CN111233779B - Preparation method of leflunomide - Google Patents
Preparation method of leflunomide Download PDFInfo
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- CN111233779B CN111233779B CN202010254354.4A CN202010254354A CN111233779B CN 111233779 B CN111233779 B CN 111233779B CN 202010254354 A CN202010254354 A CN 202010254354A CN 111233779 B CN111233779 B CN 111233779B
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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
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Abstract
The invention relates to a novel preparation process of leflunomide as a medicinal raw material drug, which is prepared by cyclizing acetoacetic ester serving as a raw material with hydroxylamine hydrochloride. The process can better control the content of the 3-methyl isomer and the 4-trifluoromethyl aniline in the leflunomide product, and has higher yield and more simplicity. The process has the advantages of less industrial waste water and waste gas, more environmental protection, and effective reduction of production cost and corrosion to equipment.
Description
Technical Field
The invention relates to a preparation process of a medicinal raw material drug, in particular to a novel preparation process of leflunomide serving as a medicinal raw material drug.
Background
Leflunomide (leflunomide) is the first new drug approved in the last decade specifically for the treatment of rheumatoid arthritis. The product has immunosuppressive and antiinflammatory effects, and has novel action mechanism, and it can inhibit cell adhesion and acid kinase activity, influence information transmission of cytokine, and inhibit activity of dihydroorotate dehydrogenase, thereby inhibiting proliferation of active lymphocyte related to rheumatoid arthritis. Animal experiments and clinical results show that leflunomide is the first effective therapeutic drug for slowing the progression of chronic diseases of rheumatoid arthritis by inhibiting local inflammation, connective tissue hyperplasia and the systemic reaction of arthritis, and not only can reduce various indications and symptoms of patients with rheumatoid arthritis, but also can prevent structural necrosis caused by the rheumatoid arthritis. The X-ray result shows that the product is obviously improved in the aspects of joint erosion, joint space narrowing and the like by using the product, which is different from the existing anti-rheumatoid arthritis drugs comprising methotrexate, sulfasalazine and the like, is the first drug showing definite curative effect on objective indexes, and has the characteristics of quick response, safe use, good tolerance, long-term taking by patients and the like.
In the preparation process of the leflunomide raw material medicine, the control of the content of 3-methyl isomer and 4-trifluoromethyl aniline of leflunomide is one of the key points in the quality control of the leflunomide raw material medicine. The high or low levels of these two impurities are critical to the adverse effects of the leflunomide formulation product. The quality standard of leflunomide raw material medicine approved by the national food and drug administration specifies that the content of leflunomide 3-methyl isomer is not more than 0.1 percent and the content of 4-trifluoromethyl aniline is not more than 0.25 percent. Leflunomide has the chemical formula structure:
the high or low regioselectivity of the cyclization reaction to form the isoxazole ring in the leflunomide synthesis process is key to determining the high or low content of 3-methyl isomer of leflunomide. The cyclization reaction for forming an isoxazole ring is mainly carried out by the following methods:
(1) ethyl acetoacetate and N, N-dimethylformamide dimethyl acetal are reacted to obtain N, N-dimethylamino methylene ethyl acetoacetate, and then the ethyl acetoacetate and hydroxylamine hydrochloride are reacted under reflux in an alcohol solvent to obtain the 5-methyl isoxazole-4-carboxylic acid ethyl ester (J.Heterocyclic chem., 1991, 28, 453; journal of Chinese medical industry, 2002, 33, 53; first university of military medicine, 1999, 19, 256; Zilu's medicine, 2004, 23, 40.).
(2) Ethyl acetoacetate and triethyl orthoformate are reacted to obtain 2-ethoxymethylene ethyl acetoacetate, and then the ethyl 2-ethoxymethylene ethyl acetoacetate is condensed with hydroxylamine hydrochloride or hydroxylamine sulfate in an alcohol solvent in the presence of sodium acetate to obtain 5-methylisoxazole-4-carboxylic acid ethyl ester (J.chem.Soc., Perkin Trans.I, 1988, 1875; EP 0257882; WO 0160363; WO 03042193; J.Chinese medical industry, 2001, 32, 49; J.Chinese medical industry, 2002, 33, 158; J.Chinese medical industry, 2000, 31, 533; Chinese medical college, 2000, 31, 330; J.Chinese medicinal chemistry, 2000, 10, 199; J.Chinese medicinal chemistry, 2000, 10, 132.).
