CN110903214A - Preparation method of teriflunomide - Google Patents
Preparation method of teriflunomide Download PDFInfo
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- CN110903214A CN110903214A CN201911233819.1A CN201911233819A CN110903214A CN 110903214 A CN110903214 A CN 110903214A CN 201911233819 A CN201911233819 A CN 201911233819A CN 110903214 A CN110903214 A CN 110903214A
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Abstract
The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of teriflunomide. The preparation method comprises the following steps: (1) mixing cyanoacetic acid, a condensing agent, an aprotic solvent and an alkaline reagent, and carrying out a condensation reaction to obtain an active ester system; (2) mixing the active ester system with 4-trifluoromethyl aniline, and carrying out condensation reaction to obtain an intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide; (3) and mixing the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide and acetyl chloride for acylation reaction to obtain teriflunomide. The method has the advantages that the cyanoacetic acid reacts with the 4-trifluoromethylaniline in the form of the active ester, so that the reaction activity of the cyanoacetic acid and the 4-trifluoromethylaniline is improved, the reaction condition is mild, the obtained active ester system can directly react with the 4-trifluoromethylaniline without purification and aftertreatment, the intermediate purification step is avoided, and the yield of the teriflunomide is improved.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of teriflunomide.
Background
Teriflunomide (Teriflunomide), chemical name: (2Z) -cyano-3-hydroxy-N- [4- (trifluoromethyl) phenyl]-2-butenamide, an oral pyrimidine synthase inhibitor and immunomodulator, which reversibly inhibits dihydroorotate dehydrogenase (DHODH). Teriflunomide (Teriflunomide) is a new drug for treating Multiple Sclerosis (MS) successfully developed by cenofine-amphetamine, is approved by the U.S. Food and Drug Administration (FDA) to be marketed at 9 months 2012, and is suitable for treating adult relapsing multiple sclerosis. Intensive research on teriflunomide is also carried out in China at present, but the teriflunomide is mainly used for treating skin diseases. The molecular formula of teriflunomide is: c12H9F3N2O2Molecular weight is 270.06, and the structure is shown in formula 1:
at present, the preparation methods of teriflunomide are mainly classified into the following two methods:
the first synthesis method comprises the following steps: ethyl acetoacetate and triethyl orthoformate are used as starting raw materials, 5-methylisoxazole-4-ethyl formate is generated by condensation and cyclization with hydroxylamine, 5-methylisoxazole-4-formic acid is generated by hydrolysis, acyl chloride is generated by the condensation with thionyl chloride, and then leflunomide is prepared by condensation with trifluoromethylaniline, and finally the leflunomide is subjected to ring opening under alkaline conditions to prepare teriflunomide, wherein the specific route is as follows:
the method has a plurality of reaction steps, is not easy to purify and has low total yield, and a large amount of thionyl chloride is used in the synthesis process, so that the method is very easy to corrode equipment and pollute the environment.
The second synthesis method comprises the following steps: taking 2-cyanoacetic acid and p-trifluoromethylaniline as starting raw materials, firstly reacting the 2-cyanoacetic acid with thionyl chloride to prepare acyl chloride, then condensing the acyl chloride with the p-trifluoromethylaniline to prepare an intermediate 2-cyano-N- (4-trifluoromethylphenyl) acetamide, and reacting the intermediate with acetyl chloride under the action of strong alkali to prepare teriflunomide, wherein the specific route is as follows:
the synthesis method also needs a large amount of thionyl chloride, and is more harmful to the environment.
Most of the existing teriflunomide synthesis methods need to use a large amount of acylation reagents, a large amount of smoke and acid are generated in the reaction, equipment is seriously corroded, and air is polluted.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing teriflunomide, which has the advantages of no need of purifying a reaction intermediate, simple operation, mild reaction conditions, easy recovery of waste liquid in post-treatment, environmental friendliness, and improved yield of teriflunomide preparation.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of teriflunomide, which comprises the following steps:
(1) mixing cyanoacetic acid, a condensing agent, an aprotic solvent and an alkaline reagent, and carrying out a condensation reaction to obtain an active ester system;
(2) mixing the active ester system with 4-trifluoromethyl aniline, and carrying out condensation reaction to obtain an intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide;
(3) and mixing the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide and acetyl chloride for acylation reaction to obtain teriflunomide.
