Preparation method of Resmetirom key intermediate

Abstract

The invention relates to the technical field of medicine synthesis, and discloses a synthesis process of a Resmetirom intermediate II, which comprises the following steps: (1) adding N-cyano acetyl urethane (SM2) and sodium nitrite into water; (2) adding a compound III and acid into a solvent for dissolving, and dropwise adding into a reaction system in the step (1) at controlled temperature; and (3) after the reaction is finished, filtering, rinsing and drying to obtain the high-quality Resmetirom intermediate II. According to the invention, the product appearance is improved, the generation of impurities is controlled, the yield is high, the product purity is high, the process is safe and reliable, and a better solution is provided for the industrial production of the Resmetirom intermediate II.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, and to a method for preparing Resmetirom key intermediate II. Background Technology

[0002] Resmetirom (trade name: Rezdiffra) is an oral, liver-targeted, selective thyroid hormone receptor beta (THR-β) agonist developed by Madrigal Pharmaceuticals Inc. It received accelerated approval from the U.S. FDA in March 2024, becoming the world's first drug specifically for the treatment of non-alcoholic steatohepatitis (NASH) with moderate to severe liver fibrosis, marking a major breakthrough in the treatment of NASH / metabolic steatohepatitis (MASH).

[0003] The structure of Resmetirom intermediate II is shown below. It is the N-1 step intermediate of Resmetirom, and its quality directly affects the quality of the final product.

[0004]

[0005] Resmetirom key intermediate II structural formula

[0006] Patents WO2007009913A1 and WO2014043706A1 report a synthetic method for Resmetirom. First, compound VI is obtained via a Minisci reaction. Compound VI is then coupled with 2,6-dichloro-4-aminophenol to obtain compound V. Compound V is then hydrolyzed, acetylated, and deacetylated to obtain compound III. Compound III is then diazotized and reacted with a Japp-Klingemann reaction to convert to compound II. Finally, an intramolecular cyclization reaction occurs to generate Resmetirom. The synthetic route is as follows:

[0007]

[0008] The final step of this route involves cyclization to obtain Resmetirom. The reaction is relatively simple with few side reactions. However, Resmetirom has poor solubility in common solvents, making crystallization and purification difficult. Therefore, the quality of Resmetirom intermediate II is particularly important, as it directly affects the quality of the final Resmetirom product. The synthesis of intermediate II from Resmetirom intermediate III involves diazotization and the Japp-Klingemann reaction, with the corresponding reaction formulas shown below:

[0009]

[0010] Several different synthetic processes have been reported for the synthesis of Resmetirom intermediate II, mainly including the following methods:

[0011] 1) The original research company, Madagascar Pharmaceuticals, reported a synthetic process for Resmetirom intermediate II in patent WO2014043706A1: Compound III, N-cyanoacetylurane, and acetic acid were first added to the reaction system. After adding hydrochloric acid, an aqueous solution of NaNO2 was added dropwise. Once compound III was completely converted to a diazonium salt, an aqueous solution of sodium acetate was added to react and generate Resmetirom intermediate II. The final yield was 91%, the purity was 90.4%, and the product color was orange.

[0012] 2) Roche Pharmaceuticals' patent WO2007009913A1 reports the synthesis process of Resmetirom intermediate II: Compound III, water, and hydrochloric acid are first added to the reaction system, followed by the dropwise addition of NaNO2 aqueous solution. After compound III is completely converted to a diazonium salt, N-cyanoacetylurane, water, and pyridine are added to generate Resmetirom intermediate II. The final yield is 76%, the product color is orange, and the purity is not disclosed.

[0013] 3) Sichuan Lingshengyi Pharmaceutical Co., Ltd.'s patent CN120441552A reports the synthesis process of Resmetirom intermediate II: Compound III, hydrochloric acid, water, and acetic acid are first added to the reaction system, followed by the dropwise addition of NaNO2 aqueous solution. After compound III is completely converted to a diazonium salt, pyridine and N-cyanoacetylurane are then added to react and generate Resmetirom intermediate II. The final yield is 87.1%, the purity is 95.1%, and the product color is pale yellow.

