CN114656401A - Method for preparing 4-chloropyridine-2-methyl formate serving as sorafenib key intermediate and suitable for industrial production - Google Patents

Abstract

The invention provides a method for preparing a sorafenib key intermediate methyl 4-chloropyridine-2-formate suitable for industrial production, which comprises the following steps: reacting 2-picolinic acid with a chlorinated reagent under the action of a catalyst to generate 4-chloropyridine-2-formyl chloride hydrochloride; adding methanol to carry out esterification reaction on the 4-chloropyridine-2-formyl chloride hydrochloride to generate a crude product of the 4-chloropyridine-2-methyl formate hydrochloride. 2-picolinic acid with low cost is used as a raw material, a chlorination reagent, the charging ratio of reaction, the chlorination and esterification temperatures, the types and the dosage of catalysts and an esterification solvent are improved, and the conversion rate is improved. The crude product of 4-chloropyridine-2-methyl formate hydrochloride is decoked by decolorizing with activated carbon. Then dissociating to obtain a crude product of the 4-chloropyridine-2-methyl formate. The tar was removed before liberation. Recrystallizing and purifying the crude product of the 4-chloropyridine-2-methyl formate. The invention optimizes the type of alkali used for dissociation, the dissociation temperature and the recrystallization system, and improves the purity of the product.

Description

A kind of method for the sorafenib key intermediate 4-chloropyridine-2-methyl formate suitable for industrialized production

technical field

The invention relates to a method for a key intermediate of sorafenib, methyl 4-chloropyridine-2-carboxylate, which is suitable for industrial production, and belongs to the field of organic synthesis.

Background technique

Nature Chemistry, 2022, vol. 14, # 1, p. 78 - 84 discloses the preparation method of the intermediate methyl 4-chloropyridine-2-carboxylate, the route of which is shown in Figure 1. The method uses methyl 4-aminopyridine-2-carboxylate as the starting material, and then uses pyrylium tetrafluoroborate to form a heterocycle with an amino group, and then uses magnesium chloride to provide a chlorine source for chlorination. Among them, the amount of pyrylium tetrafluoroborate is 1.5eq, which is expensive and difficult to obtain. Similarly, methyl 4-aminopyridine-2-carboxylate is expensive, so this route is suitable for research but not suitable for large-scale production.

SUMMARY OF THE INVENTION

The purpose of the present invention is to develop a process with simple operation, low production cost and suitable for industrial production of methyl 4-chloropyridine-2-carboxylate.

In order to achieve the above object, the present invention provides the following technical solutions: a method for the sorafenib key intermediate 4-chloropyridine-2-methyl carboxylate suitable for industrial production, the method comprises the following steps:

(1) 2-picolinic acid reacts with a chlorinating reagent under the action of a catalyst to generate 4-chloropyridine-2-formyl chloride hydrochloride;

(2) The 4-chloropyridine-2-formyl chloride hydrochloride solution generated by the reaction is de-dissolved under reduced pressure;

(3) Add solvent to dissolve acid chloride;

(4) adding methanol to esterify 4-chloropyridine-2-formyl chloride hydrochloride to generate crude 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride;

(5) Precipitating the crude product of methyl 4-chloropyridine-2-carboxylate hydrochloride under reduced pressure;

(6) adding crude 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride into water to make an aqueous solution;

(7) Use activated carbon to decolorize and decoke the aqueous solution;

(8) The aqueous solution after decolorization and decoking is freed to obtain a crude product of methyl 4-chloropyridine-2-carboxylate;

(9) using dichloromethane to extract the water suspension to obtain an organic layer;

(10) The organic layer was dried and concentrated to obtain a crude product of methyl 4-chloropyridine-2-carboxylate;

(11) The crude methyl 4-chloropyridine-2-carboxylate is recrystallized to obtain high-purity methyl 4-chloropyridine-2-carboxylate.

Further, the catalyst is one of sodium chloride, sodium bromide or sodium iodide.

Further, the chlorination reagent is one of oxalyl chloride, thionyl chloride or phosphorus oxychloride.

Further, the equivalent of the chlorination reagent is: 2.5-8.0.

Further, the equivalent weight of the catalyst is: 0.1-2.0.

Further, the 2-picolinic acid reacts with the chlorination reagent at 60-110° C. to generate 4-chloropyridine-2-carbonyl chloride.

Further, the temperature of the esterification reaction is: 0-40°C.

Further, the freeing of the water suspension refers to dropwise adding an aqueous solution of sodium bicarbonate, sodium carbonate or sodium hydroxide to the water suspension to pH=6-7.

