Synthesis method of rosemeltirol impurity B

Abstract

The invention relates to a synthesis method of a rosmelteon impurity B. The method comprises the following steps: adding 2-(3, 5-dichloro-4-((5-isopropyl-6-oxo-1, 6-dihydropyridine-3-yl) oxy) phenyl)-3, 5-dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-nitrile, THF (tetrahydrofuran) and a NaOH aqueous solution into a single-mouth flask for reaction, then quenching a reaction solution by using an HCl solution, and then adding a sodium hydroxide solution into the single-mouth flask for reaction, so as to obtain the rosmelteon impurity B, and carrying out separation operation, carrying out rotary evaporation to obtain a crude product, carrying out mixed solvent crystallization on the crude product by using THF and MTBE, and filtering and drying the reaction product to obtain the rosemeltirol impurity B. The invention further discloses a preparation method of the rosemeltirol impurity B. The invention provides the preparation method of the rosmeltirol impurity B. The synthesis method has the advantages of easily available raw materials, few steps and short preparation and purification period, fills the blank of a rosmeltirol impurity preparation technology, can improve the impurity spectrum of the rosmeltirol, and is applied to control on the quality of the rosmeltirol.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of chemical medicine analysis and drug synthesis, and particularly relates to a synthesis method of Resmetirom impurity B. BACKGROUND

[0002] Resmetirom (Rezdiffra), CAS Registry Number: 920509-32-6, is chemically named as 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy]phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, and its structural formula is as follows:

[0003]

[0004] Resmetirom (Rezdiffra TM ) is an oral thyroid hormone receptor-beta (THR-beta) agonist developed by Madrigal Pharmaceuticals, Inc., aiming at the key potential cause of metabolic dysfunction-related steatohepatitis (MASH, previously known as non-alcoholic steatohepatitis NASH). In March 2024, resmetirom obtained accelerated approval in the United States and can be used in combination with diet and exercise to treat non-cirrhotic NASH adults with moderate to severe liver fibrosis (meeting the F2 to F3 fibrosis stage). Resmetirom is also undergoing regulatory review in the European Union for the treatment of MASH / NASH.

[0005] Madrigal Pharmaceuticals announced its 2024Q3 financial report, and the non-alcoholic steatohepatitis (NASH, now known as metabolic dysfunction-related steatohepatitis / MASH) drug Rezdiffra achieved sales of 6220 million US dollars. Rezdiffra is the first and only FDA-approved MASH treatment drug, with sales of 1460 million US dollars in the first full quarter of its listing. This drug will have a relatively large demand in the future.

[0006] Looking at the main synthesis process of resmetirom, the preparation route basically goes through the following steps, and the synthesis route is as follows:

[0007]

[0008] In the specific synthesis process of resmetirom, impurity B is generated, and impurity B is generated due to overreaction in Step 2 reaction step. In addition, according to the reaction mechanism, it is indeed possible that impurity B will be generated during the synthesis of resmetirom, and the structural formula of the impurity B is as follows:

[0009]

[0010] Impurity B: 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro

[0011] -1,2,4-triazine-6-carboxamide;

[0012] Existing literature has not yet reported any impurities related to resmetiro. However, research on impurities that may be generated during the synthesis process of resmetiro or during subsequent preparation and storage is of great significance for the comprehensive control of resmetiro quality. Summary of the Invention

[0013] The technical problem to be solved by this invention is to discover and propose a method for preparing resmetiro impurity B, improve the impurity spectrum of resmetiro, and apply it to the quality control of resmetiro.

[0014] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is: a method for synthesizing resimeltiro impurity B, the specific synthetic route of which is as follows:

[0015]

[0016] The structural formula of the resimetidine impurity B is shown below:

[0017]

[0018] The specific technical solution of the present invention is as follows:

[0019] A method for synthesizing resimeltiro impurity B, the method comprising the following steps:

[0020] (1) At room temperature, 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile, THF, and 0.2M NaOH aqueous solution were added to a single-necked flask for reaction; wherein, the equivalent ratio of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile to NaOH was 1:1, and the solvent system of the above reaction consisted of THF and water.

