention, the premix is ​​preferably stirred in an ice bath; the stirring speed is preferably 800-1000 r / min, more preferably 850-950 r / min; the stirring time is preferably 20-40 min, more preferably 25-30 min.

[0046] After obtaining the mixed solution, the present invention secondly mixes the mixed solution and 3-methylpyridine-2-carboxylic acid ethyl ester oxide to obtain a liquid to be reacted for chlorination reaction. In the present invention, the molar ratio of the 3-methylpyridine-2-carboxylic acid ethyl ester oxide to the chlorinating agent is preferably 1: (3 to 7), more preferably 1: (4 to 6). In the present invention, the mass of the 3-methylpyridine-2-carboxylic acid ethyl ester oxide and the volume ratio of the second organic solvent are preferably 1g: (8 to 15) mL, more preferably 1g: (10 to 12) mL. The present invention has no special requirements for the second mixing method as long as it can be mixed evenly.

[0047] In the present invention, the temperature of the chlorination reaction is preferably 20 to 40°C, more preferably 30 to 35°C; the time of the chlorination reaction is preferably 8 to 18 hours, more preferably 10 to 15 hours. In the present invention, the chlorination reaction product is preferably mixed with an ice-water mixture to quench the chlorination reaction. In the present invention, the volume ratio of the chlorination reaction product to the ice-water mixture is preferably 0.8 to 1.2:1, more preferably 1:1.

[0048] In the present invention, the chlorination reaction preferably further comprises:

[0049] Adjust the pH value of the product after quenching the reaction to 7.5-8.5;

[0050] Extracting the system with adjusted pH value to obtain an organic phase;

[0051] The organic phase is dehydrated, filtered and rotary evaporated in sequence to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester;

[0052] The crude 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester is recrystallized and dried in sequence to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.

[0053] The present invention adjusts the pH value of the product after the quenching reaction to 7.5-8.5. In the present invention, the pH value of the system after adjusting the pH value is preferably 8-8.3. In the present invention, the pH value adjusting agent for adjusting the pH value preferably includes an aqueous sodium carbonate solution, an aqueous potassium carbonate solution, an aqueous sodium bicarbonate solution or an aqueous sodium hydroxide solution; the mass concentration of the pH value adjusting agent is preferably 10-20%, more preferably 15-18%. The present invention has no special limitation on the amount of the pH value adjusting agent, as long as the desired pH value can be achieved. The present invention is preferably accompanied by stirring when adjusting the pH value, and the stirring time is preferably 0.8-1.2h, more preferably 1h. The present invention has no special limitation on the stirring speed, and any speed can be used.

[0054] The method of the present invention adjusts the pH value to allow 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester to precipitate in an alkaline environment.

[0055] After adjusting the pH value, the present invention extracts the system with adjusted pH value to obtain an organic phase. In the present invention, the extractant for extraction preferably includes ethyl acetate. In the present invention, the volume ratio of the system after adjusting pH value and the extractant is preferably 1:(1-5), more preferably 1:(2-4). The present invention has no special limitation on the extraction method, and the conventional method in the art can be used.

[0056] After obtaining the organic phase, the present invention dehydrates the organic phase and then filters and rotary evaporates in sequence to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester. In the present invention, the dehydrating agent for dehydration preferably includes anhydrous sodium sulfate. In the present invention, the mass ratio of the anhydrous sodium sulfate to the volume of the organic phase is preferably (0.1-0.3) g:1 mL, and more preferably (0.1-0.15) g:1 mL. In the present invention, the filtration removes the dehydrating agent. The present invention has no special requirements for the filtration, and conventional methods in the art can be used. In the present invention, the rotary evaporation is used to remove the extractant; the temperature of the rotary evaporation is preferably 40-50°C, and more preferably 45-48°C. The present invention has no special requirements for the time of the rotary evaporation as long as the extractant can be removed.