(3) Ethyl acetoacetate and triethyl orthoformate are reacted to obtain 2-ethoxymethylene ethyl acetoacetate, and the 2-ethoxymethylene ethyl acetoacetate is condensed with free hydroxylamine aqueous solution in alcohol solvent to obtain 5-methyl isoxazole-4-carboxylic acid ethyl ester (WO 2007086076).
(4) The 5-methyl isoxazole-4-carboxylic acid ethyl ester is obtained by condensing N, N-dimethylamino methylene acetoacetic acid ethyl ester and free hydroxylamine aqueous solution in an alcohol solvent (patent CN 101817798).
In the above method, WO2007086076 uses free hydroxylamine aqueous solution instead of hydroxylamine hydrochloride or hydroxylamine sulfate, and the method is reported in the patent to be beneficial to the improvement of regioselectivity, and the purity of the product is more than 98%, but the content of the 3-methyl isomer in the product is not clearly shown. In practice, we have found that none of the above methods provides good control of the 3-methyl isomer content of the leflunomide product, and that multiple recrystallizations are required in the synthesis process to achieve 3-methyl isomer contents of less than 0.1%. Repeated recrystallization not only causes the complexity of the synthesis process, but also causes higher production cost of leflunomide raw material medicine and influences the product quality. The patent CN101817798 directly uses N, N-dimethyl amino methylene acetyl acetate as raw material, does not directly explain the source of the raw material, and directly purchases the raw material to cause the production cost to be irretrievable.
In the reaction step of the final synthesis of amide from leflunomide, most of the literature reports that 5-methylisoxazole-4-carboxylic acid ethyl ester is hydrolyzed under acidic conditions to obtain 5-methylisoxazole-4-carboxylic acid, and then the 5-methylisoxazole-4-carboxylic acid ethyl ester reacts with thionyl chloride to prepare an acyl chloride intermediate, and the acyl chloride intermediate reacts with 4-trifluoromethylaniline step by step or in a one-pot method to obtain leflunomide. The method uses thionyl chloride, which not only causes a large amount of industrial waste gas and acidic waste water, but also causes serious industrial pollution and serious equipment corrosion. In addition, part of the documents use more than 2 times of molar weight of 4-trifluoromethyl aniline for condensation with acyl chloride, so that the method not only causes the waste of raw materials and the increase of production cost, but also causes the content of the 4-trifluoromethyl aniline in the final leflunomide product to exceed the standard, and influences the quality of the leflunomide product.
Disclosure of Invention
The invention aims to provide a novel preparation process of leflunomide raw material medicine, and aims to overcome the defects in the conventional synthesis process. The new process for preparing leflunomide provided by the invention can better control the contents of 3-methyl isomer and 4-trifluoromethyl aniline in leflunomide products, and has higher yield and more simplicity. The process has the advantages of less industrial waste water and waste gas, more environmental protection, and effective reduction of production cost and corrosion to equipment.
A preparation method of leflunomide is characterized by comprising the following steps:
a) 5-methylisoxazole-4-carboxylic acid
And (3) putting ethyl acetoacetate in DMF-DMA, cooling to-20 ℃, slowly adding sodium hydrogen, and heating to room temperature to react for 3 hours to obtain the dimethyl enamine structure. And (2) adding N, N-dimethylamino methylene ethyl acetoacetate into ethanol, cooling to-5 ℃, adding hydroxylamine hydrochloride with equal proportional molar weight, reacting at room temperature until the raw materials disappear, spin-drying the solvent after the reaction is finished, adding 30% hydrochloric acid aqueous solution, heating and refluxing, evaporating water, and recrystallizing toluene to obtain the 5-methylisoxazole-4-carboxylic acid.
b) Leflunomide
5-methylisoxazole-4-carboxylic acid is placed in dichloromethane, cooled to 0 ℃, added with triethylamine and CDI, stirred for half an hour, added with dichloromethane solution of 4-trifluoromethylaniline, kept warm and reacted until the raw materials disappear, extracted after the reaction is finished, washed by organic phase saturated sodium bicarbonate solution, dried and rotated, and recrystallized by toluene to obtain leflunomide.