[0014] 4) Hebei University of Science and Technology patent CN119504714A reports the synthesis process of Resmetirom intermediate II: Compound III, water, and hydrochloric acid are first added to the reaction system, followed by the dropwise addition of NaNO2 aqueous solution. After compound III is completely converted to a diazonium salt, N-cyanoacetylurane, water, and sodium acetate are added to react and generate Resmetirom intermediate II. The final yield is 77.9%, the purity is 98.71%, and the product color is orange.

[0015] 5) Jiangxi Tonghe Pharmaceutical Co., Ltd.'s patent CN118271248A reports the synthesis process of Resmetirom intermediate II: Compound III, N-cyanoacetylurane, acetic acid, and hydrochloric acid are first added to the reaction system, followed by the dropwise addition of NaNO2 aqueous solution. The reaction is carried out at room temperature for 2 hours to generate Resmetirom intermediate II. The final yield is 95%, the product color is pale yellow, and the purity is not disclosed.

[0016] The different synthetic processes for Resmetirom intermediate II mainly involve the use of different acids and different order of addition, resulting in different technical effects. The differences between the different synthetic processes are shown in Table 1:

[0017] Table 1: Comparison of Synthesis Processes for Resmetirom Intermediate II

[0018]

[0019] *Note: Ⅲ represents Resmetirom intermediate Ⅲ, and SM2 represents N-cyanoacetylurethane.

[0020] Table 2 summarizes the time and temperature of diazotization and Japp-Klingemann reaction in different synthetic processes of Resmetirom intermediate II:

[0021] Table 2: Comparison of reaction temperature and reaction time for existing technologies for Resmetirom intermediate II

[0022]

[0023] *Note: Diazotization and the Japp-Klingemann reaction in step 5 were carried out together without the addition of alkali.

[0024] Analysis of existing diazotization techniques and discussion of the synthesis process of Resmetirom intermediate II:

[0025] 1) The following is a summary of the well-known methods for preparing diazonium salts (Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis [M], Amsterdam Heidelberg: Elsevier Acad. Press, 2009: 394-395.): Aromatic amines and acids are added to the reaction system, and after cooling, a nitrosating agent is added dropwise to obtain the diazonium salt. The diazonium salt is then converted into various functional groups by adding different reagents.

[0026] 2) Existing technologies for synthesizing Resmetirom intermediate II all involve adding sodium nitrite solution dropwise to a mixture of compound III and an acid. These methods can be summarized into two categories: ① Compound III and the acid are added to the reaction system, and after cooling, sodium nitrite is added dropwise to obtain a diazonium salt. Then, an aqueous solution of SM2 and an alkali is added to react and generate Resmetirom intermediate II (Roche, Sichuan Lingshengyi, Hebei University of Science and Technology). ② Compound III, SM2, and the acid are added to the reaction system, and after cooling, sodium nitrite is added dropwise to obtain a diazonium salt. Then, an aqueous solution of an alkali is added, or the reaction proceeds without adding an alkali, to obtain Resmetirom intermediate II (Madridal, Jiangxi Tonghe Pharmaceutical).

[0027] 3) In the existing synthesis process of Resmetirom intermediate II, the diazotization dropping temperature is between -5 and 10°C. After the diazonium salt is prepared, the system contains a large amount of diazonium salt. If the reaction is prolonged or the temperature is increased, the diazonium salt may decompose, thereby posing a safety risk.

[0028] 4) The synthesis processes of the above five Resmetirom intermediates II were reproduced, and the experimental results were basically consistent with those in the table above. During the replication of existing technology experiments, the following defects were found: ① During the addition of alkali, the system gradually turns bright orange, and orange Resmetirom intermediate II is separated. Decolorization by activated carbon adsorption and other methods is ineffective. The Resmetirom product prepared using intermediate II is yellow or orange, which does not meet the quality standards for color detection in the active pharmaceutical ingredient. ② It is well known in the industry that diazonium salts have poor stability and may decompose to produce nitrogen gas during the reaction. There is a risk of uncontrolled gas release and material spillage during scale-up production. Existing technologies for Resmetirom intermediate II all involve adding SM2 all at once, or adding SM2 all at once after the diazonium salt is generated, followed by the addition of alkali. All these methods pose significant safety risks during scale-up production. ③ LC-MS analysis revealed that the main impurity A generated during the reaction is produced by SM2 and sodium nitrite under acidic conditions. The generation process of impurity A is as follows:

[0029]

[0030] In summary, it is necessary to develop a new preparation method for Resmetirom intermediate II to improve product color, reduce impurity levels, ensure safe production, and lower product costs. Summary of the Invention

[0031] The purpose of this invention is to provide a new method for synthesizing Resmetirom intermediate II. The Resmetirom intermediate II obtained by this method has a light color and high purity, and the post-processing is simple and low-cost. Furthermore, there is no risk of outgassing and runaway, and it can be scaled up for industrial production.