[0057] After obtaining the crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester, the present invention sequentially recrystallizes and dries the crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester. In the present invention, the recrystallization is preferably to dissolve the crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester in petroleum ether and then cool and crystallize. In the present invention, the mass of the crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester and the volume ratio of petroleum ether are preferably 1g: (0.3-0.6) mL, more preferably 1g: (0.4-0.5) mL. In the present invention, the drying is preferably drained, and the draining preferably includes draining with a water pump or draining with an oil pump, more preferably draining with an oil pump.

[0058] In the present invention, methyl 6-chloro-3-methyl-2-pyridinecarboxylate is a yellow solid.

[0059] In the present invention, the reaction equation for synthesizing 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester is shown in Formula 1:

[0060]

[0061] In order to further illustrate the present invention, the technical solutions provided by the present invention are described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0062] Example 1

[0063] 12.0 g of methyl 3-methylpyridine-2-carboxylate was dissolved in 120 mL of dichloromethane at 0° C. to obtain a 3-methylpyridine-2-carboxylate ethyl ester solution; the 3-methylpyridine-2-carboxylate ethyl ester solution and 88 g of m-chloroperbenzoic acid were stirred at 0° C. and 800 r / min for 15 min, and then heated to 25° C. at a heating rate of 6° C. / min for oxidation reaction for 16 h; the pH value of the system after the oxidation reaction was adjusted to 7 using a 20% sodium bicarbonate solution (with stirring for 30 min); an organic phase was extracted with 130 mL of ethyl acetate; 10 g of anhydrous sodium sulfate and the organic phase were mixed, dehydrated, and then filtered, and the filtrate obtained by filtration was rotary evaporated at 40° C. to obtain 9.5 mL (8.49 g) of ethyl 3-methylpyridine-2-carboxylate oxide;

[0064] 10 mL of N,N-dimethylformamide, 50 mL of dichloromethane and 15 mL of phosphorus trichloride are stirred at a speed of 800 r / min for 30 min under an ice bath to obtain a mixed solution; the mixed solution is mixed with 5 g of 3-methylpyridine-2-carboxylic acid ethyl ester oxide, and then chlorinated at 30° C. for 10 h, and then poured into 50 mL of ice-water mixture to quench the reaction, and then the pH value is adjusted to 8 with a sodium carbonate aqueous solution with a mass concentration of 10% (accompanied by stirring for 1 h); the solution after the pH value is adjusted is extracted with 150 mL of ethyl acetate to obtain an organic phase; the organic phase is dehydrated with 20 g of anhydrous sodium sulfate and then filtered, and the filtrate obtained by filtration is rotary evaporated at 40° C. to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; the crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester is dissolved in 5 mL of petroleum ether for cooling and crystallization, and the solid obtained by cooling and crystallization is pumped dry with an oil pump to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.

[0065] The prepared 3-methylpyridine-2-carboxylic acid ethyl ester oxide and 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester were detected by liquid chromatography-mass spectrometry, and the obtained purities are listed in Table 1. Mass spectrum (m / z) of 3-methylpyridine-2-carboxylic acid ethyl ester oxide: 168.3 (M+H) + ; Mass spectrum (m / z) of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester: 185.7 (M+H) + .

[0066] Example 2

[0067] 6.0 g of methyl 3-methylpyridine-2-carboxylate was dissolved in 60 mL of chloroform at 0° C. to obtain a 3-methylpyridine-2-carboxylate ethyl ester solution; the 3-methylpyridine-2-carboxylate ethyl ester solution and 45 g of m-chloroperbenzoic acid were stirred at 0° C. and 900 r / min for 15 min, and then heated to 20° C. at a heating rate of 6° C. / min for oxidation reaction for 15 h; the pH value of the system after the oxidation reaction was adjusted to 6.5 using a 10% sodium bicarbonate solution (with stirring for 30 min); an organic phase was extracted with 70 mL of ethyl acetate; 5 g of anhydrous sodium sulfate and the organic phase were mixed, dehydrated, and then filtered, and the filtrate obtained by filtration was rotary evaporated at 45° C. to obtain 4.7 mL (4.92 g) of ethyl 3-methylpyridine-2-carboxylate oxide;