Preferably, the temperature at which sodium hydrogen is added is-20 ℃.
Preferably, the solvent used in the cyclization with hydroxylamine hydrochloride is an alcohol solvent, preferably ethanol.
Preferably, the solvent used for recrystallization is toluene.
Preferably, the acid used for hydrolysis is hydrochloric acid.
Preferably, the condensing agent used in the condensation is CDI, in order to activate the carboxyl groups.
Preferably, the solvent used in the condensation is dichloromethane.
Preferably, the solvent used for recrystallization of leflunomide is toluene.
Preferably, the molar ratio of CDI, 4-trifluoromethylaniline to 5-methylisoxazole-4-carboxylic acid is from 1 to 2: 1:1-2.
The invention has the beneficial effects that:
i. the raw materials used in the invention are all cheap and easily available, and the production cost is greatly reduced.
And ii, all reaction conditions are mild and not harsh, and the method is suitable for industrial mass production.
The content of the isomer and other impurities produced by the method meets the national relevant regulations, and the yield is higher.
The process used by the invention has the advantages of less pollution, less waste liquid generation and more environmental protection.
Detailed Description
The following exemplary reactions are provided to illustrate the present invention, and simple substitutions or modifications of the present invention by those skilled in the art are within the scope of the present invention.
Example 1
5-methylisoxazole-4-carboxylic acid
And (3) adding 50g of ethyl acetoacetate into DMF-DMA, cooling to-20 ℃, slowly adding 10.1g of sodium hydrogen, heating to room temperature for reaction for 3 hours, adding water to precipitate a solid, stirring, filtering and drying to obtain the dimethyl enamine structure. Adding N, N-dimethylamino methylene ethyl acetoacetate into ethanol, cooling to-5 ℃, adding 26.7g of hydroxylamine hydrochloride with equal proportional molar weight, reacting at room temperature until the raw materials disappear, spin-drying the solvent after the reaction is finished, adding 30% hydrochloric acid aqueous solution, heating and refluxing, evaporating to dry water, and recrystallizing toluene to obtain 48g of 5-methylisoxazole-4-carboxylic acid with the yield of 98.3%.
Leflunomide
20g of 5-methylisoxazole-4-carboxylic acid is placed in dichloromethane, the dichloromethane is cooled to 0 ℃, 25.5g of triethylamine and CDI25.5g are added, after the dichloromethane is stirred for half an hour, 25.3g of 4-trifluoromethylaniline is added, the temperature is kept continuously for reaction until the raw materials disappear, after the reaction is finished, the raw materials are extracted, the organic phase saturated sodium bicarbonate solution is washed, dried and rotated, and the toluene is recrystallized to obtain 40g of leflunomide, wherein the yield is 94%.
Example 2
5-methylisoxazole-4-carboxylic acid
And (3) adding 50g of ethyl acetoacetate into DMF-DMA, cooling to-20 ℃, slowly adding 10.1g of sodium hydrogen, heating to room temperature for reaction for 3 hours, adding water to precipitate a solid, stirring, filtering and drying to obtain the dimethyl enamine structure. Adding N, N-dimethylamino methylene ethyl acetoacetate into ethanol, cooling to-5 ℃, adding 26.7g of hydroxylamine hydrochloride with equal proportional molar weight, reacting at room temperature until the raw materials disappear, spin-drying the solvent after the reaction is finished, adding 30% hydrochloric acid aqueous solution, heating and refluxing, evaporating to dry water, and recrystallizing toluene to obtain 48g of 5-methylisoxazole-4-carboxylic acid with the yield of 98.3%.
Leflunomide
20g of 5-methylisoxazole-4-carboxylic acid is put in dichloromethane, cooled to 0 ℃, added with triethylamine and CDI38.3g, stirred for half an hour, added with 25.3g of dichloromethane solution of 4-trifluoromethylaniline, kept warm and reacted until the raw materials disappear, extracted after the reaction is finished, washed by organic phase saturated sodium bicarbonate solution, dried and rotated, and recrystallized by toluene to obtain 35g of leflunomide with the yield of 82.3%.