[0032] To achieve the above objectives, the present invention provides the following technical solution:

[0033] This invention discloses a method for synthesizing Resmetirom intermediate II, which is carried out according to the following synthesis path:

[0034]

[0035] Specifically, the synthesis method of Resmetirom intermediate II includes the following steps:

[0036] (1) Add N-cyanoacetylurane (SM2) and sodium nitrite to water;

[0037] (2) After dissolving compound III and acid in a solvent, add them dropwise to the reaction system of step (1) under controlled temperature;

[0038] (3) After the reaction is complete, filter, rinse and dry to obtain high-quality Resmetirom intermediate II.

[0039] As a preferred technical solution, the feeding sequence for implementing the technical solution is as follows: first, N-cyanoacetylurane (SM2) and sodium nitrite are added to water, then compound III and acid are added to a solvent to dissolve, and then added dropwise to the reaction system of step (1) under controlled temperature.

[0040] As a preferred technical solution, the molar ratio of N-cyanoacetylurane (SM2) added in step (1) to compound III is 1:(1.0-1.05).

[0041] As a preferred technical solution, the acid added in step (2) is 36% hydrochloric acid.

[0042] As a further preferred technical solution, the volume / weight ratio (V / W) of the 36% hydrochloric acid added in step (2) to compound III is 2~4.

[0043] As a preferred technical solution, the dropping temperature in step (2) is 10~20℃.

[0044] As a preferred technical solution, the solvent added in step (2) is DMSO.

[0045] As a further preferred technical solution, the volume / weight ratio (V / W) of DMSO added in step (2) to compound III is 1.5~2.5.

[0046] The beneficial effects achieved by this invention are mainly reflected in multiple dimensions such as product quality, economy, efficiency, safety, and industrial applicability.

[0047] Firstly, regarding the color and purity of intermediate II, unexpected results were obtained through numerous experiments. Without adding alkali, increasing the reaction temperature unexpectedly improved the color of the reaction solution from orange to pale yellow. Furthermore, by adding DMSO as a co-solvent, the product precipitated during the reaction, resulting in surprisingly good purification. After the reaction was completed, direct filtration revealed a product color ranging from off-white to white, and the product purity was also significantly improved.

[0048] Secondly, regarding impurity control and process safety, existing methods involve first converting aromatic amine compounds into diazonium salts before reacting them with SM2. However, the diazonium salt remains in excess after formation, posing a risk of uncontrolled decomposition and hindering safe industrial production. Furthermore, existing methods often introduce impurity A, generated from the reaction of SM2 with nitrous acid, during the initial dropwise addition. The unique aspect of this invention is that SM2 and sodium nitrite (which do not react in the absence of acid) are first mixed. Then, intermediate III, dissolved in an acid, is added dropwise to the reaction system. This simultaneous dropwise addition and reaction allows the Japp-Klingemann reaction to occur concurrently with the formation of the diazonium salt, resulting in immediate consumption of the diazonium salt and improved process safety. Furthermore, by increasing the reaction temperature to 10-20°C, the reaction is completed immediately upon dropwise addition, minimizing the formation of impurity A. We analyzed the reasons for the excellent technical results: SM2 and sodium nitrite were first mixed. When compound III and the acid were dissolved in the solvent and added dropwise to the reaction system, sodium nitrite first reacted with the acid to generate nitrosyl ions. Since the amino group of the aromatic amine compound (III) is much more reactive than the active methylene group of SM2, compound III preferentially reacted with the nitrosyl ions to generate diazonium salts. The generated diazonium salts simultaneously reacted with SM2 to generate Resmetirom intermediate II. Under these reaction conditions, as compound III and the acid were added dropwise to the reaction system, the acidity of the reaction system gradually increased. Surprisingly, only 1.0-1.05 equivalents of SM2 were needed for complete reaction with almost no formation of impurity A. In existing technologies, the amount of SM2 used is above 1.1 equivalents. This also achieved the technical effect of timely consumption of the diazonium salts generated during the dropwise addition process. Implementing this technical solution effectively avoids the safety risks of material overflow caused by uncontrolled gas release, which is beneficial to safe industrial production.