[0068] 3g of ferric chloride, 25mL of chloroform and 8mL of phosphorus pentachloride are stirred at a speed of 900r / min for 30min under the condition of an ice bath to obtain a mixed solution; the mixed solution is mixed with 2g of 3-methylpyridine-2-carboxylic acid ethyl ester oxide, and then chlorinated at 35°C for 12h, and then poured into 30mL of ice-water mixture to quench the reaction, and then the pH value is adjusted to 7.5 with a sodium carbonate aqueous solution with a mass concentration of 10% (accompanied by stirring for 1h); the solution after the pH value is adjusted is extracted with 80mL of ethyl acetate to obtain an organic phase; the organic phase is dehydrated with 10g of anhydrous sodium sulfate and then filtered, and the filtrate obtained by filtration is rotary evaporated at 45°C to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; the crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester is dissolved in 5mL of petroleum ether for cooling crystallization, and the solid obtained by cooling crystallization is pumped dry with an oil pump to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.

[0069] The prepared 3-methylpyridine-2-carboxylic acid ethyl ester oxide and 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester were detected by liquid chromatography-mass spectrometry, and the obtained purities are listed in Table 1. Mass spectrum (m / z) of 3-methylpyridine-2-carboxylic acid ethyl ester oxide: 168.2 (M+H) + ; Mass spectrum (m / z) of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester: 186.1 (M+H) + .

[0070] Example 3

[0071] 7.20 g of methyl 3-methylpyridine-2-carboxylate was dissolved in 75 mL of acetone at 0° C. to obtain a 3-methylpyridine-2-carboxylate ethyl ester solution; the 3-methylpyridine-2-carboxylate ethyl ester solution and 53 g of m-chloroperbenzoic acid were stirred at 0° C. and 850 r / min for 15 min, and then heated to 30° C. at a heating rate of 4° C. / min for oxidation reaction for 17 h; the pH value of the system after the oxidation reaction was adjusted to 7.5 using a 10% sodium carbonate solution (with stirring for 30 min); extracted with 60 mL of ethyl acetate to obtain an organic phase; 7 g of anhydrous sodium sulfate and the organic phase were mixed, dehydrated, and then filtered, and the filtrate obtained by filtration was rotary evaporated at 45° C. to obtain 5.6 mL (5.01 g) of ethyl 3-methylpyridine-2-carboxylate oxide;

[0072] 3.5 g of aluminum chloride, 30 mL of acetone and 9 mL of thionyl chloride are stirred at a speed of 850 r / min for 30 min under an ice bath to obtain a mixed solution; the mixed solution is mixed with 3 g of 3-methylpyridine-2-carboxylic acid ethyl ester oxide, and then the mixture is chlorinated at 30° C. for 10 h, and then poured into 40 mL of ice-water mixture to quench the reaction, and then the pH value is adjusted to 8.5 with a sodium bicarbonate aqueous solution with a mass concentration of 20% (accompanied by stirring for 1 h); the solution after the pH value is adjusted is extracted with 90 mL of ethyl acetate to obtain an organic phase; the organic phase is dehydrated with 10 g of anhydrous sodium sulfate and then filtered, and the filtrate obtained by filtration is rotary evaporated at 45° C. to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; the crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester is dissolved in 3 mL of petroleum ether for cooling crystallization, and the solid obtained by cooling crystallization is pumped dry with an oil pump to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.

[0073] The prepared 3-methylpyridine-2-carboxylic acid ethyl ester oxide and 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester were detected by liquid chromatography-mass spectrometry, and the obtained purities are listed in Table 1. Mass spectrum (m / z) of 3-methylpyridine-2-carboxylic acid ethyl ester oxide: 167.8 (M+H) + ; Mass spectrum (m / z) of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester: 185.2 (M+H) + .

