Synthesis method and intermediate of rosmeltirol

Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a synthesis method and an intermediate of rosmeltirol. The method comprises the following steps: (1) mixing SM1, organic monobasic acid and inorganic acid in proportion, stirring and dissolving, dropwise adding a sodium salt solution, and then adding SM2 and a carboxylate solution for reaction to prepare an intermediate 1; (2) dissolving the intermediate 1 in an amide compound, adding potassium salt, heating for reaction, and purifying to obtain an intermediate 2; (3) dissolving the intermediate 2 in aromatic hydrocarbon, adding boride, and performing deprotection and purification to obtain an intermediate 3; and (4) dissolving the intermediate 3 in an organic sulfide, then adding SM3 and inorganic salt, and carrying out heating reaction and purification to obtain the rosimeltirome. The method provided by the invention has the characteristics of concise, efficient and safe synthesis of the rosmeltirol, reduces by-products, is helpful for improving the purity and stability of the product, avoids the use of expensive Grignard reagent and complex purification steps, and is more suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and particularly relates to a synthesis method of resmetirole and an intermediate thereof. Background Art

[0002] Resmetirom (MGL-3196) is a selective thyroid hormone receptor β (THR-β) agonist developed by Madrigal Biotechnology, Inc., USA, mainly used to treat non-alcoholic steatohepatitis (NASH). NASH is a serious non-alcoholic fatty liver disease. If not properly managed, it may develop into cirrhosis or liver cancer, which has a significant impact on the patient's health and quality of life.

[0003] There are relatively few synthetic routes for resmetirol in the published technical solutions. Currently, there are only two routes reported by original researchers. The first one is the synthetic route provided by patent CN101228135B. In this synthetic route, the compound ( ) will produce a large number of isomers that are difficult to separate, that is, compound ( ) do not participate in the reaction selectively, resulting in the inability to obtain a large amount of products in this route, and the industrial feasibility is reduced; the second is the synthesis route provided by patent CN105008335B and its division CN108101851A. In this synthesis route, a large number of isomers will also be produced and are difficult to separate, and the Grignard reagent is reactive and prone to side reactions, requiring strict reaction conditions, difficult to operate, and low safety, resulting in the inability to obtain a large amount of products in this route, and the industrial feasibility is reduced. Summary of the invention

[0004] In order to solve the problems that the current synthesis of resmetirol has few synthetic routes, large restrictions, and is prone to produce isomeric compounds that are difficult to separate, the present invention provides a synthesis method of resmetirol and an intermediate thereof.

[0005] The main purpose of the present invention is: 1. Simplify the synthesis route; 2. Optimize the synthesis route to eliminate isomer interference; 3. Realize the industrialization of synthetic lines.

[0006] To achieve the above objectives, the present invention adopts the following technical solutions.

[0007] A synthesis method of resmetirol, The method comprises: (1) SM1, organic monobasic acid and inorganic acid are mixed in proportion and stirred to dissolve, a sodium salt solution is added dropwise, and then SM2 and a carboxylate solution are added to react to obtain intermediate 1; (2) Dissolving intermediate 1 in an amide compound, adding potassium salt, heating for reaction, and purifying to obtain intermediate 2; (3) Dissolve intermediate 2 in aromatic hydrocarbon, add boride, deprotect and purify to obtain intermediate 3; (4) Dissolving the intermediate 3 in an organic sulfide, then adding SM3 and an inorganic salt, heating the reaction, and purifying to obtain resmetiro; The structural formula of SM1 in step (1) is .

[0008] As a preference, The organic monobasic acid in step (1) is acetic acid; The inorganic acid in step (1) is concentrated hydrochloric acid; The SM1, organic monobasic acid and inorganic acid in step (1) are uniformly mixed in a mass ratio of 1: (6.33-6.35): (1.1-1.3); The stirring and dissolving in step (1) is carried out at 0-10°C.

[0009] As a preference, The sodium salt solution in step (1) is a 1.35-1.37 mol / L sodium nitrite solution, and its dosage is 3.5-4.5 mL / g SM1; The sodium salt solution in step (1) is added dropwise at a rate of 10-15%VOL / min of its total volume, and after the addition is completed, the solution is kept warm at 0-10°C for 20-30 min.

[0010] As a preference, Step (1) SM2 has the structural formula: , and its dosage is 1.31~1.33 g / g SM1.

