阅读说明：本技术 一种5-甲基异噁唑-4-甲酸的微通道连续化制备方法 (Micro-channel continuous preparation method of 5-methyl isoxazole-4-formic acid ) 是由 刘足和 于 2019-10-31 设计创作，主要内容包括：本发明涉及有机合成领域,尤其涉及一种5-甲基异噁唑-4-甲酸的微通道连续化制备方法,包括如下步骤：将2-乙氧亚甲基乙酰乙酸乙酯溶解在极性有机溶剂中得到溶液A,将盐酸羟胺和有机碱溶解在极性有机溶剂中得到溶液B；溶液A和溶液B分别通过泵同时打入微通道反应器中进行反应；反应完成后收集从微通道反应器中流出的反应液,减压除溶,加入硫酸加热水解,再结晶得5-甲基异噁唑-4-甲酸。本发明反应过程体系纯度高,减少了产品的纯化损失,使得两步反应收率达到95%以上,减少了物料消耗,节约成本,为来氟米特的生产提供了高质量的原料。(The invention relates to the field of organic synthesis, in particular to a micro-channel continuous preparation method of 5-methylisoxazole-4-formic acid, which comprises the following steps: dissolving 2-ethoxymethylene ethyl acetoacetate in a polar organic solvent to obtain a solution A, and dissolving hydroxylamine hydrochloride and organic alkali in the polar organic solvent to obtain a solution B; the solution A and the solution B are respectively pumped into a microchannel reactor by a pump to react; and after the reaction is finished, collecting the reaction liquid flowing out of the microchannel reactor, decompressing, removing the solvent, adding sulfuric acid, heating, hydrolyzing, and recrystallizing to obtain the 5-methylisoxazole-4-formic acid. The method has high system purity in the reaction process, reduces the purification loss of the product, ensures that the yield of the two-step reaction reaches more than 95 percent, reduces the material consumption, saves the cost and provides high-quality raw materials for the production of leflunomide.)

1. A micro-channel continuous preparation method of 5-methylisoxazole-4-formic acid is characterized by comprising the following steps:

(1) dissolving 2-ethoxymethylene ethyl acetoacetate in a polar organic solvent to obtain a solution A, and dissolving hydroxylamine hydrochloride and organic alkali in the polar organic solvent to obtain a solution B;

(2) the solution A and the solution B are respectively pumped into a microchannel reactor by a pump to react;

(3) after the reaction is finished, collecting the reaction liquid flowing out of the microchannel reactor, decompressing to remove the organic solvent, adding a sulfuric acid aqueous solution, heating for hydrolysis, cooling, preserving heat for crystallization, and filtering to obtain 5-methylisoxazole-4-formic acid; the specific reaction formula is as follows:

2. the microchannel continuous production method of 5-methylisoxazole-4-carboxylic acid of claim 1 wherein in step (1) the weight ratio of ethyl 2-ethoxymethyleneacetoacetate to hydroxylamine hydrochloride is from 1: 0.38 to 0.56.

3. The microchannel continuous production method of 5-methylisoxazole-4-carboxylic acid of claim 1 wherein in step (1) the polar organic solvent is selected from methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran or a mixed solvent thereof.

4. The microchannel continuous production method of 5-methylisoxazole-4-carboxylic acid of claim 1 where in step (1) the organic base is selected from the group consisting of methyldiethylamine, dimethylethylamine, triethylamine, diethylpropylamine, and tripropylamine.

5. The microchannel continuous production method of 5-methylisoxazole-4-carboxylic acid of claim 1 wherein in step (1) the molar ratio of hydroxylamine hydrochloride to organic base is from 1: 1.0 to 1.5.

6. The microchannel continuous preparation method of 5-methylisoxazole-4-carboxylic acid of claim 1 wherein in step (1) the weight ratio of ethyl 2-ethoxymethyleneacetoacetate to polar organic solvent in solution a is from 1: 1 to 5.

7. The microchannel continuous production method of 5-methylisoxazole-4-carboxylic acid of claim 1 wherein in step (1) the weight ratio of hydroxylamine hydrochloride to polar organic solvent in solution B is from 1: 5 to 10.

8. The microchannel continuous production method of 5-methylisoxazole-4-carboxylic acid according to claim 1 wherein in step (2) the flow ratio of solution a to solution B is 1: 1-6, controlling the reaction temperature of the solution A and the solution B flowing through the microchannel reactor to be 0-10 ℃, and controlling the reaction time of the solution A and the solution B flowing through the microchannel to be 2.0-5.0 min; .

9. The microchannel continuous production method of 5-methylisoxazole-4-carboxylic acid of claim 8 wherein in step (2) the flow ratio of solution a to solution B is 1: 1-3; furthermore, in the step (2), the flow ratio of the solution a to the solution B is 1: 1.4 to 2.8.