[0021] (2) At room temperature, the reaction solution of step (1) was quenched with 0.2M HCl, separated, extracted, separated, and rotary evaporated to obtain crude product. The crude product was dissolved in THF and then MTBE was added to crystallize. The crystallization temperature was 25-30℃ and the volume ratio of THF to MTBE was 1:1-2 (i.e., THF and MTBE were used for mixed solvent crystallization).

[0022] (3) After filtering and drying the reaction product of step (2), the resmetiro impurity B is obtained and named as: 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;

[0023] The structural formulas of resimeltiro impurity B and 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile are as follows:

[0024]

[0025] Impurity B: 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro

[0026] -1,2,4-triazine-6-carboxamide;

[0027]

[0028] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile.

[0029] The specific operation method of step (1) is as follows: Under room temperature conditions, 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile, THF, and 0.2M are added sequentially to a single-necked flask. NaOH aqueous solution; the reaction solution was heated to 50-60℃, and the reaction was carried out until HPLC analysis showed that 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile was completely eliminated; wherein, the equivalent ratio of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile to NaOH was 1:1, and the solvent system of the above reaction consisted of THF and water.

[0030] The specific method of step (2) is as follows: at room temperature, the reaction solution of step (1) is quenched by adding 0.2M HCl; NaCl solid is added to separate the reaction solution into layers, the upper organic phase is taken, and the aqueous phase is extracted with THF 2-3 times; the organic phases are combined, and the excess water in the organic phase is removed with an appropriate amount of Na2SO4 and filtered; the organic phase is concentrated to obtain a reddish-brown viscous solid, THF is added under stirring at room temperature to completely dissolve the crude product, and MTBE is slowly added dropwise, at which point a reddish-brown solid is precipitated.

[0031] The specific method of step (3) is as follows: filter the reaction solution of step (2), wash the filter cake with MTBE, and dry it in a hot air drying oven to obtain a reddish-brown solid, which is the resmetiro impurity B, named as: 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide.

[0032] The advantages of this invention are:

[0033] The advantages of this invention include: Addressing the gap in existing resimetidine impurity synthesis and preparation technologies, this invention provides a method for preparing resimetidine impurity B. This synthetic method uses readily available raw materials, involves few steps, and has a short preparation and purification cycle, filling the gap in resimetidine impurity preparation technology. It can provide high-quality impurity reference standards for resimetidine quality research, which is of great significance for the safe use of resimetidine; it also improves the impurity profile of resimetidine and allows for its application in the quality control of resimetidine. Attached Figure Description

[0034] Figure 1This is the NMR spectrum of resmetidine impurity B in this invention;

[0035] Figure 2 This is the LC-MS spectrum of resimetidine impurity B in this invention; Detailed Implementation

[0036] The technical solution of the present invention will be further explained and described below through specific embodiments.

[0037] Example 1

[0038] (1) At room temperature, 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile (2.6 g, 0.006 mol), THF (30.0 mL), and 0.2 M NaOH aqueous solution (30.0 mL) were added sequentially to a 250 mL single-necked flask. The reaction solution was heated to 50-60 °C until HPLC analysis showed that no 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile remained.

[0039] (2) At room temperature, the reaction solution from step (1) was quenched by adding 0.2M HCl (30.0 mL). NaCl solid was added to separate the reaction solution into layers. The upper organic phase was collected, and the aqueous phase was extracted with THF 2-3 times. The organic phases were combined, and excess water was removed with an appropriate amount of Na2SO4 and filtered. The organic phase was concentrated to obtain a reddish-brown viscous solid. 20 mL of THF was added under stirring at room temperature to completely dissolve the crude product, and 20 mL of MTBE was slowly added dropwise. At this time, a reddish-brown solid precipitated out.

[0040] (3) The reaction solution from step (2) was filtered, and the filter cake was washed with MTBE and dried in a hot air drying oven to obtain 1.5 g of reddish-brown solid, namely the resmetiro impurity B, named 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, with a yield of 55%.