Preferably, in the step (1),
the condensing agent is CDI, Pybop, HATU, DCC, EDC.HCl, HOAt, HOBt, HCTU, TBTU or isobutyl chloroformate;
the aprotic solvent is acetone, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, toluene, benzene, xylene, N-dimethylformamide, dimethyl sulfoxide, diethyl ether, tetrahydrofuran or dioxane;
the alkaline reagent is an organic base or an inorganic base, and the organic base comprises one or more of N, N-dimethylformamide, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene, triethylamine, pyridine, N-diisopropylethylamine and N-methylmorpholine; the inorganic base comprises one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride and potassium hydride.
Preferably, in the step (1), the molar ratio of the cyanoacetic acid, the condensing agent and the alkaline agent is 1: (1.1-5): (1.5-3); the mass ratio of the cyanoacetic acid to the aprotic solvent is 1: (10-30).
Preferably, in the step (1), the condensation reaction is carried out at a temperature of-5 to 10 ℃ for 1 to 5 hours.
Preferably, the molar ratio of the cyanoacetic acid in step (1) to the 4-trifluoromethylaniline in step (2) is 1: (1.1-3).
Preferably, in the step (2), the temperature of the condensation reaction is-5 to 30 ℃.
Preferably, in step (3), the molar ratio of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide to acetyl chloride is 1: (1.1-3).
Preferably, in the step (3), the acylation reaction is carried out in the presence of an aprotic solvent and a basic agent; the aprotic solvent is acetone, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, toluene, benzene, xylene, N-dimethylformamide, dimethyl sulfoxide, diethyl ether, tetrahydrofuran or dioxane; the alkaline reagent is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride or potassium hydride.
Preferably, the molar ratio of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide to basic agent is 1: (3-10); the mass ratio of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide to the solvent is 1: (10-30).
Preferably, the temperature of the acylation reaction is 20-50 ℃.
The invention provides a preparation method of teriflunomide, which comprises the following steps: (1) mixing cyanoacetic acid, a condensing agent, an aprotic solvent and an alkaline reagent, and carrying out a condensation reaction to obtain an active ester system; (2) mixing the active ester system with 4-trifluoromethyl aniline, and carrying out condensation reaction to obtain an intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide; (3) and mixing the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide and acetyl chloride for acylation reaction to obtain teriflunomide. The method has the advantages that the cyanoacetic acid reacts with the 4-trifluoromethylaniline in the form of active ester, the reactivity of the cyanoacetic acid and the 4-trifluoromethylaniline is improved, the reaction temperature is reduced, the reaction condition is mild, the obtained active ester system can directly react with the 4-trifluoromethylaniline without purification and aftertreatment, the intermediate purification step is avoided, and the yield of the teriflunomide is improved. The results of the examples show that the yield of teriflunomide prepared by the invention can reach 71.4-88.3%.
Drawings
FIG. 1 is a NMR spectrum of an intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide obtained in step (2) of example 1;
FIG. 2 is the NMR spectrum of the final product of example 1.
Detailed Description
The invention provides a preparation method of teriflunomide, which comprises the following steps:
(1) mixing cyanoacetic acid, a condensing agent, an aprotic solvent and an alkaline reagent, and carrying out a condensation reaction to obtain an active ester system;
(2) mixing the active ester system with 4-trifluoromethyl aniline, and carrying out condensation reaction to obtain an intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide;
(3) and mixing the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide and acetyl chloride for acylation reaction to obtain teriflunomide.