10. The continuous microchannel preparation method of 5-methylisoxazole-4-carboxylic acid as claimed in any one of claims 1 to 9 wherein in step (3) the organic solvent is evaporated under reduced pressure from the reaction solution flowing out of the microchannel reactor at a vacuum degree of-0.07 to-0.095 Mpa and an external bath temperature of 45 to 65 ℃; the concentration of the sulfuric acid aqueous solution is 3% -10%, the weight ratio of the amount of the sulfuric acid aqueous solution to the amount of the 2-ethoxymethylene ethyl acetoacetate is 2.5-5.0: 1.

Technical Field

The invention belongs to the technical field of medical chemistry, and particularly relates to a micro-channel continuous preparation method of 5-methylisoxazole-4-formic acid.

Background

Leflunomide (leflunomide) is also called efoliua, has a chemical name of N- (4-trifluoromethylphenyl) -5-methylisoxazole-4-formamide, and has a structural formula shown as the following formula I. Is a novel anti-inflammatory and immunoregulator with multiple activities, and is suitable for treating rheumatoid arthritis, organ transplantation and cancer. Was developed by Hoechst MarionRoussel, germany, in the end of the 70 th century, in 1998, the clinical trial of leflunomide for the treatment of rheumatoid arthritis was completed in the united states, and in the same 9 months, leflunomide was approved by the U.S. Food and Drug Administration (FDA) as a disease-modifying drug for the treatment of rheumatoid arthritis and marketed in the united states.

5-methyl isoxazole-4-ethyl formate (formula II) and 5-methyl isoxazole-4-carboxylic acid (formula III) are important intermediates for synthesizing leflunomide, and during the synthesis of 5-methyl isoxazole-4-ethyl formate, isomer 3-methyl isoxazole-4-ethyl formate (formula IV) is produced, and the content of the isomer directly influences the content of isomer 3-methyl-N- [4- (trifluoromethyl) phenyl ] -4-isoxazole formamide in leflunomide. In the quality control of the bulk drugs and preparations of the flurandrine, the content of the isomer 3-methyl-N- [4- (trifluoromethyl) phenyl ] -4-isoxazole formamide is required to be not more than 0.1 percent. In order to strictly control the isomers and content of the oxyfluormite, the generation of ethyl 3-methylisoxazole-4-carboxylate needs to be reduced as much as possible in the synthesis of ethyl 5-methylisoxazole-4-carboxylate.

Minister [ Qilu pharmacopoeia 2004,23(6):40-41], Schenon, Pietro [ Journal of heterocyclic Chemistry1991, 28 (2): 453 ion 457), plum family Ming [ journal of Chinese medicine industry 2002,33 (2): 53-54], Chenweimin [ first university of military medical science, 1999,19(3): 256-sodium acetylacetate 257] adopts N, N-dimethylamino methylene ethyl acetoacetate as a raw material to react with hydroxylamine hydrochloride in methanol and water solution, wherein sodium ethoxide with the same molar amount as the hydroxylamine hydrochloride is added in the synthesis to free hydroxylamine. After the reaction is finished, concentrating the system to obtain methanol, extracting the methanol with an organic solution, drying and distilling the methanol to obtain 5-methylisoxazole-4-ethyl formate, adding acid, heating, hydrolyzing, adjusting alkali, extracting, adjusting acid, drying the organic phase, concentrating the organic phase, crystallizing the residue with water, wherein the yield is 59-69%, and because 2-10% of isomer 3-methylisoxazole-4-ethyl formate is generated in the reaction system, the ethyl formate is hydrolyzed into acid and crystallized with water, the yield is low, and simultaneously a large amount of waste water and waste residues are generated, which is not beneficial to environmental protection, and the synthetic route is shown as a route A:

huanghuijing [ journal of pharmaceutical chemistry, 2000,10(2): 132-: 14-15, and johnsongjie [ journal of chinese pharmaceutical chemistry, 2000,10 (3): 199-200-, extracting the organic solution, drying, distilling to obtain 5-methyl isoxazole-4-ethyl formate, adding acid, heating for hydrolysis, adjusting alkali, extracting, adjusting acid for extraction, drying the organic phase, concentrating, crystallizing the residue with water, wherein the yield is 46-80%, and the isomer content is 2-10%. The synthetic route is shown as a scheme B:

suzhou dong (chemical journal, 2011,25(4): 11-14), patents EP0257882A1, US4892963A, US4983619A, CN102786489A and the like also use a synthesis route B, inorganic bases such as NaOH and the like are used to react with hydroxylamine hydrochloride in water, hydroxylamine is dissociated and then reacts with 2-ethoxymethylene ethyl acetoacetate to generate 5-methylisoxazole-4-formic acid acetic acid, and the content of the obtained isomer 3-methylisoxazole-4-formic acid acetic acid is less than 1.0%. WO2007086076A2 discloses a method for producing 3-methylisoxazole-4-carboxylic acid as an isomer by reacting 50% of free hydroxylamine aqueous solution with 2-ethoxymethylene ethyl acetoacetate in a methanol solvent instead of hydroxylamine hydrochloride or hydroxylamine sulfate and alkali aqueous solution, wherein the content of acetic acid is less than 0.5%, and the yield is 75%. Although the use of free hydroxylamine or the use of inorganic base to free hydroxylamine before the main reaction can reduce the formation of isomers, the reaction yield is not high, and the reaction process uses water as a solvent, and the post-treatment process includes concentration, extraction, drying, filtration and distillation, and the reaction process produces a large amount of waste water and waste residue, which wastes resources and causes great environmental pollution.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a micro-channel continuous preparation method of 5-methylisoxazole-4-formic acid, which has the advantages of low isomer generation, small amount of waste water and waste residue, mild reaction conditions and high reaction yield.