[0049]

[0050] Therefore, by implementing this technical solution, compared with traditional processes, the prepared Resmetirom intermediate II product has better color, higher purity, and lower safety risks. In summary, this technical solution, through the control of the acidity of the reaction system and the optimization of the combination of reaction temperature and reaction solvent, achieves improvements in quality control, safety, economy, and efficiency, providing a superior solution for the industrial production of Resmetirom intermediate II. Attached Figure Description

[0051] Figure 1 For Resmetirom intermediate II 1 HNMR spectrum.

[0052] Figure 2 For Resmetirom finished products 1 HNMR spectrum. Detailed Implementation

[0053] The invention can be understood more specifically through the following examples, but they are illustrative and not intended to limit the scope of the invention.

[0054] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0055] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0056] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0057] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0058] Example 1:

[0059] The purpose of this embodiment is to provide a method for preparing Resmetirom intermediate II, the reaction formula of which is as follows:

[0060]

[0061] The specific steps include:

[0062] (1) Add water (20.0 mL, 2.0 Vol) to a four-necked flask, then add N-cyanoacetylurane (4.97 g, 31.83 mmol) and sodium nitrite (2.63 g, 38.12 mmol) in sequence, turn on the stirrer, and adjust the reaction temperature to 10-15℃;

[0063] (2) Take another single-necked bottle and add compound III (10.0g, 31.83mmol), 36% hydrochloric acid (30.0mL, 3.0Vol) and DMSO (20.0mL, 2.0Vol) to the reaction bottle. Stir and dissolve the solution, then transfer it to a constant pressure dropping funnel. Add the solution dropwise to the reaction system in step (1) at a controlled temperature of 10-15℃. After the addition is complete, check the reaction on a TLC plate to confirm that the reaction is complete.

[0064] (3) After the reaction was completed, the filter cake was filtered, washed with water (20.0 mL, 2.0 Vol), and dried at 45 °C to obtain 14.42 g of white solid with a yield of 94.1% and a purity of 99.6%. Impurity A was not detected.

[0065] The NMR spectrum of the prepared Resmetirom intermediate II is attached. Figure 1 As shown, the NMR data are as follows:

[0066] 1 H NMR (400 MHz, DMSO) δ 12.22 (s, 1H), 12.12 (br, 1H), 10.91 (s,1H), 7.99 (s, 2H), 7.37 (d, J = 0.7 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.05(dd, J = 13.6, 6.8 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.8 Hz, 6H).

[0067] Example 2:

[0068] Preparation of Resmetirom intermediate II:

[0069] (1) Add water (20.0 mL, 2.0 Vol) to a four-necked flask, then add N-cyanoacetylurane (5.22 g, 33.43 mmol) and sodium nitrite (2.63 g, 38.12 mmol) in sequence, turn on the stirrer, and adjust the reaction temperature to 10-15℃;

[0070] (2) Take another single-necked bottle and add compound III (10.0g, 31.83mmol), 36% hydrochloric acid (30.0mL, 3.0Vol) and DMSO (20.0mL, 2.0Vol) to the reaction bottle. Stir and dissolve the solution, then transfer it to a constant pressure dropping funnel. Add the solution dropwise to the reaction system in step (1) at a controlled temperature of 10-15℃. After the addition is complete, check the reaction on a TLC plate to confirm that the reaction is complete.

[0071] (3) After the reaction was completed, the filter cake was filtered, washed with water (20.0 mL, 2.0 Vol), and dried at 45 °C to obtain 14.14 g of white solid with a yield of 92.3% and a purity of 99.5%. Impurity A was not detected.

[0072] Example 3:

[0073] Preparation of Resmetirom intermediate II:

[0074] (1) Add water (20.0 mL, 2.0 Vol) to a four-necked flask, then add N-cyanoacetylurane (4.97 g, 31.83 mmol) and sodium nitrite (2.63 g, 38.12 mmol) in sequence, turn on the stirrer, and adjust the reaction temperature to 10-15℃;

[0075] (2) Take another single-necked bottle and add compound III (10.00g, 31.83mmol), 36% hydrochloric acid (20.0mL, 2.0Vol) and DMSO (20.0mL, 2.0Vol) to the reaction bottle respectively. Stir and dissolve the solution, then transfer it to a constant pressure dropping funnel. Control the temperature of the dropping at 10-15℃ and add the solution to the reaction system in step (1). After the dropping is completed, check the reaction on a TLC plate to see if it is complete.

