CN114656401A - Method for preparing 4-chloropyridine-2-methyl formate serving as sorafenib key intermediate and suitable for industrial production - Google Patents
Method for preparing 4-chloropyridine-2-methyl formate serving as sorafenib key intermediate and suitable for industrial production Download PDFInfo
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- CN114656401A CN114656401A CN202210408898.0A CN202210408898A CN114656401A CN 114656401 A CN114656401 A CN 114656401A CN 202210408898 A CN202210408898 A CN 202210408898A CN 114656401 A CN114656401 A CN 114656401A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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
Technical Field
The invention relates to a method for industrially producing a sorafenib key intermediate 4-chloropyridine-2-methyl formate, belonging to the field of organic synthesis.
Background
Nature Chemistry, 2022, vol. 14, # 1, p. 78-84 discloses the preparation of the intermediate methyl 4-chloropyridine-2-carboxylate, the route of which is shown in FIG. 1. The method takes 4-aminopyridine-2-methyl formate as a starting material, and uses pyrylium tetrafluoroborate and amino to form a heterocyclic ring, and then uses magnesium chloride to provide a chlorine source for chlorination. Wherein the dosage of the pyrylium tetrafluoroborate is 1.5eq, and the pyrylium tetrafluoroborate is expensive and difficult to obtain. Also, methyl 4-aminopyridine-2-carboxylate is expensive, so the route is suitable for research and is not suitable for large-scale production.
Disclosure of Invention
The invention aims to develop a process which is simple to operate, low in production cost and suitable for industrial production of 4-chloropyridine-2-methyl formate.
In order to achieve the purpose, the invention provides the following technical scheme: a method for industrially producing a sorafenib key intermediate methyl 4-chloropyridine-2-carboxylate, which comprises the following steps:
(1) reacting 2-picolinic acid with a chlorinated reagent under the action of a catalyst to generate 4-chloropyridine-2-formyl chloride hydrochloride;
(2) decompressing and desolventizing the 4-chloropyridine-2-formyl chloride hydrochloride solution generated by the reaction;
(3) adding a solvent to dissolve acyl chloride;
(4) 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;
(5) carrying out decompression desolventizing on the crude product of the 4-chloropyridine-2-methyl formate hydrochloride;
(6) adding the crude product of 4-chloropyridine-2-methyl formate hydrochloride into water to prepare an aqueous solution;
(7) decoloring and decoking the aqueous solution by using activated carbon;
(8) dissociating the water solution after decoloring and decoking to obtain a crude product of 4-chloropyridine-2-methyl formate;
(9) extracting the aqueous suspension with dichloromethane to obtain an organic layer;
(10) drying and concentrating the organic layer to obtain a crude product of 4-chloropyridine-2-methyl formate;
(11) recrystallizing the crude product of the 4-chloropyridine-2-methyl formate to prepare the high-purity 4-chloropyridine-2-methyl formate.
Further, the catalyst is one of sodium chloride, sodium bromide or sodium iodide.
Further, the chlorinating agent is one of oxalyl chloride, thionyl chloride or phosphorus oxychloride.
Further, the equivalent weight of the chlorinating agent is: 2.5-8.0.
Further, the equivalent weight of the catalyst is: 0.1-2.0.
Further, the 2-picolinic acid reacts with a chlorinating reagent at 60-110 ℃ to generate 4-chloropyridine-2-formyl chloride.
Further, the temperature of the esterification reaction is: 0 to 40 ℃.
Further, said liberating of the aqueous suspension means adding dropwise an aqueous solution of sodium bicarbonate, sodium carbonate or sodium hydroxide to the aqueous suspension to a pH = 6-7.
Further, the free temperature is: 0 to 35 ℃.
Further, the recrystallization refers to heating the n-heptane, the ethyl acetate and the alcohol-water system solution of the crude product of the 4-chloropyridine-2-methyl formate to 50-55 ℃ for dissolution, stirring for 0.5h, cooling to 10-15 ℃ for crystallization, carrying out suction filtration, and drying a filter cake to obtain a pure product of the 4-chloropyridine-2-methyl formate.