The invention mixes cyanoacetic acid, condensing agent, aprotic solvent and alkaline reagent to carry out condensation reaction, thus obtaining the active ester system. In the present invention, the condensing agent is preferably CDI, Pybop, HATU, DCC, edc.hcl, HOAt, HOBt, HCTU, TBTU or isobutyl chloroformate; the aprotic solvent is preferably acetone, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, toluene, benzene, xylene, N-dimethylformamide, dimethyl sulfoxide, diethyl ether, tetrahydrofuran or dioxane; the basic reagent is preferably an organic or inorganic base, the organic base preferably comprising one or more of N, N-dimethylformamide, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene, triethylamine, pyridine, N-diisopropylethylamine and N-methylmorpholine; the inorganic base preferably comprises one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride and potassium hydride.
In the present invention, the molar ratio of the cyanoacetic acid, the condensing agent and the alkali agent is preferably 1: (1.1-5): (1.5-3), more preferably 1: (1.5-2): (1.5-3); the mass ratio of the cyanoacetic acid to the aprotic solvent is preferably 1: (10-30), more preferably 1: (15-25).
In the process of mixing cyanoacetic acid, the condensing agent, the aprotic solvent and the alkaline agent according to the present invention, it is preferable that cyanoacetic acid is dissolved in the aprotic solvent and placed in an ice bath, and then the condensing agent and the alkaline agent are added.
In the invention, the condensation reaction temperature is preferably-5-10 ℃, and more preferably 0 ℃; the time of the condensation reaction is preferably 1-5 h, and more preferably 1-3 h. In the present invention, the condensation reaction is preferably carried out under stirring conditions, and the stirring rate is not particularly limited in the present invention, and a stirring rate well known in the art may be selected. In the condensation reaction process of the invention, cyanoacetic acid and a condensing agent undergo a condensation reaction to generate corresponding active ester, such as: when the condensing agent is HATU, the obtained active ester is an active ester with a structure shown in a formula 2; when the condensing agent is CDI, the obtained active ester is the active ester with the structure shown in the formula 3; the active ester can be reacted with 4-trifluoromethylaniline.
After the condensation reaction is finished, the invention does not need any purification step or other post-treatment steps, and directly mixes the obtained active ester system with 4-trifluoromethyl aniline for condensation reaction to obtain the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide.
In the present invention, the amount of the 4-trifluoromethylaniline is preferably determined according to the amount of the cyanoacetic acid used in the step (1), and the molar ratio of the cyanoacetic acid to the 4-trifluoromethylaniline is preferably 1: (1.1 to 3), more preferably 1: 1.5. the active ester system and the 4-trifluoromethyl aniline are preferably mixed according to the invention: 4-Trifluoromethylaniline was added to the active ester system. In the invention, the condensation reaction in the step (2) is preferably carried out at a temperature of-5 ℃ to 30 ℃, more preferably at a temperature of 25 ℃ to 30 ℃. The invention has no special requirements on the time of the condensation reaction, and the completion of the condensation reaction is preferably monitored by TLC.
The method has the advantages that the cyanoacetic acid reacts with the 4-trifluoromethylaniline in the form of active ester, the reactivity of the cyanoacetic acid and the 4-trifluoromethylaniline is improved, the reaction temperature is reduced, the reaction condition is mild, the obtained active ester system can directly react with the 4-trifluoromethylaniline without purification and aftertreatment, the intermediate purification step is avoided, and the yield of the teriflunomide is improved.
After the condensation reaction is finished, the invention preferably pours the reaction liquid into ice water and stirs for 30min, separates out a large amount of light yellow solid, filters, washes the filter cake with water, dries and gets the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide.
After obtaining the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide, the invention mixes the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide with acetyl chloride for acylation reaction to obtain teriflunomide.