[0076] (3) After the reaction was completed, the filter cake was filtered, washed with water (20.0 mL, 2.0 Vol), and dried at 45 °C to obtain 14.35 g of white solid with a yield of 93.7% and a purity of 99.3%. Impurity A was not detected.

[0077] Example 4:

[0078] Preparation of Resmetirom intermediate II:

[0079] (1) Add water (20.0 mL, 2.0 Vol) to a four-necked flask, then add N-cyanoacetylurane (4.97 g, 31.83 mmol) and sodium nitrite (2.63 g, 38.12 mmol) in sequence, turn on the stirrer, and adjust the reaction temperature to 10-15℃;

[0080] (2) Take another single-necked bottle and add compound III (10.00g, 31.83mmol), 36% hydrochloric acid (40.0mL, 4.0Vol) and DMSO (20.0mL, 2.0Vol) to the reaction bottle. Stir and dissolve the solution, then transfer it to a constant pressure dropping funnel. Add the solution dropwise to the reaction system in step (1) at a controlled temperature of 10-15℃. After the addition is complete, check the reaction on a TLC plate to confirm that the reaction is complete.

[0081] (3) After the reaction was completed, the filter cake was filtered, washed with water (20.0 mL, 2.0 Vol), and dried at 45 °C to obtain 14.51 g of white solid with a yield of 94.7% and a purity of 99.7%. Impurity A was not detected.

[0082] Example 5:

[0083] Preparation of Resmetirom intermediate II:

[0084] (1) Add water (20.0 mL, 2.0 Vol) to a four-necked flask, then add N-cyanoacetylurane (4.97 g, 31.83 mmol) and sodium nitrite (2.63 g, 38.12 mmol) in sequence, turn on the stirrer, and adjust the reaction temperature to 10-15℃;

[0085] (2) Take another single-necked bottle and add compound III (10.00g, 31.83mmol), 36% hydrochloric acid (30.0mL, 3.0Vol) and DMSO (15.0mL, 1.5Vol) to the reaction bottle. Stir and dissolve the solution, then transfer it to a constant pressure dropping funnel. Add the solution dropwise to the reaction system in step (1) at a controlled temperature of 10-15℃. After the addition is complete, check the reaction on a TLC plate to confirm that the reaction is complete.

[0086] (3) After the reaction was completed, the filter cake was filtered, washed with water (20.0 mL, 2.0 Vol), and dried at 45 °C to obtain 14.66 g of white solid with a yield of 95.7% and a purity of 99.1%. Impurity A was not detected.

[0087] Example 6:

[0088] Preparation of Resmetirom intermediate II:

[0089] (1) Add water (20.0 mL, 2.0 Vol) to a four-necked flask, then add N-cyanoacetylurane (4.97 g, 31.83 mmol) and sodium nitrite (2.63 g, 38.12 mmol) in sequence, turn on the stirrer, and adjust the reaction temperature to 10-15℃;

[0090] (2) Take another single-necked bottle and add compound III (10.00g, 31.83mmol), 36% hydrochloric acid (30.0mL, 3.0Vol) and DMSO (25.0mL, 2.5Vol) to the reaction bottle. Stir and dissolve the solution, then transfer it to a constant pressure dropping funnel. Add the solution dropwise to the reaction system in step (1) at a controlled temperature of 10-15℃. After the addition is complete, check the reaction on a TLC plate to confirm that the reaction is complete.

[0091] (3) After the reaction was completed, the filter cake was filtered, washed with water (20.0 mL, 2.0 Vol), and dried at 45 °C to obtain 14.14 g of white solid with a yield of 92.3% and a purity of 99.8%. Impurity A was not detected.