Further, the free temperature is: 0-35°C.

Further, the recrystallization refers to heating the n-heptane, n-heptane, ethyl acetate and alcohol-water system solution of the crude methyl 4-chloropyridine-2-carboxylate to 50-55°C to dissolve, stirring for 0.5h After cooling to 10-15°C for crystallization, suction filtration, and drying of the filter cake to obtain pure methyl 4-chloropyridine-2-carboxylate.

Compared with the prior art, the beneficial effect of the present invention is that the mechanism of the reaction is shown in FIG. 2 .

The invention adopts 2-picolinic acid with lower cost as raw material, improves the chlorination reagent, the charging ratio of the reaction, the chlorination and esterification temperature, the type and amount of catalyst, and the esterification solvent, and improves the conversion rate. After the reaction was completed, the crude product of methyl 4-chloropyridine-2-carboxylate hydrochloride was obtained.

Different from other processes, we dissolve the crude 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride with hot water, and use activated carbon for decolorization and decoking. After decoking, it is freed to obtain a crude product of methyl 4-chloropyridine-2-carboxylate. Removing the tar before dissociation avoids the tar being brought to the recrystallization step and affecting the crystallization of the product. In this step, the amount of activated carbon, the type and equivalent of the base when the base is adjusted to free, and the temperature of the base adjustment are optimized to improve the quality of the crude 4-chloropyridine-2-carboxylate hydrochloride. We can improve the purity and yield by improving the recrystallization system.

According to the reaction mechanism, thionyl chloride acts as both an acylating reagent and a chlorinating reagent. The theoretical dosage is 2 equivalents. The design equivalent of the present invention is: 2.5-8.0. The chlorination reagent is preferably oxalyl chloride, thionyl chloride or phosphorus oxychloride. Sodium bromide in it may form thionyl bromide with thionyl chloride, which is easier to react with the starting material.

The above description is only an overview of the technical solution of the present invention. In order to understand the technical means of the present invention more clearly and implement it according to the content of the description, the following detailed description is given with the preferred embodiments of the present invention and the accompanying drawings.

Description of drawings

Fig. 1 is the reaction route introduced in the background technology part;

FIG. 2 is a reaction path shown in an embodiment of the present invention.

Detailed ways

The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are a part of the embodiments of the present invention, but not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

Example 1: 100.0g of 2-picolinic acid, 83.62g of sodium bromide and 410ml of thionyl chloride were added to a 1000L four-necked flask. The temperature was controlled at 80-85°C and the reaction was sampled for 6 hours (sampling and methanol derivatization) to monitor the consumption of the raw material 2-picolinic acid below 1.0% and the main production of methyl 4-chloropyridine-2-carboxylate> 90.0%, then stop the reaction. After precipitation under reduced pressure, 400 ml of toluene was added to dissolve the acid chloride, the temperature was lowered to 30-40° C., and 78.78 g of anhydrous methanol was added dropwise to it for esterification. At this temperature, the reaction was carried out for 1 h and monitored until the consumption of the raw material 2-picolinic acid was less than 1.0%, and the main production of methyl 4-chloropyridine-2-carboxylate was more than 90.0%, and the reaction was stopped.

Post-treatment: precipitation under reduced pressure to obtain crude 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride. The crude product was suspended in 1760 ml of water and heated to 50-55°C. The temperature was kept for 0.5h, 5.0g of activated carbon was added to it, and the mixture was stirred for 0.5h. Filter while hot, add 100.0 ml of hot water to the filter cake to rinse, and filter with suction. The filtrate was combined, the filtrate was cooled to room temperature, and the saturated Na2CO3 aqueous solution was added dropwise to it at a temperature of 10-15°C to pH=6-7. Add 300ml*2 dichloromethane to it and extract twice. The layers were left to stand, and the organic layers were combined. The organic layer was dried and concentrated to obtain 111.5 g of crude methyl 4-chloropyridine-2-carboxylate. The crude product was recrystallized from 890.0 ml of n-heptane. Heat to 50-55°C to dissolve. Stir at this temperature for 0.5 h. Cool to 10-15°C for crystallization. After 0.5h of insulation, suction filtration. The filter cake was vacuum-dried to obtain 78 g of pure methyl 4-chloropyridine-2-carboxylate. Yield 56%, purity 99.2%

Example 2: 100.0g of 2-picolinic acid, 12.58g of sodium iodide and 477ml of oxalyl chloride were added to a 1000L four-necked flask. The temperature was controlled at 60-65°C for 9 hours and sampling (sampling plus methanol derivatization) was monitored until the consumption of the raw material 2-picolinic acid was less than 1.0%, and the main production of methyl 4-chloropyridine-2-carboxylate was more than 90.0%, and the reaction was stopped. After precipitation under reduced pressure, 400 ml of dichloromethane was added to dissolve the acid chloride, the temperature was lowered to 20-30° C., and 105.04 g of anhydrous methanol was added dropwise to it for esterification. At this temperature, the reaction was carried out for 1 h and monitored until the consumption of the raw material 2-picolinic acid was less than 1.0%, and the main production of methyl 4-chloropyridine-2-carboxylate was more than 90.0%, and the reaction was stopped.