Compared with the prior art, the invention has the beneficial effects that: the mechanism of this reaction is shown in FIG. 2.
The invention adopts 2-picolinic acid with lower cost as a raw material, improves a chlorination reagent, the charging ratio of reaction, the chlorination and esterification temperature, the type and the dosage of a catalyst and an esterification solvent, and improves the conversion rate. After the reaction is finished, the crude product of the 4-chloropyridine-2-methyl formate hydrochloride is obtained by treatment.
Different from other processes, the crude product of 4-chloropyridine-2-methyl formate hydrochloride is dissolved in hot water and decolorized and decoked by using activated carbon. After the coke is removed, the raw product of the 4-chloropyridine-2-methyl formate is obtained by dissociation. The tar is removed before dissociation, so that the tar is prevented from being brought to a recrystallization step to influence the crystallization of the product. In the step, the dosage of the active carbon, the type and the equivalent of the alkali during the alkali dissociation and the alkali adjusting temperature are optimized, so that the quality of the crude product of the 4-chloropyridine-2-methyl formate hydrochloride is improved. By improving the recrystallization system, the purity and the yield can be improved.
According to the reaction mechanism, thionyl chloride serves as both an acylating agent and a chlorinating agent. The theoretical amount is 2 equivalents. The design equivalent of the invention is as follows: 2.5-8.0. The chlorinating agent is preferably oxalyl chloride, thionyl chloride or phosphorus oxychloride. In which sodium bromide may react with thionyl chloride to form thionyl bromide, which is more readily reacted with the starting material.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following detailed description is given with reference to the preferred embodiments of the present invention and the accompanying drawings.
Drawings
FIG. 1 is a reaction scheme described in the background section;
FIG. 2 shows a reaction scheme according to an embodiment of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it should be understood that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1: A1000L four-necked flask was charged with 100.0g of 2-pyridinecarboxylic acid, 83.62g of sodium bromide, and 410ml of thionyl chloride. Controlling the temperature to be 80-85 ℃, reacting for 6h, sampling (sampling and adding methanol for derivatization) and stopping the reaction until the consumption of the raw material 2-picolinic acid is less than 1.0 percent and the main product 4-chloropyridine-2-methyl formate is more than 90.0 percent. After decompression desolventizing, 400ml of toluene is added to dissolve acyl chloride, the temperature is reduced to 30-40 ℃, and 78.78g of anhydrous methanol is added dropwise to carry out esterification. The reaction is carried out for 1 hour at the temperature, sampling and monitoring are carried out until the consumption of the raw material 2-picolinic acid is less than 1.0 percent and the main yield of 4-chloropyridine-2-methyl formate is more than 90.0 percent, and then the reaction is stopped.
And (3) post-treatment: decompressing and desolventizing to obtain the crude product of the 4-chloropyridine-2-methyl formate hydrochloride. The crude product is suspended in 1760ml of water and heated to 50-55 ℃. The temperature is kept at this temperature for 0.5h, 5.0g of activated carbon is added thereto, and stirring is carried out for 0.5 h. Filtering while hot, adding 100.0ml hot water into the filter cake for rinsing, and filtering. Combining the filtrates, cooling the filtrate to room temperature, controlling the temperature at 10-15 ℃, and dropwise adding saturated Na2CO3 aqueous solution to the filtrate until the pH is = 6-7. To this was added 300ml of 2 dichloromethane and extracted twice. Standing for layering, and combining organic layers. The organic layer was dried and concentrated to obtain 111.5g of crude methyl 4-chloropyridine-2-carboxylate. The crude product was recrystallized from 890.0ml of n-heptane. Heating to 50-55 deg.C to dissolve. Stirring was carried out at this temperature for 0.5 h. Cooling to 10-15 deg.C for crystallization. Keeping the temperature for 0.5h and then performing suction filtration. The filter cake was vacuum dried to obtain 78g of pure 4-chloropyridine-2-carboxylic acid methyl ester. The yield is 56 percent, and the purity is 99.2 percent
Example 2: A1000L four-necked flask was charged with 100.0g of 2-pyridinecarboxylic acid, 12.58g of sodium iodide, and 477ml of oxalyl chloride. Controlling the temperature to be 60-65 ℃, reacting for 9h, sampling (sampling and adding methanol for derivatization) and stopping the reaction until the consumption of the raw material 2-picolinic acid is less than 1.0 percent and the main product 4-chloropyridine-2-methyl formate is more than 90.0 percent. After decompression and desolventization, 400ml of dichloromethane is added to dissolve acyl chloride, the temperature is reduced to 20-30 ℃, and 105.04g of anhydrous methanol is added dropwise to carry out esterification. The reaction is carried out for 1 hour at the temperature, sampling and monitoring are carried out until the consumption of the raw material 2-picolinic acid is less than 1.0 percent and the main yield of 4-chloropyridine-2-methyl formate is more than 90.0 percent, and then the reaction is stopped.