[0092] Example 7:

[0093] Preparation of Resmetirom intermediate II:

[0094] (1) Add water (20.0 mL, 2.0 Vol) to a four-necked flask, then add N-cyanoacetylurane (4.97 g, 31.83 mmol) and sodium nitrite (2.63 g, 38.12 mmol) in sequence, turn on the stirrer, and adjust the reaction temperature to 10-15℃;

[0095] (2) Take another single-necked bottle and add compound III (10.00g, 31.83mmol), 36% hydrochloric acid (30.0mL, 3.0Vol) and DMSO (20.0mL, 2.0Vol) to the reaction bottle. Stir and dissolve the solution, then transfer it to a constant pressure dropping funnel. Add the solution dropwise to the reaction system in step (1) at a controlled temperature of 15-20℃. After the addition is complete, check the reaction on a TLC plate to confirm that the reaction is complete.

[0096] (3) After the reaction was completed, the filter cake was filtered, washed with water (20.0 mL, 2.0 Vol), and dried at 45 °C to obtain 13.83 g of white solid with a yield of 90.3% and a purity of 99.4%. Impurity A was not detected.

[0097] Comparative Example 1:

[0098] Preparation of Resmetirom intermediate II: repeating existing techniques (Madridgal Company)

[0099]

[0100] The specific steps include:

[0101] (1) Add acetic acid (45.0 mL, 4.5 Vol) and compound III (10.00 g, 31.83 mmol) to a four-necked flask, start stirring, add N-cyanoacetylurane (5.47 g, 35.03 mmol) and water (20.0 mL, 2.0 Vol), cool to 5.5 °C, add 36% hydrochloric acid (9.5 mL, 0.95 Vol), and control the temperature to 4.8-8.8 °C;

[0102] (2) Dissolve sodium nitrite (2.20 g, 31.89 mmol) in water (5.0 mL, 0.5 Vol) and add it dropwise to the system in step (1) at a controlled temperature of 5.8-8.7 °C, stirring until it is completely converted into diazonium salt;

[0103] (3) Add sodium acetate (7.83 g, 95.45 mmol) dissolved in water (30.0 mL, 3.0 Vol) to step (2). After the addition is complete, the reaction is allowed to proceed for 47 min. The reaction is monitored to ensure completeness. The mixture is then filtered, the filter cake is washed with water, and the filter cake is dried at 45 °C to obtain 14.14 g of orange solid. The yield is 92.3%, the purity is 89.4%, and the impurity A is 5.4%.

[0104] Comparative Example 2:

[0105] Preparation of Resmetirom intermediate II: repeating existing technology (Roche).

[0106]

[0107] The specific steps include:

[0108] (1) Add water (45.0 mL, 4.5 Vol), compound III (10.00 g, 31.83 mmol) and 36% hydrochloric acid (20.0 mL, 2.0 Vol) to a four-necked flask, turn on the stirrer, and cool to 0 °C;

[0109] (2) Dissolve sodium nitrite (2.64 g, 38.27 mmol) in water (15.0 mL, 1.5 Vol) and add it dropwise to the system in step (1) at 0 °C. Keep the temperature at 0 °C for 30 min.

[0110] (3) Add N-cyanoacetylurane (5.47 g, 35.03 mmol), water (70.0 mL, 7.0 Vol) and pyridine (35.0 mL, 3.5 Vol) to step (2), keep the reaction at 0 °C for 30 min, monitor the reaction to ensure it is complete, filter, wash the filter cake with water, and dry the filter cake at 45 °C to obtain 12.91 g of orange solid, yield 84.3%, purity 90.2%, impurity A: 3.1%.

[0111] Comparative Example 3:

[0112] Preparation of Resmetirom intermediate II: Repetition of existing techniques (Sichuan Lingshengyi)

[0113]

[0114] The specific steps include:

[0115] (1) Add compound III (10.00 g, 31.83 mmol), acetic acid (80.0 mL, 8.0 Vol), water (20.0 mL, 2.0 Vol) and 36% hydrochloric acid (15.0 mL, 1.5 Vol) to a four-necked flask, turn on the stirrer, and cool to 0 °C;

[0116] (2) Dissolve sodium nitrite (2.28g, 33.05mmol) in water (5.0mL, 0.5Vol) and add it dropwise to the system in step (1) at a controlled temperature of 0-10℃. Keep the temperature at 0-10℃ for 30min and control the reaction to be complete.