Post-treatment: precipitation under reduced pressure to obtain crude 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride. The crude product was suspended in 1800 ml of water and heated to 50-55°C. The temperature was kept for 0.5h, 5.0g of activated carbon was added to it, and the mixture was stirred for 0.5h. Filter while hot, filter cake heated with water to rinse, suction filtration. The filtrate was combined, the filtrate was cooled to room temperature, and the aqueous alkali NaOH solution was added dropwise to pH=6-7 under temperature control at 0-5°C. Add 300ml*2 dichloromethane to it and extract twice. The layers were left to stand, and the organic layers were combined. The organic layer was dried and concentrated to obtain 120.0 g of crude methyl 4-chloropyridine-2-carboxylate. The crude product was recrystallized from 960.0 ml of n-heptane. Heat to 50-55°C to dissolve. Stir at this temperature for 0.5 h. Cool to 10-15°C for crystallization. After 0.5h of insulation, suction filtration. The filter cake was vacuum dried to obtain 82.0 g of pure methyl 4-chloropyridine-2-carboxylate. Yield 58.8%, purity 99.0%

Example 3: 100.0g of 2-picolinic acid, 47.89g of sodium chloride and 526.2ml of phosphorus oxychloride were added to a 1000L four-necked flask. The temperature was controlled at 100-105°C and the reaction was carried out for 3h and sampling (sampling and methanol derivatization) were monitored until the consumption of the raw material 2-picolinic acid was below 1.0%, and the main production of methyl 4-chloropyridine-2-carboxylate was more than 90.0%, and the reaction was stopped. After precipitation under reduced pressure, the temperature was lowered to 10-20° C. and 500 ml of anhydrous methanol was added dropwise to it for esterification. At this temperature, the reaction was carried out for 1 h and monitored until the consumption of the raw material 2-picolinic acid was less than 1.0%, and the main production of methyl 4-chloropyridine-2-carboxylate was more than 90.0%, and the reaction was stopped.

Post-treatment: precipitation under reduced pressure to obtain crude 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride. The crude product was suspended in 1800 ml of water and heated to 50-55°C. The temperature was kept for 0.5h, 10.0g of activated carbon was added to it, and the mixture was stirred for 0.5h. Filter while hot, filter cake heated with water to rinse, suction filtration. The filtrate was combined, the filtrate was cooled to room temperature, and a saturated aqueous NaHCO3 solution was added dropwise to pH=6-7 under temperature control at 30-35°C. Add 300ml*2 dichloromethane to it and extract twice. The layers were left to stand, and the organic layers were combined. The organic layer was dried and concentrated to obtain 105.0 g of crude methyl 4-chloropyridine-2-carboxylate. The crude product was recrystallized from 840.0 ml of n-heptane. Heat to 50-55°C to dissolve. Stir at this temperature for 0.5 h. Cool to 10-15°C for crystallization. After 0.5h of insulation, suction filtration. The filter cake was vacuum dried to obtain 82.0 g of pure methyl 4-chloropyridine-2-carboxylate. Yield 52.4%, purity 99.1%

Example 4: 100.0g of 2-picolinic acid, 62.5g of sodium iodide and 200ml of thionyl chloride were added to a 1000L four-necked flask. The temperature was controlled at 80-85°C and the reaction was sampled for 5 hours (sampling and methanol derivatization) to monitor the consumption of the raw material 2-picolinic acid to less than 1.0% and the main production of methyl 4-chloropyridine-2-carboxylate> 90.0%, then stop the reaction. After desolvation under reduced pressure, 400 ml of dichloromethane was added to dissolve the acid chloride, the temperature was lowered to 0-10° C., and 52.52 g of anhydrous methanol was added dropwise to it for esterification. At this temperature, the reaction was carried out for 1 h and monitored until the consumption of the raw material 2-picolinic acid was less than 1.0%, and the main production of methyl 4-chloropyridine-2-carboxylate was more than 90.0%, and the reaction was stopped.