In the present invention, the molar ratio of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide to acetyl chloride is preferably 1: (1.1 to 3), more preferably 1: (1.5-2). In the present invention, the acylation reaction is preferably carried out in the presence of an aprotic solvent and a basic agent; the aprotic solvent is preferably acetone, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, toluene, benzene, xylene, N-dimethylformamide, dimethyl sulfoxide, diethyl ether, tetrahydrofuran or dioxane, more preferably dichloromethane or N, N-dimethylformamide; the alkaline agent is preferably potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride or potassium hydride. In the present invention, the molar ratio of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide to basic agent is preferably 1: (3-10), more preferably 1: (3-5); the mass ratio of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide to the solvent is preferably 1: (10-30).
The invention preferably dissolves the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide in an aprotic solvent, then places the mixture in an ice bath, adds an alkaline reagent, finally dropwise adds acetyl chloride, and removes the ice bath after the dropwise addition is finished to carry out acylation reaction. The invention has no special requirement on the dropping rate of the acetyl chloride, and the dropping rate well known in the field can be selected. In the present invention, the temperature of the acylation reaction is preferably 20 to 50 ℃, more preferably 25 to 30 ℃. The present invention has no special requirement on the time of the acylation reaction, and the completion of the reaction is preferably monitored by TLC.
After the acylation reaction is finished, adding an aprotic solvent used for the acylation reaction into a system obtained by the reaction, carrying out suction filtration, collecting filtrate, dropwise adding hydrochloric acid with the concentration of 1mol/L into the filtrate, adjusting the pH value to 2, separating out a large amount of milky white solid, carrying out suction filtration, and drying the solid to obtain white solid, namely the teriflunomide.
The preparation method of teriflunomide provided by the present invention is described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
(1) 50g (0.59mol) of cyanoacetic acid are dissolved in 500mL of dichloromethane and placed in an ice bath; 245g of HATU (0.65mol) is added into the reaction system, 114.4g (1.6mol) of N, N-diisopropylethylamine is added, and the mixture is stirred in an ice bath for 1 hour to complete the condensation reaction, so that an active ester system is obtained, and the active ester system is directly used for the next reaction without purification and post-treatment.
(2) Adding 100g (0.62mol) of 4-trifluoromethyl aniline into the active ester system, stirring for 3h at 0 ℃ for condensation reaction, and tracking the reaction by TLC until the reaction of the raw materials is finished. After the reaction is finished, pouring the reaction solution into 1L of ice water, stirring for 30min, precipitating a large amount of light yellow solid, filtering, washing a filter cake with 500mL of water, drying and weighing 110g of solid, wherein the yield is 82%.
The obtained light yellow solid compound is identified by using nuclear magnetic resonance hydrogen spectrum, the result is shown in figure 1, and the nuclear magnetic resonance hydrogen spectrum data corresponding to figure 1 are as follows:1h NMR (600MHz, DMSO-d6) δ 10.65(s,1H),7.75(d, J ═ 8.5Hz,2H),7.70(d, J ═ 8.6Hz,2H),3.96(s,2H), consistent with the hydrogen spectrum shifts of the reported literature patents, indicated that the resulting product was intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide, formula 4.
(3) Dissolving 100g (0.44mol) of intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide in 1L of tetrahydrofuran, placing the mixture in an ice bath, adding 52.8g (1.32mol) of sodium hydroxide to react for 10min, then dropwise adding 41.5g (0.53mol) of acetyl chloride, removing the ice bath after the dropwise adding is finished, carrying out acylation reaction at room temperature of 25 ℃, and tracking the reaction by TLC until the reaction of the raw materials is finished. After the reaction is finished, adding 200mL of tetrahydrofuran into the reaction solution, carrying out suction filtration, collecting filtrate, dropwise adding hydrochloric acid with the concentration of 1mol/L into the filtrate, adjusting the pH value to 2, separating out a large amount of milky white solid, carrying out suction filtration, and drying the solid to obtain 96g of white solid with the yield of 80.7%.
The obtained white solid compound is identified by using nuclear magnetic resonance hydrogen spectrum, and the result is shown in figure 2, and the nuclear magnetic resonance hydrogen spectrum data corresponding to figure 2 are as follows:1h NMR (600MHz, DMSO-d6) δ 10.76(s,1H),7.77(d, J ═ 8.5Hz,2H),7.66(d, J ═ 8.6Hz,2H),2.26(s,3H), consistent essentially with the reported hydrogen spectrum shifts for teriflunomide, indicating that the product obtained was teriflunomide.