Example 3
5-methylisoxazole-4-carboxylic acid
And (3) adding 50g of ethyl acetoacetate into DMF-DMA, cooling to-20 ℃, slowly adding 10.1g of sodium hydrogen, heating to room temperature for reaction for 3 hours, adding water to precipitate a solid, stirring, filtering and drying to obtain the dimethyl enamine structure. Adding N, N-dimethylamino methylene ethyl acetoacetate into ethanol, cooling to-5 ℃, adding 26.7g of hydroxylamine hydrochloride with equal proportional molar weight, reacting at room temperature until the raw materials disappear, spin-drying the solvent after the reaction is finished, adding 30% hydrochloric acid aqueous solution, heating and refluxing, evaporating to dry water, and recrystallizing toluene to obtain 48g of 5-methylisoxazole-4-carboxylic acid with the yield of 98.3%.
Leflunomide
20g of 5-methylisoxazole-4-carboxylic acid is placed in dichloromethane, the dichloromethane is cooled to 0 ℃, 25.5g of triethylamine and CDI25.5g are added, after the dichloromethane is stirred for half an hour, 38g of dichloromethane solution of 4-trifluoromethylaniline is added, the temperature is kept continuously for reaction until the raw materials disappear, after the reaction is finished, extraction is carried out, the organic phase saturated sodium bicarbonate solution is washed, dried and dried, toluene is recrystallized to obtain 25g of leflunomide, and the yield is 58.8%.
Example 4
5-methylisoxazole-4-carboxylic acid
And (3) adding 50g of ethyl acetoacetate into DMF-DMA, cooling to-20 ℃, slowly adding 10.1g of sodium hydrogen, heating to room temperature for reaction for 3 hours, adding water to precipitate a solid, stirring, filtering and drying to obtain the dimethyl enamine structure. Adding N, N-dimethylamino methylene ethyl acetoacetate into ethanol, cooling to-5 ℃, adding 26.7g of hydroxylamine hydrochloride with equal proportional molar weight, reacting at room temperature until the raw materials disappear, spin-drying the solvent after the reaction is finished, adding 30% hydrochloric acid aqueous solution, heating and refluxing, evaporating to dry water, and recrystallizing toluene to obtain 48g of 5-methylisoxazole-4-carboxylic acid with the yield of 98.3%.
Leflunomide
20g of 5-methylisoxazole-4-carboxylic acid is placed in dichloromethane, the dichloromethane is cooled to 0 ℃, 18g of triethylamine and methylsulfonyl chloride are added, 25.3g of dichloromethane solution of 4-trifluoromethylaniline is added after stirring for half an hour, the temperature is kept continuously for reaction until the raw materials disappear, extraction is carried out after the reaction is finished, the organic phase saturated sodium bicarbonate solution is washed, dried and dried, toluene is recrystallized to obtain 36g of leflunomide, and the yield is 85%.
Comparative example 1
5-methylisoxazole-4-carboxylic acid
And (3) adding 50g of ethyl acetoacetate into DMF-DMA, cooling to-20 ℃, slowly adding 10.1g of sodium hydrogen, heating to room temperature for reaction for 3 hours, adding water to precipitate a solid, stirring, filtering and drying to obtain the dimethyl enamine structure. Adding N, N-dimethylamino methylene ethyl acetoacetate into ethanol, cooling to-5 ℃, adding 26.7g of hydroxylamine hydrochloride with equal proportional molar weight, reacting at room temperature until the raw materials disappear, spin-drying the solvent after the reaction is finished, adding 30% hydrochloric acid aqueous solution, heating and refluxing, evaporating to dry water, and recrystallizing toluene to obtain 48g of 5-methylisoxazole-4-carboxylic acid with the yield of 98.3%.
Leflunomide
20g of 5-methylisoxazole-4-carboxylic acid is placed in dichloromethane, the dichloromethane is cooled to 0 ℃, 25.5g of triethylamine and CDI25.5g are added, after stirring for half an hour, 63.4g of dichloromethane solution of 4-trifluoromethylaniline is added, the temperature is kept continuously for reaction until the raw materials disappear, after the reaction is finished, extraction is carried out, the organic phase saturated sodium bicarbonate solution is washed, dried and rotated, and toluene is recrystallized to obtain 15g of leflunomide, wherein the yield is 35.3%.