[0011] The carboxylate solution in step (1) is a 40-50 g / 100 mL sodium acetate aqueous solution, and its dosage is 3.5-4.5 mL / g SM1; The reaction in step (1) is carried out at a temperature of 0 to 10°C for 1 to 2 hours. After the reaction is completed, at least 20 times the volume of distilled water is added and stirred for 20 to 40 minutes until a solid precipitates. The solid is collected by filtration and washed with water until it is neutral to obtain intermediate 1.

[0012] As a preference, The amide compound in step (2) is N,N-dimethylformamide, and the amount used is 8-10 mL / g of intermediate 1; The potassium salt in step (2) is potassium acetate, and the amount used is 0.25-0.35 g / g of intermediate 1.

[0013] As a preference, The heating reaction in step (2) is stirred for 2 to 3 hours at a temperature of 115 to 125°C. The purification in step (2) is as follows: the solution after the reaction is completed is poured into a solution of acetic acid: water (3-9) mL: 360 mL, and after solids are precipitated, the solids are collected by filtering after stirring for 15-25 min, washed with water until neutral, dried and dissolved in acetonitrile, stirred thoroughly, added with at least 200 mL of distilled water, stirred thoroughly for 2-3 h until solids are precipitated, and the solids are collected by filtering again, washed with water and dried to obtain intermediate 2.

[0014] As a preference, The aromatic hydrocarbon in step (3) is toluene, and the amount used is 14-16 mL / g of intermediate 2; The process of dissolving the intermediate 2 in the aromatic hydrocarbon in step (3) is carried out in a nitrogen atmosphere at a temperature of 0 to 10°C; The boride in step (3) is boron tribromide, and the amount used is 1.5-1.7 mL / g of intermediate 2, and it is dripped at a dripping rate of 3-6%VOL / min of the total amount; The deprotection in step (3) is carried out in a nitrogen atmosphere at a temperature of 40 to 50 °C for 4 to 5 hours; The purification in step (3) is as follows: cooling the solution after the reaction to 0-10°C, adding methanol in an amount of 2.5-4 mL / g of intermediate 2 to quench the reaction, adding distilled water to dilute, extracting with ethyl acetate, drying the organic phase, and then recrystallizing the obtained crude product and filtering to obtain intermediate 3; The recrystallization process sequentially adopts a solution in which the volume ratio of n-hexane to ethyl acetate is (2.5-3.5):1 and a solution in which the volume ratio of n-hexane to ethyl acetate is (4.5-5.5):1.

[0015] As a preference, The organic sulfide in step (4) is dimethyl sulfoxide, and the amount used is 11-13 mL / g intermediate 3; The structural formula of SM3 in step (4) is , the dosage is 0.68-0.70 g / g intermediate 3; The inorganic salt in step (4) is potassium carbonate, and the usage amount is 0.9-1.1 g / g of intermediate 3.

[0016] As a preference, The heating reaction in step (4) is carried out in a nitrogen atmosphere at a temperature of 90 to 100° C. for 5 to 7 hours; The purification in step (4) is to extract the solution after the reaction with distilled water and ethyl acetate, dry the organic phase and spin dry it to obtain a crude product, and then crystallize it with a solution having a volume ratio of n-hexane to ethyl acetate of (2.5 to 3.5):1, and filter to obtain resmetiro.

[0017] A synthetic intermediate of resmetirol, The intermediate is 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dicarbonyl-1,2,4-triazine-6-carbonitrile; The structural formula of the intermediate is: .

[0018] As mentioned above, the overall synthesis path of the present invention is as follows: .

[0019] A previous breakthrough in the synthesis route of resmetiro has been fully and thoroughly described in patents CN105008335B and CN116406356A. The core of this achievement lies in the synthesis of the key intermediate, 6-(4-amino-2,6-dichlorophenyl)-4-isopropylpyridazine-3(2H)-one. However, although this pioneering technology has opened up a new situation, its limitations cannot be ignored: First, the synthesis process is inefficient. The construction of the core intermediate involves a series of complex chemical transformation steps, and the conversion rate of each step is relatively low, resulting in an overall yield far lower than expected. Secondly, the cost of raw materials is high. The use of specific high-cost reagents, such as isopropyl Grignard reagents, has a high purchase price and harsh storage conditions, which significantly increases the cost of synthesis and poses a major challenge to economic efficiency. Furthermore, the operation requirements are strict and there are safety hazards. The Grignard reagents involved in the synthesis process are highly reactive and extremely sensitive to environmental conditions, making the synthesis process full of uncertainty, complex operation and potential accident risks. In addition, there is a serious problem of by-product pollution. Nitrosamine impurities generated in the synthesis pathway pose a serious threat to human health, and their complete removal requires cumbersome purification procedures, which further affects production efficiency. Therefore, in order to improve synthesis efficiency, reduce production costs and ensure production safety, it is necessary to explore a new synthesis route.