[0074] Example 4

[0075] 8.5 g of methyl 3-methylpyridine-2-carboxylate was dissolved in 90 mL of acetonitrile at 0° C. to obtain a 3-methylpyridine-2-carboxylate ethyl ester solution; the 3-methylpyridine-2-carboxylate ethyl ester solution and 61 g of m-chloroperbenzoic acid were stirred at 0° C. and 950 r / min for 15 min, and then heated to 40° C. at a heating rate of 4° C. / min for oxidation reaction for 13 h; the pH value of the system after the oxidation reaction was adjusted to 6.5 using a 15% potassium carbonate solution (accompanied by stirring for 30 min); an organic phase was extracted with 100 mL of ethyl acetate; 10 g of anhydrous sodium sulfate and the organic phase were mixed, dehydrated, and then filtered, and the filtrate obtained by filtration was rotary evaporated at 50° C. to obtain 6.6 mL (5.89 g) of ethyl 3-methylpyridine-2-carboxylate oxide;

[0076] 7 mL of N,N-dimethylformamide, 35 mL of acetonitrile and 11 mL of carbon tetrachloride were stirred at a speed of 950 r / min for 30 min under an ice bath to obtain a mixed solution; the mixed solution was mixed with 3.5 g of 3-methylpyridine-2-carboxylic acid ethyl ester oxide, and then chlorinated at 35° C. for 18 h, and then poured into 50 mL of ice-water mixture to quench the reaction, and then the pH value was adjusted to 8 with a potassium carbonate aqueous solution with a mass concentration of 20% (accompanied by stirring for 1 h); the solution after the pH value was adjusted was extracted with 150 mL of ethyl acetate to obtain an organic phase; the organic phase was dehydrated with 15 g of anhydrous sodium sulfate and then filtered, and the filtrate obtained by filtration was rotary evaporated at 50° C. to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; the crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester was dissolved in 5 mL of petroleum ether for cooling and crystallization, and the solid obtained by cooling and crystallization was pumped dry with an oil pump to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.

[0077] The prepared 3-methylpyridine-2-carboxylic acid ethyl ester oxide and 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester were detected by liquid chromatography-mass spectrometry, and the obtained purities are listed in Table 1. Mass spectrum (m / z) of 3-methylpyridine-2-carboxylic acid ethyl ester oxide: 169.1 (M+H) + ; Mass spectrum (m / z) of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester: 186.4 (M+H) + .

[0078] Example 5

[0079] 24.0 g of methyl 3-methylpyridine-2-carboxylate was dissolved in 240 mL of tetrahydrofuran at 0° C. to obtain a 3-methylpyridine-2-carboxylate ethyl ester solution; the 3-methylpyridine-2-carboxylate ethyl ester solution and 175 g of m-chloroperbenzoic acid were stirred at 0° C. and 1000 r / min for 15 min, and then heated to 30° C. at a heating rate of 10° C. / min for oxidation reaction for 20 h; the pH value of the system after the oxidation reaction was adjusted to 7 using a 20% sodium hydroxide solution (with stirring for 30 min); an organic phase was extracted with 250 mL of ethyl acetate; 30 g of anhydrous sodium sulfate and the organic phase were mixed, dehydrated, and then filtered, and the filtrate obtained by filtration was rotary evaporated at 40° C. to obtain 19 mL (16.97 g) of ethyl 3-methylpyridine-2-carboxylate oxide;

[0080] 20 mL of N,N-dimethylformamide, 100 mL of tetrahydrofuran and 30 mL of oxalyl chloride are stirred at a speed of 1000 r / min for 30 min under an ice bath to obtain a mixed solution; the mixed solution is mixed with 10 g of 3-methylpyridine-2-carboxylic acid ethyl ester oxide, and then chlorinated at 30° C. for 10 h, and then poured into 100 mL of ice-water mixture to quench the reaction, and then the pH value is adjusted to 8 with a sodium hydroxide aqueous solution with a mass concentration of 10% (accompanied by stirring for 1 h); the solution after the pH value is adjusted is extracted with 250 mL of ethyl acetate to obtain an organic phase; the organic phase is dehydrated with 25 g of anhydrous sodium sulfate and then filtered, and the filtrate obtained by filtration is rotary evaporated at 40° C. to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; the crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester is dissolved in 20 mL of petroleum ether for cooling and crystallization, and the solid obtained by cooling and crystallization is pumped dry with an oil pump to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.