[0117] (3) Add pyridine (11.9 mL, 1.19 Vol) and N-cyanoacetylurane (5.62 g, 35.99 mmol) to step (2) at a controlled temperature of 0-10℃. Keep the temperature at 0-10℃ for 30 min, then cool to room temperature and react for 2 h. Filter and dry the filter cake at 45℃ to obtain 13.86 g of orange solid. The yield is 90.5%, the purity is 93.9%, and the impurity A is 1.9%.

[0118] Comparative Example 4:

[0119] Preparation of Resmetirom intermediate II: Replication of existing techniques (Hebei University of Science and Technology)

[0120]

[0121] The specific steps include:

[0122] (1) Add compound III (10.00 g, 31.83 mmol) and water (40.0 mL, 4.0 Vol) to a four-necked flask, start stirring, add 36% hydrochloric acid (40.0 mL, 4.0 Vol) and cool to 0~-5℃;

[0123] (2) Dissolve sodium nitrite (2.43g, 35.22mmol) in water (5.0mL, 0.5Vol) and add it dropwise to the system in step (1) at a controlled temperature of 0~-5℃. Keep the temperature at 0~-5℃ for 30min and control the reaction to be complete.

[0124] (3) N-cyanoacetylurane (8.23 g, 52.71 mmol), water (30.0 mL, 3.0 Vol) and sodium acetate (11.79 g, 143.73 mmol) were mixed and pre-cooled to 0 °C, and then added to step (1). The mixture was reacted for 1 h, filtered, and slurried twice with deionized water (130.0 mL, 13.0 Vol). Then, it was slurried for 1 h with acetic acid (30.0 mL, 3.0 Vol) at 60 °C. The mixture was cooled to room temperature and filtered. The filter cake was dried at 45 °C to obtain 10.82 g of orange solid with a yield of 70.6%, a purity of 98.2%, and impurity A of 0.5%.

[0125] Comparative Example 5:

[0126] Preparation of Resmetirom intermediate II: repeating existing technology (Jiangxi Tonghe Pharmaceutical).

[0127]

[0128] The specific steps include:

[0129] (1) Compound III (10.00 g, 31.83 mmol), N-cyanoacetylurane (6.82 g, 43.68 mmol) and acetic acid (45.0 mL, 4.5 Vol) were added to a four-necked flask, cooled to 1-10 °C, and 36% hydrochloric acid (14.0 mL, 1.4 Vol) was added in portions.

[0130] (2) Dissolve sodium nitrite (3.00 g, 43.48 mmol) in water (18.0 mL, 1.8 Vol) and add the solution dropwise to the system in step (1) at a controlled temperature of 5-10 °C. After the addition is complete, stir the reaction at room temperature for 2 h to ensure the reaction is complete.

[0131] (3) Pour the reaction solution into water (180.0 mL, 18.0 Vol), stir for 10 min, filter, and slurry the filter cake with potassium carbonate aqueous solution (45.0 mL, 4.5 Vol) for 30 min, filter, rinse the filter cake with water (27.0 mL, 2.7 Vol), and dry the filter cake at 45 °C to obtain 14.35 g of pale yellow solid, with a yield of 93.7%, a purity of 97.2%, and impurity A of 1.1%.

[0132] Application Example 1

[0133] Preparation of Resmetirom finished product: Resmetirom intermediate II obtained in Example 1 was synthesized into the final Resmetirom product.

[0134]

[0135] Resmetirom intermediate II (12.0 g, 24.93 mmol), sodium acetate (2.69 g, 32.79 mmol), and DMAc (56.0 mL, 4.6 Vol) were added to a reaction flask. After stirring, nitrogen was purged, and the mixture was heated to 115 °C under nitrogen protection. The reaction was maintained at this temperature for 2 h, and the reaction was monitored to ensure completeness. The mixture was then cooled to 25 °C, and acetic acid (3.0 mL, 0.25 Vol) was added. The mixture was stirred for 3 h, cooled to 10 °C, and water (108.0 mL, 9.0 Vol) was added dropwise while maintaining the temperature at 5-15 °C. The mixture was filtered, and the filter cake was washed with a solution of ethanol:water = 1:1 (60.0 mL, 5.0 Vol) pre-cooled to 10 °C. The filter cake was dried at 45 °C to obtain 10.37 g of white solid, with a yield of 95.6% and a purity of 99.9%.