Example 2
(1) 50g (0.59mol) of cyanoacetic acid are dissolved in 500mL of dichloromethane and placed in an ice bath; 368.4g (0.65mol) PyBop is added into the reaction system, 161.9g (1.6mol) triethylamine is added, and the mixture is stirred in ice bath for 1h to complete condensation reaction, so that an active ester system is obtained, and the active ester system is directly used for next reaction without purification and post-treatment.
(2) The same as in example 1.
(3) Dissolving 100g (0.44mol) of intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide in 1L of acetonitrile, placing the mixture in an ice bath, adding 31.68g (1.32mol) of sodium hydride for reaction for 10min, then dropwise adding 41.5g (0.53mol) of acetyl chloride, removing the ice bath after the dropwise addition is finished, carrying out acylation reaction at room temperature of 25 ℃, and tracking the reaction by TLC until the reaction of the raw materials is finished. After the reaction is finished, adding 200mL of acetonitrile into the reaction solution, carrying out suction filtration and collecting filtrate, dropwise adding 1mol/L hydrochloric acid into the filtrate, adjusting the pH to 2, separating out a large amount of milky solid, carrying out suction filtration and drying the solid to obtain 105g of white solid, wherein the yield is 88.3%. And (3) identifying the obtained white solid compound by adopting a nuclear magnetic resonance hydrogen spectrum, wherein the nuclear magnetic resonance hydrogen spectrum data is as follows:1h NMR (600MHz, DMSO-d6) δ 10.76(s,1H),7.77(d, J ═ 8.5Hz,2H),7.66(d, J ═ 8.6Hz,2H),2.26(s,3H), consistent essentially with the reported hydrogen spectrum shifts for teriflunomide, indicating that the product obtained was teriflunomide.
Example 3
50g (0.59mol) of cyanoacetic acid are dissolved in 500mL of dichloromethane and placed in an ice bath; adding 88.8g (0.65mol) of isobutyl chloroformate into the reaction system, adding 161.8g (1.6mol) of N-methylmorpholine, stirring in ice bath for 1h to complete condensation reaction, and obtaining an active ester system, wherein the active ester system is directly used for next reaction without purification and post-treatment.
(2) The same as in example 1.
(3) Dissolving 100g (0.44mol) of intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide in 1L of methanol, placing the mixture in an ice bath, adding 182.16g (1.32mol) of potassium carbonate to react for 10min, then dropwise adding 41.5g (0.53mol) of acetyl chloride, removing the ice bath after the dropwise adding is finished, carrying out acylation reaction at room temperature of 25 ℃, and tracking the reaction by TLC until the reaction of the raw materials is finished. After the reaction, 200mL of methanol was added to the reaction mixture, which was then filtered and collectedAnd (3) collecting the filtrate, dropwise adding 1mol/L hydrochloric acid into the filtrate, adjusting the pH to 2, separating out a large amount of milky solid, performing suction filtration, and drying the solid to obtain 85g of white solid with the yield of 71.4%. And (3) identifying the obtained white solid compound by adopting a nuclear magnetic resonance hydrogen spectrum, wherein the nuclear magnetic resonance hydrogen spectrum data is as follows:1h NMR (600MHz, DMSO-d6) δ 10.76(s,1H),7.77(d, J ═ 8.5Hz,2H),7.66(d, J ═ 8.6Hz,2H),2.26(s,3H), consistent essentially with the reported hydrogen spectrum shifts for teriflunomide, indicating that the product obtained was teriflunomide.
Example 4
50g (0.59mol) of cyanoacetic acid are dissolved in 500mL of dichloromethane and placed in an ice bath; 134.1g (0.65mol) of DCC is added into the reaction system, 161.9g (1.6mol) of triethylamine is added, and the mixture is stirred in ice bath for 1h to complete condensation reaction, so that an active ester system is obtained, and the active ester system is directly used for next reaction without purification and post-treatment.