Post-treatment: precipitation under reduced pressure to obtain crude 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride. The crude product was suspended in 1000 ml of water and heated to 50-55°C. The temperature was kept for 0.5h, 10.0g of activated carbon was added to it, and the mixture was stirred for 0.5h. Filter while hot, filter cake heated with water to rinse, suction filtration. The filtrate was combined, the filtrate was cooled to room temperature, and the saturated Na2CO3 aqueous solution was added dropwise to pH=6-7 under temperature control at 20-25°C. Add 300ml*2 dichloromethane to it and extract twice. The layers were left to stand, and the organic layers were combined. The organic layer was dried and concentrated to obtain 125.0 g of crude methyl 4-chloropyridine-2-carboxylate. The crude product was dissolved in 125.0 ml of ethyl acetate by heating to 40-45°C. At this temperature, 1250.0 ml of n-heptane was added dropwise, and the mixture was kept stirring for 0.5 h. Cool to 10-15°C for crystallization. After 0.5h of insulation, suction filtration. The filter cake was dried under vacuum to obtain 80.0 g of pure methyl 4-chloropyridine-2-carboxylate. Yield 57.44%, purity 99.6%

Example 5: 100.0g of 2-picolinic acid, 62.5g of sodium iodide and 200ml of thionyl chloride were added to a 1000L four-necked flask. The temperature was controlled at 80-85°C and the reaction was sampled for 5 hours (sampling and methanol derivatization) to monitor the consumption of the raw material 2-picolinic acid to less than 1.0% and the main production of methyl 4-chloropyridine-2-carboxylate> 90.0%, then stop the reaction. After desolvation under reduced pressure, add 400 ml of dichloromethane to dissolve the acid chloride, cool down to 10-15°C, and dropwise add 52.52 g of anhydrous methanol to it for esterification. At this temperature, the reaction was carried out for 1 h and monitored until the consumption of the raw material 2-picolinic acid was less than 1.0%, and the main production of methyl 4-chloropyridine-2-carboxylate was more than 90.0%, and the reaction was stopped.

Post-treatment: precipitation under reduced pressure to obtain crude 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride. The crude product was suspended in 1000 ml of water and heated to 50-55°C. The temperature was kept for 0.5h, 10.0g of activated carbon was added to it, and the mixture was stirred for 0.5h. Filter while hot, filter cake heated with water to rinse, suction filtration. The filtrate was combined, the filtrate was cooled to room temperature, and the saturated Na2CO3 aqueous solution was added dropwise to pH=6-7 under temperature control at 20-25°C. Add 300ml*2 dichloromethane to it and extract twice. The layers were left to stand, and the organic layers were combined. The organic layer was dried and concentrated to obtain 122.0 g of crude methyl 4-chloropyridine-2-carboxylate. The crude product was recrystallized from 1830.0 ml of water. Heat to 55-60°C to dissolve. Stir at this temperature for 0.5 h. Cool to 10-15°C for crystallization. After 0.5h of insulation, suction filtration. The filter cake was dried under vacuum to obtain 70.5 g of pure methyl 4-chloropyridine-2-carboxylate. Yield 50.6%, purity 99.7%

Example 6: 100.0g of 2-picolinic acid, 62.5g of sodium iodide and 200ml of thionyl chloride were added to a 1000L four-necked flask. The temperature was controlled at 80-85°C and the reaction was sampled for 5 hours (sampling and methanol derivatization) to monitor the consumption of the raw material 2-picolinic acid to less than 1.0% and the main production of methyl 4-chloropyridine-2-carboxylate> 90.0%, then stop the reaction. After desolvation under reduced pressure, add 400 ml of dichloromethane to dissolve the acid chloride, cool down to 10-15°C, and dropwise add 52.52 g of anhydrous methanol to it for esterification. At this temperature, the reaction was carried out for 1 h and monitored until the consumption of the raw material 2-picolinic acid was less than 1.0%, and the main production of methyl 4-chloropyridine-2-carboxylate was more than 90.0%, and the reaction was stopped.