[0020] For the present invention, the core lies in synthesizing a new intermediate, and through further chemical processing of 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dicarbonyl-1,2,4-triazine-6-carbonitrile, the purpose of simplifying the synthesis steps, improving the reaction yield, reducing the production cost, and reducing safety hazards is achieved. The synthesis route can be simplified as follows: first, SM1 is dissolved in glacial acetic acid and hydrochloric acid, sodium nitrite is added, and after the reaction, SM2 and sodium acetate are added to react to obtain intermediate 1; secondly, intermediate 1 is dissolved in DMF, potassium acetate is added, and heated to react to obtain intermediate 2; furthermore, intermediate 2 is dissolved in toluene, lithium chloride is added, and intermediate 3 is obtained after deprotection; finally, intermediate 3 is dissolved in DMSO, SM3 and potassium carbonate are added, and heated to react to obtain resmetiro. In the technical solution of the present invention, although the sodium acetate solution used is excessive and is easy to precipitate or has been precipitated under the required conditions, in order to ensure that the reaction proceeds in the forward direction, thereby improving the yield of intermediate 1, the use of excessive sodium acetate has a better use effect. In the reaction process, sodium acetate plays the role of an alkaline substance, which can effectively neutralize the acidic by-products generated during the reaction and keep the pH value of the reaction system in a stable state, which helps the reaction to smoothly advance in the direction of generating the target product. In addition, the excessive use of sodium acetate can also increase the solubility of the reactants and accelerate the reaction rate. By reasonably adjusting the reaction conditions, including temperature, time and the amount of sodium acetate used, the selectivity of the reaction can be further enhanced, the yield can be improved, and the probability of the occurrence of side reactions can be reduced, thereby ensuring the efficiency and safety of the entire synthesis process.

[0021] Compared with the currently published synthetic route, CN105008335B contains six steps of reaction, while the present invention only requires four steps of covalent bond reaction, and the operation procedure is more simplified. In addition, each step of the reaction in the route of the present invention has a single selectivity, and there is no need to face the problem of isomers. At the same time, the present invention successfully circumvents the problem of the route in CN101228135B, that is, in the synthesis of compounds ( ) will produce a large number of isomers and are difficult to separate. The fundamental reason is that the compound ( ) lacks selectivity in the reaction. Furthermore, the present invention also avoids the dangerous reactions caused by the Grignard reagent in CN105008335B, and all reactions can be carried out safely under normal conditions without any dangerous reactions. In addition, the present invention also avoids the synthetic route in CN105008335B and the protection steps involved in CN116406356A, significantly improving the preparation efficiency. Equally important, the present invention also bypasses the steps in the synthetic routes of CN105008335B and CN108101851A that are prone to produce impurities and lead to a decrease in product quality, because it is in the synthesis of the compound ( ) when the Grignard reagent and the compound ( ) reactions also lack selectivity and produce a large number of isomers that are difficult to separate.

[0022] The synthesis method proposed in the present invention not only significantly improves the synthesis efficiency and safety of resmetirole by simplifying the steps, improving the specificity of the reaction, eliminating high-risk operations, avoiding unnecessary protection steps and solving the isomer problem, but the new synthesis route has also made progress in reducing the formation of by-products, which is helpful to improve the purity and stability of the product, especially avoiding the use of highly dangerous Grignard reagents and complicated purification steps, making the method more suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the H'-NMR spectrum of resmetiro prepared in Example 1; Figure 2 is the H'-NMR spectrum of intermediate 1; Figure 3 is the H'-NMR spectrum of intermediate 2; Figure 4 is the H'-NMR spectrum of intermediate 3. DETAILED DESCRIPTION

[0024] The present invention is further described in detail below in conjunction with specific embodiments and the accompanying drawings. A person of ordinary skill in the art will be able to implement the present invention based on these descriptions. In addition, the embodiments of the present invention involved in the following description are generally only embodiments of a part of the present invention, rather than all embodiments. Therefore, based on the embodiments of the present invention, all other embodiments obtained by a person of ordinary skill in the art without making creative work should fall within the scope of protection of the present invention.

[0025] Unless otherwise specified, the raw materials used in the embodiments of the present invention are all commercially available or available to those skilled in the art; unless otherwise specified, the methods used in the embodiments of the present invention are all methods known to those skilled in the art.