[0081] The prepared 3-methylpyridine-2-carboxylic acid ethyl ester oxide and 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester were detected by liquid chromatography-mass spectrometry, and the purity obtained is listed in Table 1. Mass spectrum (m / z) of 3-methylpyridine-2-carboxylic acid ethyl ester oxide: 168.5 (M+H) + ; Mass spectrum (m / z) of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester: 186.3 (M+H) + .

[0082] Example 6

[0083] 120g of methyl 3-methylpyridine-2-carboxylate was dissolved in 1200mL of dichloromethane at 0°C to obtain a 3-methylpyridine-2-carboxylate ethyl ester solution; the 3-methylpyridine-2-carboxylate ethyl ester solution and 880g of m-chloroperbenzoic acid were stirred at 0°C and 900r / min for 15min, and then heated to 25°C at a heating rate of 3°C / min for oxidation reaction for 16h; the pH value of the system after the oxidation reaction was adjusted to 7 using a 20% sodium bicarbonate solution (with stirring for 30min); an organic phase was extracted with 1300mL of ethyl acetate; 130g of anhydrous sodium sulfate and the organic phase were mixed, dehydrated, and then filtered, and the filtrate obtained by filtration was rotary evaporated at 40°C to obtain 78.4mL (70.1g) of ethyl 3-methylpyridine-2-carboxylate oxide;

[0084] 100 mL of N,N-dimethylformamide, 500 mL of dichloromethane and 150 mL of phosphorus trichloride were stirred at a speed of 900 r / min for 30 min in an ice bath to obtain a mixed solution; the mixed solution and 50 g of The 3-methylpyridine-2-carboxylic acid ethyl ester oxide is mixed and chlorinated at 30° C. for 10 hours, and then poured into 500 mL of ice-water mixture to quench the reaction, and then the pH value is adjusted to 8 with a sodium carbonate aqueous solution with a mass concentration of 10% (accompanied by stirring for 1 hour); the solution after the pH value is adjusted is extracted with 1500 mL of ethyl acetate to obtain an organic phase; the organic phase is dehydrated with 200 g of anhydrous sodium sulfate and then filtered, and the filtrate obtained by filtration is rotary evaporated at 40° C. to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; the crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester is dissolved in 50 mL of petroleum ether for cooling and crystallization, and the solid obtained by cooling and crystallization is pumped dry by an oil pump to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.

[0085] The prepared 3-methylpyridine-2-carboxylic acid ethyl ester oxide and 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester were detected by liquid chromatography-mass spectrometry, and the obtained purities are listed in Table 1. Mass spectrum (m / z) of 3-methylpyridine-2-carboxylic acid ethyl ester oxide: 168.2 (M+H) + ; Mass spectrum (m / z) of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester: 186.2 (M+H) + .

[0086] According to the mass spectrometry results of Examples 1 to 6, the substance prepared according to the preparation method provided by the present invention is 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.