(2) The same as in example 1.
(3) Dissolving 100g (0.44mol) of intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide in 1L dioxane, placing the mixture in an ice bath, adding 74.05g (1.32mol) of potassium hydroxide to react for 10min, then dropwise adding 41.5g (0.53mol) of acetyl chloride, removing the ice bath after finishing dropping, carrying out acylation reaction at room temperature of 25 ℃, and tracking the reaction by TLC until the reaction of the raw materials is finished. After the reaction is finished, 200mL of dioxane is added into the reaction solution, the reaction solution is subjected to suction filtration and filtrate collection, 1mol/L hydrochloric acid is added into the filtrate dropwise, the pH value is adjusted to 2, a large amount of milky white solid is separated out, and the white solid 92g is obtained by suction filtration and drying of the solid, wherein the yield is 77.4%. And (3) identifying the obtained light yellow solid compound by adopting a nuclear magnetic resonance hydrogen spectrum, wherein the nuclear magnetic resonance hydrogen spectrum data is as follows:1h NMR (600MHz, DMSO-d6) δ 10.76(s,1H),7.77(d, J ═ 8.5Hz,2H),7.66(d, J ═ 8.6Hz,2H),2.26(s,3H), consistent essentially with the reported hydrogen spectrum shifts for teriflunomide, indicating that the product obtained was teriflunomide.
Example 5
50g (0.59mol) of cyanoacetic acid are dissolved in 500mL of dichloromethane and placed in an ice bath; 105.4g (0.65mol) of CDI is added into the reaction system, 99.0g (1.6mol) of 1, 8-diazabicycloundecen-7-ene is added, and the mixture is stirred in ice bath for 1h to complete condensation reaction, so that an active ester system is obtained, and the active ester system is directly used for next reaction without purification and post-treatment.
(2) The same as in example 1.
(3) Dissolving 100g (0.44mol) of intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide in 1L dioxane, placing the mixture in an ice bath, adding 74.05g (1.32mol) of potassium hydroxide to react for 10min, then dropwise adding 41.5g (0.53mol) of acetyl chloride, removing the ice bath after finishing dropping, carrying out acylation reaction at room temperature of 25 ℃, and tracking the reaction by TLC until the reaction of the raw materials is finished. After the reaction is finished, 200mL of dioxane is added into the reaction solution, the reaction solution is subjected to suction filtration and filtrate collection, 1mol/L hydrochloric acid is added into the filtrate dropwise, the pH value is adjusted to 2, a large amount of milky white solid is separated out, and the white solid is obtained by suction filtration and drying, wherein the yield is 79.9%. And (3) identifying the obtained light yellow solid compound by adopting a nuclear magnetic resonance hydrogen spectrum, wherein the nuclear magnetic resonance hydrogen spectrum data is as follows:1h NMR (600MHz, DMSO-d6) δ 10.76(s,1H),7.77(d, J ═ 8.5Hz,2H),7.66(d, J ═ 8.6Hz,2H),2.26(s,3H), consistent essentially with the reported hydrogen spectrum shifts for teriflunomide, indicating that the product obtained was teriflunomide.
Example 6
(1) 50g (0.59mol) of cyanoacetic acid are dissolved in 500mL of dichloromethane and placed in an ice bath; 268.9g (0.65mol) of HCTU is added into the reaction system, 195.8g (1.6mol) of 4-dimethylamino pyridine is added, and the mixture is stirred in ice bath for 1 hour to complete the condensation reaction, so that an active ester system is obtained, and the active ester system is directly used for the next reaction without purification and post-treatment.
(2) The same as in example 1.