[0026] Example 1 A method for synthesizing resmetirox. The method comprises: (1) SM1, acetic acid and concentrated hydrochloric acid were mixed in a mass ratio of 1:6.33:1.1, stirred and dissolved in an environment with a temperature of 0°C, and a sodium nitrite solution with a concentration of 1.35 mol / L was added dropwise at a rate of 10%VOL / min of its total volume according to the amount of 3.5 mL per gram of SM1. After the addition was completed, the mixture was kept warm at a temperature of 0°C for 40 min, and then SM2 with a concentration of 1.31 g / g SM1 and a sodium acetate aqueous solution with a concentration of 40 g / 100 mL were added. The amount of the sodium acetate aqueous solution was 3.5 mL / g SM1. The mixture was reacted at a temperature of 0°C for 2 h. After the reaction was completed, 30 times the volume of distilled water was added, stirred for 30 min, and solids were precipitated. The solids were collected by filtration and washed with water until neutral to obtain intermediate 1. The H'-NMR spectrum of the obtained intermediate 1 is shown as follows: Figure 2 As shown; (2) Dissolve each gram of intermediate 1 in 8 mL of N,N-dimethylformamide, add 0.25 g of potassium acetate per gram of intermediate 1, and stir the reaction at 115 °C for 3 h. Pour the solution after the reaction into a mixed solution of acetic acid: water in a volume ratio of 3 mL:360 mL. After solid precipitation, stir for 20 min, filter, collect the solid, and wash with water until the filtrate is neutral. After drying the obtained solid, add 60 mL of acetonitrile, stir well, add 300 mL of distilled water, stir well for 2 h, and solid precipitation occurs. Filter and collect the solid again, wash with water, and dry to obtain intermediate 2. The H'-NMR spectrum of the obtained intermediate 2 is shown as follows: Figure 3 As shown; (3) Dissolve each gram of intermediate 2 in 14 mL of toluene, add 1.5 mL of boron tribromide per gram of intermediate 2, and drip at a rate of 3%VOL / min of the total amount, and carry out the reaction in a nitrogen atmosphere at a temperature of 40°C for 5 h. After the reaction is completed, cool the solution to 0°C, add 10 mL of methanol at a rate of 2.5 mL / g of intermediate 2 to quench the reaction, and add 50 mL of distilled water to dilute it. Use ethyl acetate as the organic phase for extraction, dry the organic phase, and spin-dry. The crude product is recrystallized from a mixed solution of n-hexane: ethyl acetate with a volume ratio of 2.5:1 and a mixed solution of n-hexane: ethyl acetate with a volume ratio of 4.5:1, respectively, and filter to obtain intermediate 3. The H'-NMR spectrum of the obtained intermediate 3 is shown as follows: Figure 4 As shown; (4) Each gram of intermediate 3 was dissolved in 11 mL of dimethyl sulfoxide, and then 0.68 g of SM3 and 0.9 g of potassium carbonate were added per gram of intermediate 3. The reaction was carried out in a nitrogen atmosphere at a temperature of 90°C for 7 h. The solution after the reaction was completed was added with 60 mL of distilled water and 10 mL of ethyl acetate for extraction three times. The organic phase was dried and spin-dried. The crude product was recrystallized with a mixed solution of n-hexane:ethyl acetate in a volume ratio of 2.5:1, filtered, and resmetiro was obtained. The calculated yield was 76.0%. The H'-NMR spectrum characterization results are shown as follows: Figure 1 shown.