Comparative example 2
5-methylisoxazole-4-carboxylic acid
And (3) adding 50g of ethyl acetoacetate into DMF-DMA, cooling to-20 ℃, slowly adding 10.1g of sodium hydrogen, heating to room temperature for reaction for 3 hours, adding water to precipitate a solid, stirring, filtering and drying to obtain the dimethyl enamine structure. Adding N, N-dimethylamino methylene ethyl acetoacetate into ethanol, cooling to-5 ℃, adding 26.7g of hydroxylamine hydrochloride with equal proportional molar weight, reacting at room temperature until the raw materials disappear, spin-drying the solvent after the reaction is finished, adding 30% hydrochloric acid aqueous solution, heating and refluxing, evaporating to dry water, and recrystallizing toluene to obtain 48g of 5-methylisoxazole-4-carboxylic acid with the yield of 98.3%.
Leflunomide
20g of 5-methylisoxazole-4-carboxylic acid is put in dichloromethane, cooled to 0 ℃, added with triethylamine and CDI63.8g, stirred for half an hour, added with 25.3g of dichloromethane solution of 4-trifluoromethylaniline, kept warm and reacted until the raw materials disappear, extracted after the reaction is finished, washed by organic phase saturated sodium bicarbonate solution, dried and rotated, and recrystallized by toluene to obtain 32g of leflunomide with the yield of 75.3%.
Comparative example 3
5-methylisoxazole-4-carboxylic acid
And (3) adding 50g of ethyl acetoacetate into DMF-DMA, cooling to-20 ℃, slowly adding 10.1g of sodium hydrogen, heating to room temperature for reaction for 3 hours, adding water to precipitate a solid, stirring, filtering and drying to obtain the dimethyl enamine structure. Adding N, N-dimethylamino methylene ethyl acetoacetate into ethanol, cooling to-5 ℃, adding 26.7g of hydroxylamine hydrochloride with equal proportional molar weight, reacting at room temperature until the raw materials disappear, spin-drying the solvent after the reaction is finished, adding 30% hydrochloric acid aqueous solution, heating and refluxing, evaporating to dry water, and recrystallizing toluene to obtain 48g of 5-methylisoxazole-4-carboxylic acid with the yield of 98.3%.
Leflunomide
20g of 5-methylisoxazole-4-carboxylic acid is put in dichloromethane, cooled to 0 ℃, added with 14.9g of triethylamine and methyl chloroformate, stirred for half an hour, added with 25.3g of dichloromethane solution of 4-trifluoromethylaniline, kept warm and reacted until the raw materials disappear, extracted after the reaction is finished, washed by organic phase saturated sodium bicarbonate solution, dried and rotated, and recrystallized by toluene to obtain 36g of leflunomide with the yield of 85%.
Comparative example 4
According to patent CN101817798
The preparation method comprises the following steps:
1: 5-Methylisoxazole-4-carboxylic acid ethyl ester
Adding N, N-dimethyl amino methylene ethyl acetoacetate (185g, 1.0mol) into 600ml of methanol, starting stirring, starting freezing, cooling a reaction system to-5 ℃, slowly dropwise adding 50% hydroxylamine aqueous solution (66g, 1.0mol), and keeping the reaction system stable at-5-0 ℃ in the dropwise adding process. After the dropwise addition, the temperature is raised to 10-15 ℃ for continuous reaction until the raw materials disappear. After completion of the reaction, the reaction solution (200 ml. times.3) was extracted with methylene chloride, and the organic phases were combined. The organic phase was washed once more with saturated aqueous sodium bicarbonate (300ml) and water (300ml), dried over anhydrous sodium sulfate, and concentrated to give 143g of a milky white liquid with a yield of 92.2%.