Post-treatment: precipitation under reduced pressure to obtain crude 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride. The crude product was suspended in 1000 ml of water and heated to 50-55°C. The temperature was kept for 0.5h, 10.0g of activated carbon was added to it, and the mixture was stirred for 0.5h. Filter while hot, filter cake heated with water to rinse, suction filtration. The filtrate was combined, the filtrate was cooled to room temperature, and the saturated Na2CO3 aqueous solution was added dropwise to pH=6-7 under temperature control at 20-25°C. Add 300ml*2 dichloromethane to it and extract twice. The layers were left to stand, and the organic layers were combined. The organic layer was dried and concentrated to obtain 124.0 g of crude methyl 4-chloropyridine-2-carboxylate. The crude product was dissolved in 124.0 ml of ethanol by heating to 30-35°C. At this temperature, 620.0 ml of water was added dropwise, and the mixture was kept stirring for 0.5 h. Cool to 10-15°C for crystallization. After 0.5h of insulation, suction filtration. The filter cake was vacuum-dried to obtain 75.0 g of pure methyl 4-chloropyridine-2-carboxylate. Yield 53.85%, purity 99.7%

The above-mentioned embodiments only represent several embodiments of the present invention, and the descriptions thereof are specific and detailed, but should not be construed as a limitation on the scope of the invention patent. It should be pointed out that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can also be made, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.

Claims (10)

1. a method for the sorafenib key intermediate 4-chloropyridine-2-methyl formate suitable for industrialized production, is characterized in that, described method may further comprise the steps: (1) 2-picolinic acid reacts with a chlorinating reagent under the action of a catalyst to generate 4-chloropyridine-2-formyl chloride hydrochloride; (2) The 4-chloropyridine-2-formyl chloride hydrochloride solution generated by the reaction is de-dissolved under reduced pressure; (3) Add solvent to dissolve acid chloride; (4) adding methanol to esterify 4-chloropyridine-2-formyl chloride to generate crude 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride; (5) Precipitating the crude product of methyl 4-chloropyridine-2-carboxylate hydrochloride under reduced pressure; (6) adding crude 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride into water to make an aqueous solution; (7) Use activated carbon to decolorize and decoke the aqueous solution; (8) dissociating the aqueous solution after decolorization and decoking to obtain a crude product of methyl 4-chloropyridine-2-carboxylate; (9) using dichloromethane to extract the aqueous solution to obtain an organic layer; (10) The organic layer was dried and concentrated to obtain a crude product of methyl 4-chloropyridine-2-carboxylate; (11) The crude methyl 4-chloropyridine-2-carboxylate is recrystallized to obtain high-purity methyl 4-chloropyridine-2-carboxylate. 2. the method for a kind of sorafenib key intermediate 4-chloropyridine-2-methyl formate suitable for suitability for industrialized production according to claim 1, is characterized in that, described catalyzer is sodium chloride, sodium bromide or one of sodium iodide. 3. the method for a kind of sorafenib key intermediate 4-chloropyridine-2-methyl formate suitable for suitability for industrialized production according to claim 1, is characterized in that, described chlorination reagent is oxalyl chloride, chlorinated A type of sulfoxide or phosphorus oxychloride. 4. the method for a kind of sorafenib key intermediate 4-chloropyridine-2-methyl formate suitable for industrialized production according to claim 1, is characterized in that, the equivalent of described chlorination reagent is: 2.5- 8.0. 5. the method for the sorafenib key intermediate 4-chloropyridine-2-methyl carboxylate suitable for industrialized production according to claim 1, is characterized in that, the equivalent of described catalyst is: 0.1-2.0. 6. the method for the sorafenib key intermediate 4-chloropyridine-2-methyl formate of suitability for industrialized production according to claim 1, is characterized in that, described 2-picolinic acid and chlorination reagent are in 4-chloropyridine-2-carbonyl chloride hydrochloride is formed by the reaction at 60-110°C. 7. the method for a kind of Sorafenib key intermediate 4-chloropyridine-2-methyl formate suitable for industrialized production according to claim 1, is characterized in that, the temperature of described esterification is: 0- 40°C. 8. a kind of method that is suitable for the sorafenib key intermediate 4-chloropyridine-2-methyl carboxylate of suitability for industrialized production according to claim 1, it is characterised in that the described aqueous solution is freed to point to drop in the aqueous solution Add sodium bicarbonate, sodium carbonate or sodium hydroxide aqueous solution to pH=6-7. 9. the method for the sorafenib key intermediate 4-chloropyridine-2-methyl carboxylate suitable for industrial production according to claim 1, is characterized in that, described free temperature is: 0-35 ℃. 10. the method for a kind of sorafenib key intermediate 4-chloropyridine-2-methyl carboxylate suitable for industrialized production according to claim 1, is characterized in that, described recrystallization refers to described 4- The n-heptane and n-heptane, ethyl acetate, and alcohol-water system solutions of the crude methyl chloropyridine-2-carboxylate were heated to 50-55 °C to dissolve, stirred for 0.5 h, cooled to 10-15 °C for crystallization, suction filtered, The filter cake was dried to obtain pure methyl 4-chloropyridine-2-carboxylate.

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