[0027] Example 2 A method for synthesizing resmetirox. The method comprises: (1) SM1, acetic acid and concentrated hydrochloric acid were mixed in a mass ratio of 1:6.34:1.2, stirred and dissolved in an environment with a temperature of 5°C, and a sodium nitrite solution with a concentration of 1.36 mol / L was added dropwise at a rate of 13%VOL / min of its total volume according to the amount of 4 mL per gram of SM1. After the addition was completed, the mixture was kept warm for 30 min in an environment with a temperature of 5°C, and then SM2 with a concentration of 1.32 g / g SM1 and a sodium acetate aqueous solution with a concentration of 45 g / 100 mL were added. The amount of the sodium acetate aqueous solution was 4 mL / g SM1. The mixture was reacted in an environment with a temperature of 5°C for 1.5 h. After the reaction was completed, 30 times the volume of distilled water was added, stirred for 30 min, and the solid was precipitated. The solid was collected by filtration and washed with water until neutral, thereby obtaining intermediate 1; (2) Dissolve each gram of intermediate 1 in 9 mL of N,N-dimethylformamide, add 0.3 g of potassium acetate per gram of intermediate 1, stir and react at 120 °C for 2.5 h, pour the solution after the reaction into a mixed solution of acetic acid: water in a volume ratio of 6 mL:360 mL, wait for solid to precipitate, stir for 20 min, filter, collect the solid, wash with water until the filtrate is neutral, dry the obtained solid, add 60 mL of acetonitrile, stir well, add 300 mL of distilled water, solid precipitates, stir well for 2.5 h, filter and collect the solid again, wash with water, and dry to obtain intermediate 2; (3) Dissolve each gram of intermediate 2 in 15 mL of toluene, add 1.6 mL of boron tribromide per gram of intermediate 2, and drip at a rate of 4.5%VOL / min of the total amount, and carry out the reaction in a nitrogen atmosphere at a temperature of 45°C for 4.5 hours. After the reaction is completed, cool the solution to 5°C, add 10 mL of methanol at a rate of 3 mL / g of intermediate 2 to quench the reaction, and add 50 mL of distilled water to dilute it. Use ethyl acetate as the organic phase for extraction, dry the organic phase, and spin-dry. The crude product is recrystallized from a mixed solution of n-hexane: ethyl acetate in a volume ratio of 3:1 and a mixed solution of n-hexane: ethyl acetate in a volume ratio of 5:1, respectively, and filter to obtain intermediate 3; (4) Each gram of intermediate 3 was dissolved in 11-13 mL of dimethyl sulfoxide, and then 0.69 g of SM3 and 1 g of potassium carbonate were added per gram of intermediate 3. The reaction was carried out in a nitrogen atmosphere at a temperature of 95 °C for 6 h. The solution after the reaction was completed was extracted three times with 60 mL of distilled water and 10 mL of ethyl acetate. The organic phase was dried and spin-dried. The crude product was recrystallized with a mixed solution of n-hexane: ethyl acetate in a volume ratio of 3:1 and filtered to obtain resmetiro. The calculated yield was 76.4%.

[0028] Example 3 A method for synthesizing resmetirox. The method comprises: (1) SM1, acetic acid and concentrated hydrochloric acid were mixed in a mass ratio of 1:6.35:1.3, stirred and dissolved in an environment with a temperature of 10 ℃, and a sodium nitrite solution with a concentration of 1.37 mol / L was added dropwise at a rate of 15%VOL / min of its total volume according to the amount of 4.5 mL per gram of SM1. After the addition was completed, the mixture was kept warm for 20 min in an environment with a temperature of 10 ℃, and then SM2 with a concentration of 1.33 g / g SM1 and a sodium acetate aqueous solution with a concentration of 50 g / 100 mL were added. The amount of the sodium acetate aqueous solution was 4.5 mL / g SM1. The mixture was reacted in an environment with a temperature of 10 ℃ for 1 h. After the reaction was completed, 20 times the volume of distilled water was added, stirred for 40 min, and the solid was precipitated. The solid was collected by filtration and washed with water until neutral, thereby obtaining intermediate 1; (2) Dissolve each gram of intermediate 1 in 10 mL of N,N-dimethylformamide, add 0.35 g of potassium acetate per gram of intermediate 1, stir and react at 125 °C for 2 h, pour the solution after the reaction into a mixed solution of acetic acid: water in a volume ratio of 9 mL:360 mL, wait for solid to precipitate, stir for 25 min, filter, collect the solid, wash with water until the filtrate is neutral, dry the obtained solid, add 60 mL of acetonitrile, stir well, add 200 mL of distilled water, solid precipitates, stir well for 3 h, filter and collect the solid again, wash with water, and dry to obtain intermediate 2; (3) Dissolve each gram of intermediate 2 in 16 mL of toluene, add 1.7 mL of boron tribromide per gram of intermediate 2, and drip at a rate of 6%VOL / min of the total amount, and carry out the reaction in a nitrogen atmosphere at a temperature of 50°C for 4 h. After the reaction is completed, cool the solution to 10°C, add 10 mL of methanol at a rate of 4 mL / g of intermediate 2 to quench the reaction, and add 50 mL of distilled water to dilute it. Use ethyl acetate as the organic phase for extraction, dry the organic phase, and spin-dry. The crude product is recrystallized from a mixed solution of n-hexane: ethyl acetate with a volume ratio of 3.5:1 and a mixed solution of n-hexane: ethyl acetate with a volume ratio of 5.5:1, respectively, and filter to obtain intermediate 3; (4) Each gram of intermediate 3 was dissolved in 13 mL of dimethyl sulfoxide, and then 0.70 g of SM3 and 1.1 g of potassium carbonate were added per gram of intermediate 3. The reaction was carried out in a nitrogen atmosphere at a temperature of 100 °C for 5 h. The solution after the reaction was completed was extracted three times with 60 mL of distilled water and 10 mL of ethyl acetate. The organic phase was dried and spin-dried. The crude product was recrystallized with a mixed solution of n-hexane: ethyl acetate in a volume ratio of 3.5:1, filtered, and resmetiro was obtained. The calculated yield was 76.2%.