And (3) post-treatment: decompressing and desolventizing to obtain the crude product of the 4-chloropyridine-2-methyl formate hydrochloride. The crude product is suspended in 1800ml of water and heated to 50-55 ℃. The temperature is kept at this temperature for 0.5h, 5.0g of activated carbon is added thereto, and stirring is carried out for 0.5 h. Filtering while hot, rinsing the filter cake with hot water, and suction filtering. And (3) combining the filtrates, cooling the filtrate to room temperature, controlling the temperature to be 0-5 ℃, and dropwise adding a liquid caustic soda aqueous solution into the filtrate until the pH is = 6-7. To this was added 300ml of 2 dichloromethane and extracted twice. Standing for layering, and combining organic layers. The organic layer was dried and concentrated to obtain 120.0g of crude 4-chloropyridine-2-carboxylic acid methyl ester. The crude product was recrystallized from 960.0ml of n-heptane. Heating to 50-55 deg.C to dissolve. Stirring was carried out at this temperature for 0.5 h. Cooling to 10-15 deg.C for crystallization. Keeping the temperature for 0.5h and then performing suction filtration. The filter cake is dried in vacuum to obtain 82.0g of 4-chloropyridine-2-methyl formate pure product. The yield is 58.8 percent, and the purity is 99.0 percent
Example 3: A1000L four-necked flask was charged with 100.0g of 2-picolinic acid, 47.89g of sodium chloride, and 526.2ml of phosphorus oxychloride. Controlling the temperature to be 100 ℃ and reacting at 105 ℃ for 3h, sampling (sampling and adding methanol for derivatization) and stopping the reaction until the consumption of the raw material 2-picolinic acid is below 1.0 percent and the main product 4-chloropyridine-2-methyl formate is more than 90.0 percent. After decompression desolventizing, the temperature is reduced to 10 to 20 ℃, and 500ml of anhydrous methanol is dripped into the mixture for esterification. The reaction is carried out for 1 hour at the temperature, sampling and monitoring are carried out until the consumption of the raw material 2-picolinic acid is less than 1.0 percent and the main yield of 4-chloropyridine-2-methyl formate is more than 90.0 percent, and then the reaction is stopped.