[0087] Comparative Example 1

[0088] According to the method of Example 1, 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester was prepared, except that acetic acid and hydrogen peroxide were used as oxidants. The specific steps are as follows:

[0089] 5 g of methyl 3-methylpyridine-2-carboxylate, 50 g of acetic acid and 35 g of hydrogen peroxide were mixed and subjected to oxidation reaction at 60° C. for 8 h; the pH value of the system after the oxidation reaction was adjusted to 7 using a 20% sodium bicarbonate solution (with stirring for 30 min); an organic phase was extracted with 100 mL of ethyl acetate; 10 g of anhydrous sodium sulfate was mixed with the organic phase, the mixture was dehydrated and filtered, and the filtrate obtained by filtration was rotary evaporated at 40° C. to obtain 2.8 mL (2.5 g) of ethyl 3-methylpyridine-2-carboxylate oxide;

[0090] 10 mL of N,N-dimethylformamide, 50 mL of dichloromethane and 15 mL of phosphorus trichloride are stirred at a speed of 900 r / min for 30 min under an ice bath to obtain a mixed solution; the mixed solution is mixed with 5 g of 3-methylpyridine-2-carboxylic acid ethyl ester oxide, and then chlorinated at 30° C. for 10 h, and then poured into 50 mL of ice-water mixture to quench the reaction, and then the pH value is adjusted to 8 with a sodium carbonate aqueous solution with a mass concentration of 10% (accompanied by stirring for 1 h); the solution after the pH value is adjusted is extracted with 150 mL of ethyl acetate to obtain an organic phase; the organic phase is dehydrated with 20 g of anhydrous sodium sulfate and then filtered, and the filtrate obtained by filtration is rotary evaporated at 40° C. to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; the crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester is dissolved in 5 mL of petroleum ether for cooling and crystallization, and the solid obtained by cooling and crystallization is pumped dry with an oil pump to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.

[0091] Comparative Example 2

[0092] Methyl 6-chloro-3-methyl-2-pyridinecarboxylate was prepared according to the method of Example 1, except that no catalyst was added, that is, 10 mL of N,N-dimethylformamide was not added during the chlorination reaction.

[0093] The purity of 3-methylpyridine-2-carboxylic acid ethyl ester oxide and 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester prepared in Comparative Example 1 and Comparative Example 2 was tested by liquid chromatography-mass spectrometry, and the results are listed in Table 1.

[0094] Table 1 Yield and purity of the products prepared in Implementation 1 to 6

[0095]

[0096] It can be seen from Table 1 that the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester prepared according to the preparation method provided by the present invention has a higher yield and purity.

[0097] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester, comprising the following steps: Mixing 3-methylpyridine-2-carboxylic acid methyl ester, m-chloroperbenzoic acid and a first organic solvent, and performing an oxidation reaction to obtain 3-methylpyridine-2-carboxylic acid methyl ester oxide; the molar ratio of the 3-methylpyridine-2-carboxylic acid methyl ester to the m-chloroperbenzoic acid is 1:(2-7); the oxidation reaction temperature is 20-40° C., and the time is 10-20 h; The 3-methylpyridine-2-carboxylic acid methyl ester oxide, a chlorinating agent, a catalyst and a second organic solvent are mixed to carry out a chlorination reaction to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; the chlorinating agent includes phosphorus trichloride, phosphorus pentachloride, thionyl chloride, carbon tetrachloride or oxalyl chloride, and the molar ratio of the 3-methylpyridine-2-carboxylic acid methyl ester oxide to the chlorinating agent is 1:(3-7); the catalyst includes N,N-dimethylformamide, ferric chloride or aluminum chloride, and the molar ratio of the catalyst to the chlorinating agent is 1:(1-5); the temperature of the chlorination reaction is 20-40°C, and the time is 8-18 hours.

2. The preparation method according to claim 1, characterized in that: The mass ratio of the 3-methylpyridine-2-carboxylic acid methyl ester to the volume ratio of the first organic solvent is 1 g: (8-15) mL.

3. The preparation method according to claim 1, characterized in that: The mass ratio of the 3-methylpyridine-2-carboxylic acid methyl ester oxide to the volume ratio of the second organic solvent is 1 g: (8-15) mL.

4. The preparation method according to claim 1, characterized in that: The first organic solvent and the second organic solvent independently include dichloromethane, chloroform, acetone, acetonitrile or tetrahydrofuran.

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