[0029] Comparative Example 1 A method for synthesizing resmetiroxin, the specific preparation method is the same as that in Example 2, only the temperature range limited by the intermediate 1 of the present invention is changed, and the method for synthesizing resmetiroxin is carried out, and the specific operation is as follows: A method for synthesizing resmetirox. The method comprises: (1) SM1, acetic acid and concentrated hydrochloric acid were mixed in a mass ratio of 1:6.34:1.2, stirred and dissolved in an environment with a temperature of 20°C, and a sodium nitrite solution with a concentration of 1.36 mol / L was added dropwise at a rate of 13%VOL / min of its total volume according to the amount of 4 mL per gram of SM1. After the addition was completed, the mixture was kept warm for 30 min in an environment with a temperature of 20°C, and then SM2 with a concentration of 1.32 g / g SM1 and a sodium acetate aqueous solution with a concentration of 45 g / 100 mL were added. The amount of the sodium acetate aqueous solution was 4 mL / g SM1. The mixture was reacted in an environment with a temperature of 20°C for 1.5 h. After the reaction was completed, 20 times the volume of distilled water was added, stirred for 30 min, and the solid was precipitated. The solid was collected by filtration and washed with water until neutral, thereby obtaining intermediate 1; (2) Dissolve each gram of intermediate 1 in 9 mL of N,N-dimethylformamide, add 0.3 g of potassium acetate per gram of intermediate 1, stir and react at 120 °C for 2.5 h, pour the solution after the reaction into a mixed solution of acetic acid: water in a volume ratio of 6 mL:360 mL, wait for solid to precipitate, stir for 20 min, filter, collect the solid, wash with water until the filtrate is neutral, dry the obtained solid, add 60 mL of acetonitrile, stir well, add 200 mL of distilled water, solid precipitates, stir well for 2.5 h, filter and collect the solid again, wash with water, and dry to obtain intermediate 2; (3) Dissolve each gram of intermediate 2 in 15 mL of toluene, add 1.6 mL of boron tribromide per gram of intermediate 2, and drip at a drip rate of 4.5%VOL / min of the total amount, and carry out the reaction in a nitrogen atmosphere at a temperature of 45°C for 4.5 hours. After the reaction is completed, cool the solution to 5°C, add 10 mL of methanol at a dosage of 3 mL / g of intermediate 2 to quench the reaction, and add 50 mL of distilled water to dilute, use ethyl acetate as the organic phase for extraction, dry the organic phase, and spin-dry. The crude product is recrystallized from a mixed solution of n-hexane: ethyl acetate with a volume ratio of 3.5:1 and a mixed solution of n-hexane: ethyl acetate with a volume ratio of 5.5:1, respectively, and filter to obtain intermediate 3; (4) Each gram of intermediate 3 was dissolved in 11-13 mL of dimethyl sulfoxide, and then 0.69 g of SM3 and 1 g of potassium carbonate were added per gram of intermediate 3. The reaction was carried out in a nitrogen atmosphere at a temperature of 95 °C for 6 h. The solution after the reaction was completed was extracted three times with 60 mL of distilled water and 10 mL of ethyl acetate. The organic phase was dried and spin-dried. The crude product was recrystallized with a mixed solution of n-hexane: ethyl acetate in a volume ratio of 3:1, filtered, and resmetiro was obtained. The calculated yield was 16.7%.

[0030] Analysis of the comparative data above shows that the yield of resmetiro has decreased significantly. After further research and analysis, it was found that during the acid-catalyzed cleavage process, highly unstable secondary carbene ions will be produced due to the high temperature. These ions show extremely high activity, making it difficult to detect effectively, and are prone to unexpected decomposition reactions instead of generating target products. This phenomenon leads to deviations in the synthetic route, making the effective synthesis of resmetiro impossible to achieve.