(3) Dissolving 100g (0.44mol) of intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide in 1L dioxane, placing the mixture in an ice bath, adding 74.05g (1.32mol) of potassium hydroxide to react for 10min, then dropwise adding 41.5g (0.53mol) of acetyl chloride, removing the ice bath after finishing dropping, carrying out acylation reaction at room temperature of 25 ℃, and tracking the reaction by TLC until the reaction of the raw materials is finished. After the reaction is finished, 200mL of dioxane is added into the reaction solution, the reaction solution is subjected to suction filtration and filtrate collection, 1mol/L hydrochloric acid is added into the filtrate dropwise, the pH value is adjusted to 2, a large amount of milky white solid is separated out, the solid is subjected to suction filtration and drying to obtain 105g of white solid, and the yield is 88.30%. Identifying the obtained light yellow solid compound by adopting nuclear magnetic resonance hydrogen spectrumThe spectral data are:1h NMR (600MHz, DMSO-d6) δ 10.76(s,1H),7.77(d, J ═ 8.5Hz,2H),7.66(d, J ═ 8.6Hz,2H),2.26(s,3H), consistent essentially with the reported hydrogen spectrum shifts for teriflunomide, indicating that the product obtained was teriflunomide.
According to the preparation method of teriflunomide provided by the invention, a reaction intermediate is not required to be purified, the operation is simple and convenient, the reaction condition is mild, waste liquid in post-treatment is easy to recover, the environment is protected, the yield of teriflunomide preparation is improved, and the yield can reach 71.4-88.3%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A preparation method of teriflunomide is characterized by comprising the following steps:
(1) mixing cyanoacetic acid, a condensing agent, an aprotic solvent and an alkaline reagent, and carrying out a condensation reaction to obtain an active ester system;
(2) mixing the active ester system with 4-trifluoromethyl aniline, and carrying out condensation reaction to obtain an intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide;
(3) and mixing the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide and acetyl chloride for acylation reaction to obtain teriflunomide.
2. The production method according to claim 1, wherein, in the step (1),
the condensing agent is CDI, Pybop, HATU, DCC, EDC.HCl, HOAt, HOBt, HCTU, TBTU or isobutyl chloroformate;
the aprotic solvent is acetone, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, toluene, benzene, xylene, N-dimethylformamide, dimethyl sulfoxide, diethyl ether, tetrahydrofuran or dioxane;
the alkaline reagent is an organic base or an inorganic base, and the organic base comprises one or more of N, N-dimethylformamide, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene, triethylamine, pyridine, N-diisopropylethylamine and N-methylmorpholine; the inorganic base comprises one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride and potassium hydride.
3. The production method according to claim 2, wherein in the step (1), the molar ratio of the cyanoacetic acid, the condensing agent and the alkali agent is 1: (1.1-5): (1.5-3); the mass ratio of the cyanoacetic acid to the aprotic solvent is 1: (10-30).
4. The method according to any one of claims 1 to 3, wherein in the step (1), the condensation reaction is carried out at a temperature of-5 to 10 ℃ for 1 to 5 hours.
5. The method according to claim 1, wherein the molar ratio of the cyanoacetic acid in the step (1) to the 4-trifluoromethylaniline in the step (2) is 1: (1.1-3).
6. The method according to claim 5, wherein in the step (2), the condensation reaction is carried out at a temperature of-5 to 30 ℃.
7. The process of claim 1, wherein in step (3), the molar ratio of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide to acetyl chloride is 1: (1.1-3).
8. The production method according to claim 1, wherein in the step (3), the acylation reaction is carried out in the presence of an aprotic solvent and a basic agent; the aprotic solvent is acetone, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, toluene, benzene, xylene, N-dimethylformamide, dimethyl sulfoxide, diethyl ether, tetrahydrofuran or dioxane; the alkaline reagent is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydride or potassium hydride.
9. The process according to claim 8, wherein the molar ratio of intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide to basic agent is 1: (3-10); the mass ratio of the intermediate 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide to the solvent is 1: (10-30).
10. The method according to any one of claims 7 to 9, wherein the temperature of the acylation reaction is 20 to 50 ℃.
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