2: 5-methylisoxazole-4-carboxylic acid
Ethyl 5-methylisoxazole-4-carboxylate (155g, 1.0mol) was added to a mixed solvent of 36% hydrochloric acid (300ml) and glacial acetic acid (150ml), stirring was turned on, and heating was carried out to reflux until the disappearance of the starting materials. After the reaction is finished, the solvent is evaporated to obtain a grey brown solid, toluene (150ml) is added, the mixture is heated to 90-100 ℃ to be dissolved, after the mixture is cooled to room temperature, solid crystals are separated out, the mixture is filtered, a filter cake is washed by toluene and water, and the white solid 82g is obtained after drying, and the yield is 64.6%.
3: leflunomide
Dissolving 5-methyl isoxazole-4-carboxylic acid (127g, 1.0mol) in dichloromethane (600ml), cooling to-5 ℃ in an ice water bath, slowly adding triethylamine (106g, 1.05mol), keeping the temperature not to exceed 0 ℃, after the addition is finished, slowly adding a dichloromethane (200ml) solution of methyl chloroformate (94.5g, 1.0mol), and keeping the temperature not to exceed 0 ℃ in the adding process. After the completion of the addition, the reaction was continued at 0 ℃ for half an hour, and then a solution of 4-trifluoromethylaniline (169g, 1.05mol) in methylene chloride (200ml) was added dropwise while keeping the temperature at 0 ℃ or lower. After the dropwise addition is finished, the reaction is continued at the temperature of between 5 ℃ below zero and 0 ℃ until the raw materials disappear. After the reaction, the reaction solution was washed with an aqueous sodium bicarbonate solution (300 ml. times.2), water (300 ml. times.2) and a saturated saline solution (300 ml. times.2) to separate an organic phase, after the solvent was distilled off, the residual solid was dissolved in toluene, decolorized, cooled to room temperature, crystallized, filtered, the cake was washed with toluene and water, dried and pulverized to obtain 230g of a white crystalline solid with a yield of 85.2%.
| Example 1 | Example 2 | Example 3 | Example 4 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | |
| Condensing agent, 4-trifluoromethylaniline and 5-methylisoxazole-4-carboxylic acid Mole ratio of | 1:1:1 | 1.5:1:1 | 1:1.5:1 | 1:1:1 | 1:2.5:1 | 2.5:1:1 | 1:1:1 | 1:1:1 |
| Condensing agent | CDI | CDI | CDI | Methanesulfonyl chloride | CDI | CDI | Chloroformic acid methyl ester | Chloroformic acid methyl ester |
| Yield% | 94 | 82.3 | 58.8 | 85 | 35.3 | 75.3 | 85 | 85.2。 |
Claims (1)
1. A preparation method of leflunomide is characterized by comprising the following steps:
1) 5-methylisoxazole-4-carboxylic acid
Placing ethyl acetoacetate in DMF-DMA, cooling to-20 ℃, slowly adding sodium hydrogen, heating to room temperature for reaction for 3 hours to obtain a dimethyl enamine structure, placing N, N-dimethyl amino methylene ethyl acetoacetate in ethanol, cooling to-5 ℃, adding hydroxylamine hydrochloride with equal proportional molar weight, reacting at room temperature until raw materials disappear, drying the solvent after the reaction is finished, adding 30% hydrochloric acid aqueous solution, heating for reflux, evaporating water, and recrystallizing toluene to obtain 5-methylisoxazole-4-carboxylic acid;
2) leflunomide
5-methylisoxazole-4-carboxylic acid is placed in dichloromethane, cooled to 0 ℃, added with triethylamine and CDI, stirred for half an hour, added with dichloromethane solution of 4-trifluoromethylaniline, kept warm and reacted until the raw materials disappear, extracted after the reaction is finished, washed by organic phase saturated sodium bicarbonate solution, dried and rotated, and recrystallized by toluene to obtain leflunomide;
the molar ratio of CDI, 4-trifluoromethylaniline to 5-methylisoxazole-4-carboxylic acid is 1-2: 1:1-2.
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Effective date of registration: 20221221 Address after: Room 801, No. 1719-8, Huishan Avenue, Huishan District, Wuxi City, Jiangsu Province, 214000 Patentee after: Huangtu Pharmaceutical (Wuxi) Co.,Ltd. Address before: Kunming Medical University, 1168 Chunrong West Road, Yuhua street, Chenggong District, Kunming City, Yunnan Province, 650500 Patentee before: Liao Wenying |
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