[0031] Comparative Example 2 A method for synthesizing resmetiroxin, the specific preparation method is the same as that in Example 2, only the temperature range limited by the intermediate 1 of the present invention is changed, and the method for synthesizing resmetiroxin is carried out, and the specific operation is as follows: A method for synthesizing resmetirox. The method comprises: (1) SM1, acetic acid and concentrated hydrochloric acid were mixed in a mass ratio of 1:6.34:1.2, stirred and dissolved in an environment at a temperature of -5 °C, and a sodium nitrite solution with a concentration of 1.36 mol / L was added dropwise at a rate of 13%VOL / min of its total volume according to the amount of 4 mL per gram of SM1. After the addition was completed, the mixture was stirred and kept warm for 30 min in an environment at a temperature of -5 °C, and then 1.32 g / g SM1 of SM2 and a sodium acetate aqueous solution with a concentration of 45 g / 100 mL were added. The amount of the sodium acetate aqueous solution was 4 mL / g SM1. The reaction was stirred and stirred for 1.5 h in an environment at a temperature of -5 °C. After the reaction was completed, 20 times the volume of distilled water was added, stirred for 30 min, and the solid was precipitated. The solid was collected by filtration and washed with water until neutral, thereby obtaining intermediate 1; (2) Dissolve each gram of intermediate 1 in 9 mL of N,N-dimethylformamide, add 0.3 g of potassium acetate per gram of intermediate 1, stir and react at 120 °C for 2.5 h, pour the solution after the reaction into a mixed solution of acetic acid: water in a volume ratio of 6 mL:360 mL, wait for solid to precipitate, stir for 20 min, filter, collect the solid, wash with water until the filtrate is neutral, dry the obtained solid, add 60 mL of acetonitrile, stir well, add 200 mL of distilled water, solid precipitates, stir well for 2.5 h, filter and collect the solid again, wash with water, and dry to obtain intermediate 2; (3) Dissolve each gram of intermediate 2 in 15 mL of toluene, add 1.6 mL of boron tribromide per gram of intermediate 2, and drip at a drip rate of 4.5%VOL / min of the total amount, and carry out the reaction in a nitrogen atmosphere at a temperature of 45°C for 4.5 hours. After the reaction is completed, cool the solution to 5°C, add 10 mL of methanol at a dosage of 3 mL / g of intermediate 2 to quench the reaction, and add 50 mL of distilled water to dilute, use ethyl acetate as the organic phase for extraction, dry the organic phase, and spin-dry. The crude product is recrystallized from a mixed solution of n-hexane: ethyl acetate with a volume ratio of 3.5:1 and a mixed solution of n-hexane: ethyl acetate with a volume ratio of 5.5:1, respectively, and filter to obtain intermediate 3; (4) Each gram of intermediate 3 was dissolved in 11-13 mL of dimethyl sulfoxide, and then 0.69 g of SM3 and 1 g of potassium carbonate were added per gram of intermediate 3. The reaction was carried out in a nitrogen atmosphere at a temperature of 95 °C for 6 h. The solution after the reaction was completed was extracted three times with 60 mL of distilled water and 10 mL of ethyl acetate. The organic phase was dried and spin-dried. The crude product was recrystallized with a mixed solution of n-hexane:ethyl acetate in a volume ratio of 3:1 and filtered to obtain resmetiro. The calculated yield was 56.3%.

[0032] Analysis of the comparative data above shows that the yield of resmetiro has decreased significantly. After further research and analysis, in the process of covalent bonding, the less the molecular kinetic energy, the slower the movement speed, the insufficient collision frequency and energy, and it is difficult to overcome the activation energy required for the reaction, thereby significantly inhibiting the covalent bond reaction. In this regard, the reaction time of intermediate 1 in Benli was subsequently extended from 30 min to 2 h, and the final yield of resmetiro was 68.2%. Therefore, in order to shorten the preparation time of resmetiro, the preparation temperature of intermediate 1 should not be too low.

Claims

1. A method for synthesizing resmetirol, characterized in that: The method comprises: (1) SM1, organic monobasic acid and inorganic acid are mixed in proportion and stirred to dissolve, a sodium salt solution is added dropwise, and then SM2 and a carboxylate solution are added to react to obtain intermediate 1; (2) Dissolving intermediate 1 in an amide compound, adding potassium salt, heating for reaction, and purifying to obtain intermediate 2; (3) Dissolve intermediate 2 in aromatic hydrocarbon, add boride, deprotect and purify to obtain intermediate 3; (4) Dissolving the intermediate 3 in an organic sulfide, then adding SM3 and an inorganic salt, heating the reaction, and purifying to obtain resmetiro; The structural formula of SM1 in step (1) is .