The technical scheme for realizing the above purpose of the invention is as follows: a micro-channel continuous preparation method of 5-methylisoxazole-4-formic acid comprises the following steps:

(1) dissolving 2-ethoxymethylene ethyl acetoacetate in a polar organic solvent to obtain a solution A, and dissolving hydroxylamine hydrochloride and organic alkali in the polar organic solvent to obtain a solution B;

(2) the solution A and the solution B are respectively pumped into a microchannel reactor through a pump to react;

(3) collecting reaction liquid flowing out of the microchannel reactor after the reaction is finished, decompressing to remove the organic solvent, adding a sulfuric acid aqueous solution, heating for hydrolysis, cooling, preserving heat for crystallization, and filtering to obtain 5-methylisoxazole-4-formic acid; the specific reaction formula is as follows:

preferably, in the step (1), the weight ratio of the ethyl 2-ethoxymethyleneacetoacetate to the hydroxylamine hydrochloride is 1: 0.38 to 0.56.

Preferably, in the step (1), the polar organic solvent is selected from methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, or a mixed solvent thereof.

Preferably, in the step (1), the organic base is selected from methyldiethylamine, dimethylethylamine, triethylamine, diethylpropylamine or tripropylamine.

Preferably, in the step (1), the molar ratio of the hydroxylamine hydrochloride to the organic base is 1: 1.0 to 1.5.

Preferably, in the step (1), the weight ratio of the ethyl 2-ethoxymethyleneacetoacetate to the polar organic solvent in the solution A is 1: 1-5; further, in the step (1), the weight ratio of the 2-ethoxymethylene ethyl acetoacetate to the polar organic solvent in the solution A is 1: 1 to 2.

Preferably, in the step (1), the weight ratio of the hydroxylamine hydrochloride to the polar organic solvent in the solution B is 1: 5-10; further, in the step (1), the weight ratio of the hydroxylamine hydrochloride to the polar organic solvent in the solution B is 1: 8 to 10.

Preferably, in the step (2), the flow ratio of the solution a to the solution B is 1: 1-6, controlling the reaction temperature of the solution A and the solution B flowing through the microchannel reactor to be 0-10 ℃, and controlling the reaction time of the solution A and the solution B flowing through the microchannel to be 2.0-5.0 min; further, in the step (2), the flow ratio of the solution a to the solution B is 1: 1-3; furthermore, in the step (2), the flow ratio of the solution a to the solution B is 1: 1.4 to 2.8.

Preferably, in the step (3), the organic solvent is evaporated from the reaction solution flowing out of the microchannel reactor under reduced pressure, the vacuum degree is-0.07 to-0.095 Mpa, and the external bath temperature is 45 to 65 ℃; the concentration of the sulfuric acid aqueous solution is 3% -10%, the weight ratio of the amount of the sulfuric acid aqueous solution to the amount of the 2-ethoxymethylene ethyl acetoacetate is 2.5-5.0: 1. the heating hydrolysis temperature of the sulfuric acid aqueous solution is as follows: 70-95 ℃, heat preservation and crystallization temperature: -5 to 10 ℃.

The invention has the following beneficial effects: the invention provides a method for reacting 2-ethoxymethylene ethyl acetoacetate with hydroxylamine added with organic alkali, which comprises the following steps: the organic base is used as the free base of the hydroxylamine hydrochloride, so that the fluidity of the solution B can be increased, and the reactants are more suitable for reaction by using a microchannel reactor. Therefore, the product utilizes the microchannel reactor to carry out reaction, has high yield and low production raw material cost, is suitable for continuously producing the 5-methyl isoxazole-4-ethyl formate, the content of the isomer 3-methyl isoxazole-4-ethyl formate generated in the reaction is less than 0.2 percent, other side reactions are few, and the content of the target product can reach more than 98.0 percent. After the reaction solution after the microchannel reaction is concentrated and the solvent is removed, the next hydrolysis reaction can be directly carried out, and the amount of waste water and the amount of waste residues during drying are reduced. Because the purity of the reaction process system is high, the purification loss of the product is reduced, the yield of the two-step reaction reaches more than 95 percent, the material consumption is reduced, the cost is saved, and a high-quality raw material is provided for the production of leflunomide.

Drawings

FIG. 1 is a flow chart of an embodiment of the present invention.

Reference numerals: 1. a container A; 2. a container B; 3. a pump A; 4. a pump B; 5. a microchannel reactor; 6. a receiver; 7. a reduced pressure distillation device.

Detailed Description

The present invention will be further specifically described below with reference to examples, but is not limited thereto.