And (3) post-treatment: decompressing and desolventizing to obtain the crude product of the 4-chloropyridine-2-methyl formate hydrochloride. The crude product is suspended in 1800ml of water and heated to 50-55 ℃. The temperature is kept at this temperature for 0.5h, 10.0g of activated carbon is added thereto, and stirring is carried out for 0.5 h. Filtering while hot, rinsing the filter cake with hot water, and suction filtering. The filtrates were combined, the filtrate was cooled to room temperature and saturated aqueous NaHCO3 solution was added dropwise thereto at controlled temperature of 30-35 ℃ to pH = 6-7. To this was added 300ml of 2 dichloromethane and extracted twice. Standing for layering, and combining organic layers. The organic layer was dried and concentrated to give 105.0g of crude methyl 4-chloropyridine-2-carboxylate. The crude product was recrystallized from 840.0ml of n-heptane. Heating to 50-55 deg.C to dissolve. Stirring was carried out at this temperature for 0.5 h. Cooling to 10-15 deg.C for crystallization. Keeping the temperature for 0.5h and then performing suction filtration. The filter cake is dried in vacuum to obtain 82.0g of 4-chloropyridine-2-methyl formate pure product. The yield is 52.4 percent, and the purity is 99.1 percent
Example 4: A1000L four-necked flask was charged with 100.0g of 2-pyridinecarboxylic acid, 62.5g of sodium iodide, and 200ml of thionyl chloride. Controlling the temperature to be 80-85 ℃, reacting for 5h, sampling (sampling and adding methanol for derivatization) and stopping the reaction until the consumption of the raw material 2-picolinic acid is less than 1.0 percent and the main product 4-chloropyridine-2-methyl formate is more than 90.0 percent. After decompression and desolventization, 400ml of dichloromethane is added to dissolve acyl chloride, the temperature is reduced to 0-10 ℃, and 52.52g of anhydrous methanol is added dropwise to carry out esterification. The reaction is carried out for 1 hour at the temperature, sampling and monitoring are carried out until the consumption of the raw material 2-picolinic acid is less than 1.0 percent and the main yield of 4-chloropyridine-2-methyl formate is more than 90.0 percent, and then the reaction is stopped.
And (3) post-treatment: decompressing and desolventizing to obtain the crude product of the 4-chloropyridine-2-methyl formate hydrochloride. The crude product is suspended in 1000ml of water and heated to 50-55 ℃. The temperature is kept at this temperature for 0.5h, 10.0g of activated carbon is added thereto, and stirring is carried out for 0.5 h. Filtering while hot, rinsing the filter cake with hot water, and suction filtering. Combining the filtrates, cooling the filtrate to room temperature, controlling the temperature to be 20-25 ℃, and dropwise adding saturated Na2CO3 aqueous solution to the filtrate until the pH is = 6-7. To this was added 300ml of 2 dichloromethane and extracted twice. Standing for layering, and combining organic layers. The organic layer was dried and concentrated to obtain 125.0g of crude methyl 4-chloropyridine-2-carboxylate. The crude product was dissolved with 125.0ml ethyl acetate heated to 40-45 ℃. 1250.0ml of n-heptane are added dropwise at this temperature and stirring is carried out for 0.5h while maintaining the temperature. Cooling to 10-15 deg.C for crystallization. Keeping the temperature for 0.5h and then performing suction filtration. The filter cake is dried in vacuum to obtain 80.0g of pure 4-chloropyridine-2-methyl formate. The yield is 57.44 percent, and the purity is 99.6 percent
Example 5: A1000L four-necked flask was charged with 100.0g of 2-pyridinecarboxylic acid, 62.5g of sodium iodide, and 200ml of thionyl chloride. Controlling the temperature to be 80-85 ℃, reacting for 5h, sampling (sampling and adding methanol for derivatization) and stopping the reaction until the consumption of the raw material 2-picolinic acid is less than 1.0 percent and the main product 4-chloropyridine-2-methyl formate is more than 90.0 percent. After decompression and desolventization, 400ml of dichloromethane is added to dissolve acyl chloride, the temperature is reduced to 10-15 ℃, and 52.52g of anhydrous methanol is added dropwise to the mixture for esterification. The reaction is carried out for 1 hour at the temperature, sampling and monitoring are carried out until the consumption of the raw material 2-picolinic acid is less than 1.0 percent and the main yield of 4-chloropyridine-2-methyl formate is more than 90.0 percent, and then the reaction is stopped.