2. The method for synthesizing resmetirol according to claim 1, characterized in that: The organic monobasic acid in step (1) is acetic acid; The inorganic acid in step (1) is concentrated hydrochloric acid; The SM1, organic monobasic acid and inorganic acid in step (1) are uniformly mixed in a mass ratio of 1: (6.33-6.35): (1.1-1.3); The stirring and dissolving in step (1) is carried out at 0-10°C.

3. The method for synthesizing resmetirol according to claim 1, characterized in that: The sodium salt solution in step (1) is a 1.35-1.37 mol / L sodium nitrite solution, and its dosage is 3.5-4.5 mL / gSM1; The sodium salt solution in step (1) is added dropwise at a rate of 10-15%VOL / min of its total volume, and after the addition is completed, the solution is kept warm at 0-10°C for 20-30 min.

4. The method for synthesizing resmetirol according to claim 1, characterized in that: Step (1) SM2 has the structural formula: , the dosage is 1.31-1.33 g / g SM1; The carboxylate solution in step (1) is a 40-50 g / 100 mL sodium acetate aqueous solution, and its dosage is 3.5-4.5 mL / g SM1; The reaction in step (1) is carried out at a temperature of 0 to 10°C for 1 to 2 hours. After the reaction is completed, at least 20 times the volume of distilled water is added and stirred for 20 to 40 minutes until a solid precipitates. The solid is collected by filtration and washed with water until it is neutral to obtain intermediate 1.

5. The method for synthesizing resmetirol according to claim 1, characterized in that: The amide compound in step (2) is N,N-dimethylformamide, and the amount used is 8-10 mL / g of intermediate 1; The potassium salt in step (2) is potassium acetate, and the amount used is 0.25-0.35 g / g of intermediate 1.

6. A method for synthesizing resmetirol according to claim 1 or 5, characterized in that: The heating reaction in step (2) is stirred for 2 to 3 hours at a temperature of 115 to 125°C. The purification in step (2) is as follows: the solution after the reaction is completed is poured into a solution of acetic acid: water (3-9) mL: 360 mL, and after solids are precipitated, the solids are collected by filtering after stirring for 15-25 min, washed with water until neutral, dried and dissolved in acetonitrile, stirred thoroughly, added with at least 200 mL of distilled water, stirred thoroughly for 2-3 h until solids are precipitated, and the solids are collected by filtering again, washed with water and dried to obtain intermediate 2.

7. The method for synthesizing resmetirol according to claim 1, characterized in that: The aromatic hydrocarbon in step (3) is toluene, and the amount used is 14-16 mL / g of intermediate 2; The process of dissolving the intermediate 2 in the aromatic hydrocarbon in step (3) is carried out in a nitrogen atmosphere at a temperature of 0 to 10°C; The boride in step (3) is boron tribromide, and the amount used is 1.5-1.7 mL / g of intermediate 2, and it is dripped at a dripping rate of 3-6%VOL / min of the total amount; The deprotection in step (3) is carried out in a nitrogen atmosphere at a temperature of 40 to 50 °C for 4 to 5 hours; The purification in step (3) is as follows: cooling the solution after the reaction to 0-10°C, adding methanol in an amount of 2.5-4 mL / g of intermediate 2 to quench the reaction, adding distilled water to dilute, extracting with ethyl acetate, drying the organic phase, and then recrystallizing the obtained crude product and filtering to obtain intermediate 3; The recrystallization process sequentially adopts a solution in which the volume ratio of n-hexane to ethyl acetate is (2.5-3.5):1 and a solution in which the volume ratio of n-hexane to ethyl acetate is (4.5-5.5):

1.

8. The method for synthesizing resmetirol according to claim 1, characterized in that: The organic sulfide in step (4) is dimethyl sulfoxide, and the amount used is 11-13 mL / g intermediate 3; The structural formula of SM3 in step (4) is , the dosage is 0.68-0.70 g / g intermediate 3; The inorganic salt in step (4) is potassium carbonate, and the usage amount is 0.9-1.1 g / g of intermediate 3.

9. A method for synthesizing resmetirole according to claim 1 or 8, characterized in that: The heating reaction in step (4) is carried out in a nitrogen atmosphere at a temperature of 90 to 100° C. for 5 to 7 hours; The purification in step (4) is to extract the solution after the reaction with distilled water and ethyl acetate, dry the organic phase and spin dry it to obtain a crude product, and then crystallize it with a solution having a volume ratio of n-hexane to ethyl acetate of (2.5 to 3.5):1, and filter to obtain resmetiro.

10. A synthetic intermediate of resmetirol, characterized in that: The intermediate is 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dicarbonyl-1,2,4-triazine-6-carbonitrile; The structural formula of the intermediate is: .

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