[0136] The NMR spectrum of the prepared Resmetirom product is attached. Figure 2 As shown, the NMR data are as follows:

[0137] 1 H NMR (600 MHz, DMSO) δ 13.30 (s, 1H), 12.26 (s, 1H), 7.79 (s, 2H), 7.45 (s, 1H), 3.11 – 3.01 (m, 1H), 1.20 (d, J = 6.9 Hz, 6H).

[0138] Application Example 2

[0139] Preparation of Resmetirom product: Resmetirom intermediate II obtained in Comparative Example 1 was synthesized into the final Resmetirom product.

[0140] Resmetirom intermediate II (12.0 g, 24.93 mmol), sodium acetate (2.69 g, 32.79 mmol), and DMAc (56.0 mL, 4.6 Vol) were added to a reaction flask. After stirring, nitrogen was purged, and the mixture was heated to 115 °C under nitrogen protection. The reaction was maintained at this temperature for 2 h, and the reaction was monitored to ensure completeness. The mixture was then cooled to 25 °C, and acetic acid (3.0 mL, 0.25 Vol) was added. The mixture was stirred for 3 h, cooled to 10 °C, and water (108.0 mL, 9.0 Vol) was added dropwise at a controlled temperature of 5-15 °C. The mixture was filtered, and the filter cake was washed with a solution of ethanol:water = 1:1 (60.0 mL, 5.0 Vol) pre-cooled to 10 °C. The filter cake was dried at 45 °C to obtain 9.59 g of orange solid, with a yield of 88.4% and a purity of 93.9%.

[0141] Application Example 3

[0142] Preparation of Resmetirom product: Resmetirom intermediate II obtained in Comparative Example 5 was synthesized into the final Resmetirom product.

[0143] Resmetirom intermediate II (12.0 g, 24.93 mmol), sodium acetate (2.69 g, 32.79 mmol), and DMAc (56.0 mL, 4.6 Vol) were added to a reaction flask. After stirring, nitrogen was purged, and the mixture was heated to 115 °C under nitrogen protection. The reaction was maintained at this temperature for 2 h, and the reaction was monitored to ensure completeness. The mixture was then cooled to 25 °C, and acetic acid (3.0 mL, 0.25 Vol) was added. The mixture was stirred for 3 h, cooled to 10 °C, and water (108.0 mL, 9.0 Vol) was added dropwise at a controlled temperature of 5-15 °C. The mixture was filtered, and the filter cake was washed with a solution of ethanol:water = 1:1 (60.0 mL, 5.0 Vol) pre-cooled to 10 °C. The filter cake was dried at 45 °C to obtain 10.02 g of white solid, with a yield of 92.3% and a purity of 98.9%.

Claims

1. A synthetic process for Resmetirom intermediate II, the chemical reaction formula of which is as follows: ； Its features are: Includes the following steps: (1) Add N-cyanoacetylurane (SM2) and sodium nitrite to water; (2) After dissolving compound III and acid in a solvent, add them dropwise to the reaction system of step (1) under controlled temperature; (3) After the reaction is complete, filter, rinse and dry to obtain high-quality Resmetirom intermediate II.

2. The method for preparing Resmetirom intermediate II according to claim 1, characterized in that: The feeding sequence for achieving the above technical solution is as follows: first, add N-cyanoacetylurane (SM2) and sodium nitrite to water, then add compound III and acid to the solvent to dissolve, and then add them dropwise to the reaction system of step (1) under controlled temperature.

3. The method for preparing Resmetirom intermediate II according to claim 1, characterized in that: The molar ratio of N-cyanoacetylurane (SM2) added in step (1) to compound III is 1:(1.0-1.05).

4. The method for preparing Resmetirom intermediate II according to claim 1, characterized in that: The acid added in step (2) is 36% hydrochloric acid.

5. The method for preparing Resmetirom intermediate II according to claim 4, characterized in that: The volume / weight ratio (V / W) of the 36% hydrochloric acid added in step (2) to compound III is 2~4.

6. The method for preparing Resmetirom intermediate II according to claim 1, characterized in that: The dropping temperature in step (2) is 10~20℃.

7. The method for preparing Resmetirom intermediate II according to claim 1, characterized in that: The solvent added in step (2) is DMSO.

8. The method for preparing Resmetirom intermediate II according to claim 7, characterized in that: The volume / weight ratio (V / W) of DMSO added in step (2) to compound III is 1.5~2.5.

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