And (3) post-treatment: decompressing and desolventizing to obtain the crude product of the 4-chloropyridine-2-methyl formate hydrochloride. The crude product is suspended in 1000ml of water and heated to 50-55 ℃. The temperature is kept at this temperature for 0.5h, 10.0g of activated carbon is added thereto, and stirring is carried out for 0.5 h. Filtering while hot, rinsing the filter cake with hot water, and suction filtering. Combining the filtrates, cooling the filtrate to room temperature, controlling the temperature to be 20-25 ℃, and dropwise adding saturated Na2CO3 aqueous solution to the filtrate until the pH is = 6-7. To this was added 300ml of 2 dichloromethane and extracted twice. Standing for layering, and combining organic layers. The organic layer was dried and concentrated to give 122.0g of crude methyl 4-chloropyridine-2-carboxylate. The crude product was recrystallized from 1830.0ml of water. Heating to 55-60 deg.C to dissolve. Stirring was carried out at this temperature for 0.5 h. Cooling to 10-15 deg.C for crystallization. Keeping the temperature for 0.5h and then performing suction filtration. The filter cake is dried in vacuum to obtain 70.5g of 4-chloropyridine-2-methyl formate pure product. The yield is 50.6 percent, and the purity is 99.7 percent
Example 6: A1000L four-necked flask was charged with 100.0g of 2-pyridinecarboxylic acid, 62.5g of sodium iodide, and 200ml of thionyl chloride. Controlling the temperature to be 80-85 ℃, reacting for 5h, sampling (sampling and adding methanol for derivatization) and stopping the reaction until the consumption of the raw material 2-picolinic acid is less than 1.0 percent and the main product 4-chloropyridine-2-methyl formate is more than 90.0 percent. After decompression and desolventization, 400ml of dichloromethane is added to dissolve acyl chloride, the temperature is reduced to 10-15 ℃, and 52.52g of anhydrous methanol is added dropwise to carry out esterification. The reaction is carried out for 1 hour at the temperature, sampling and monitoring are carried out until the consumption of the raw material 2-picolinic acid is less than 1.0 percent and the main yield of 4-chloropyridine-2-methyl formate is more than 90.0 percent, and then the reaction is stopped.
And (3) post-treatment: decompressing and desolventizing to obtain the crude product of the 4-chloropyridine-2-methyl formate hydrochloride. The crude product is suspended in 1000ml of water and heated to 50-55 ℃. The temperature is kept at this temperature for 0.5h, 10.0g of activated carbon is added thereto, and stirring is carried out for 0.5 h. Filtering while hot, rinsing the filter cake with hot water, and suction filtering. Combining the filtrates, cooling the filtrate to room temperature, controlling the temperature to be 20-25 ℃, and dropwise adding saturated Na2CO3 aqueous solution to the filtrate until the pH is = 6-7. To this was added 300ml of 2 dichloromethane and extracted twice. Standing for layering, and combining organic layers. The organic layer was dried and concentrated to give 124.0g of crude methyl 4-chloropyridine-2-carboxylate. The crude product is dissolved in 124.0ml ethanol by heating to 30-35 ℃. 620.0ml of water is added dropwise at the temperature, and the mixture is stirred for 0.5h under the condition of heat preservation. Cooling to 10-15 deg.C for crystallization. Keeping the temperature for 0.5h and then performing suction filtration. The filter cake is dried in vacuum to obtain 75.0g of pure 4-chloropyridine-2-methyl formate. The yield is 53.85 percent, and the purity is 99.7 percent
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A method for industrially producing a sorafenib key intermediate methyl 4-chloropyridine-2-carboxylate, which is characterized by comprising the following steps:
(1) reacting 2-picolinic acid with a chlorinated reagent under the action of a catalyst to generate 4-chloropyridine-2-formyl chloride hydrochloride;
(2) decompressing and desolventizing the 4-chloropyridine-2-formyl chloride hydrochloride solution generated by the reaction;
(3) adding a solvent to dissolve acyl chloride;
(4) adding methanol to carry out esterification reaction on the 4-chloropyridine-2-formyl chloride to generate a crude product of 4-chloropyridine-2-methyl formate hydrochloride;
(5) carrying out decompression desolvation on the crude product of the 4-chloropyridine-2-methyl formate hydrochloride;
(6) adding the crude product of 4-chloropyridine-2-methyl formate hydrochloride into water to prepare an aqueous solution;
(7) decoloring and decoking the aqueous solution by using activated carbon;
(8) dissociating the decolored and decoked aqueous solution to obtain a crude product of 4-chloropyridine-2-methyl formate;
(9) extracting the aqueous solution with dichloromethane to obtain an organic layer;
(10) drying and concentrating the organic layer to obtain a crude product of 4-chloropyridine-2-methyl formate;
(11) recrystallizing the crude product of the 4-chloropyridine-2-methyl formate to prepare the high-purity 4-chloropyridine-2-methyl formate.
2. The method for industrially producing the sorafenib key intermediate methyl 4-chloropyridine-2-carboxylate according to claim 1, wherein the catalyst is one of sodium chloride, sodium bromide or sodium iodide.
3. The method for industrially producing methyl 4-chloropyridine-2-carboxylate as key intermediate of sorafenib according to claim 1, wherein the chlorinating reagent is one of oxalyl chloride, thionyl chloride or phosphorus oxychloride.
4. The method for industrially producing the sorafenib key intermediate methyl 4-chloropyridine-2-carboxylate according to claim 1, wherein the equivalent weight of the chlorinated reagent is as follows: 2.5-8.0.
5. The method for preparing methyl 4-chloropyridine-2-carboxylate, a sorafenib key intermediate, suitable for industrial production according to claim 1, is characterized in that the equivalent weight of the catalyst is as follows: 0.1-2.0.
6. The method for industrially producing the sorafenib key intermediate methyl 4-chloropyridine-2-carboxylate according to claim 1, wherein the 2-picolinic acid is reacted with a chlorinated reagent at 60-110 ℃ to produce 4-chloropyridine-2-formyl chloride hydrochloride.
7. The method for industrially producing the sorafenib key intermediate methyl 4-chloropyridine-2-carboxylate according to claim 1, wherein the esterification reaction temperature is as follows: 0 to 40 ℃.
8. The method for industrially producing methyl 4-chloropyridine-2-carboxylate, which is a key intermediate of sorafenib, as claimed in claim 1, wherein the step of dissociating the aqueous solution is to drop an aqueous solution of sodium bicarbonate, sodium carbonate or sodium hydroxide into the aqueous solution until the pH is = 6-7.
9. The method for industrially producing the sorafenib key intermediate methyl 4-chloropyridine-2-carboxylate according to claim 1, wherein the free temperature is: 0 to 35 ℃.
10. The method for industrially producing the key intermediate 4-chloropyridine-2-methyl formate of sorafenib according to claim 1, wherein the recrystallization is to heat the n-heptane, ethyl acetate and alcohol-water system solution of the crude 4-chloropyridine-2-methyl formate to 50-55 ℃ for dissolution, stir for 0.5h, cool to 10-15 ℃ for crystallization, suction filter and dry a filter cake to obtain a pure 4-chloropyridine-2-methyl formate.
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|---|---|---|---|---|
| CN105175325A (en) * | 2015-10-21 | 2015-12-23 | 济南诚汇双达化工有限公司 | Preparation method of 4-chlorine-2-pyridine methyl formate |
| CN105218436A (en) * | 2015-10-21 | 2016-01-06 | 济南诚汇双达化工有限公司 | A kind of method preparing 4-Chloro-2-Pyridyle methyl-formiate |
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2022
- 2022-04-19 CN CN202210408898.0A patent/CN114656401A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175325A (en) * | 2015-10-21 | 2015-12-23 | 济南诚汇双达化工有限公司 | Preparation method of 4-chlorine-2-pyridine methyl formate |
| CN105218436A (en) * | 2015-10-21 | 2016-01-06 | 济南诚汇双达化工有限公司 | A kind of method preparing 4-Chloro-2-Pyridyle methyl-formiate |
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