[0041] Example 2

[0042] (1) At room temperature, 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile (2.6 g, 0.006 mol), THF (30.0 mL), and 0.2 M NaOH aqueous solution (30.0 mL) were added sequentially to a 250 mL single-necked flask. The reaction solution was heated to 50-60 °C until HPLC analysis showed that no 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile remained.

[0043] (2) At room temperature, the reaction solution from step (1) was quenched by adding 0.2M HCl (30.0 mL). NaCl solid was added to separate the reaction solution into layers. The upper organic phase was collected, and the aqueous phase was extracted with THF 2-3 times. The organic phases were combined, and excess water was removed with an appropriate amount of Na2SO4 and filtered. The organic phase was concentrated to obtain a reddish-brown viscous solid. 20 mL of THF was added under stirring at room temperature to completely dissolve the crude product, and 40 mL of MTBE was slowly added dropwise. At this time, a reddish-brown solid precipitated out.

[0044] (3) The reaction solution from step (2) was filtered, and the filter cake was washed with MTBE and dried in a hot air drying oven to obtain 2.1 g of reddish-brown solid, namely the resmetiro impurity B, named 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, with a yield of 77%.

[0045] Example 3

[0046] (1) At room temperature, 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile (2.6 g, 0.006 mol), THF (60.0 mL), and 0.2 M NaOH aqueous solution (30.0 mL) were added sequentially to a 250 mL single-necked flask. The reaction solution was heated to 50-60 °C until HPLC analysis showed that there was no residue of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile.

[0047] (2) At room temperature, the reaction solution from step (1) was quenched by adding 0.2M HCl (30.0 mL). NaCl solid was added to separate the reaction solution into layers. The upper organic phase was collected, and the aqueous phase was extracted with THF 2-3 times. The organic phases were combined, and excess water was removed with an appropriate amount of Na2SO4 and filtered. The organic phase was concentrated to obtain a reddish-brown viscous solid. 20 mL of THF was added under stirring at room temperature to completely dissolve the crude product, and 40 mL of MTBE was slowly added dropwise. At this time, a reddish-brown solid precipitated out.

[0048] (3) The reaction solution from step (2) was filtered, and the filter cake was washed with MTBE and dried in a hot air drying oven to obtain 2.3 g of reddish-brown solid, namely the resmetiro impurity B, named 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide, with a yield of 85%.

[0049] The obtained resimetidine impurity B was subjected to mass spectrometry and NMR analysis. The results were as follows: LC-MS: m / z 453 (M+H). + m / z 451(MH) - . 1 ¹H NMR (400MHz, DMSO-d⁶) δ 12.23 (s, 1H), 8.13 (s, 1H), 7.95 (s, 1H), 7.87 (s, 2H), 7.45 (s, 1H), 3.06 (dt, J = 13.3, 6.5Hz, 1H), 1.21 (d, J = 6.8Hz, 6H). The corresponding spectra are shown below. Figure 1 , 2 As shown.

[0050] In the preparation of resimetidine, impurity B is generated due to overreaction in Step 2. Therefore, it is crucial to control the reaction time in this step and promptly quench the reaction after it passes the control test to reduce the formation of this overreaction impurity, thereby ensuring the quality of the API and improving the overall yield.

[0051] The above description is merely a preferred embodiment of the present invention, and therefore should not be construed as limiting the scope of the present invention. All equivalent changes and modifications made in accordance with the scope of the present invention and the contents of the specification should still fall within the scope of the present invention.

Claims

1. A method for synthesizing resimeltiro impurity B, characterized in that: The synthesis method includes the following steps: (1) At room temperature, 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile, THF, and 0.2M NaOH aqueous solution were added to a single-necked flask for reaction; wherein, the equivalent ratio of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile to NaOH was 1:1, and the solvent system of the above reaction consisted of THF and water. (2) At room temperature, the reaction solution of step (1) was quenched with 0.2M HCl, separated, extracted, separated, and rotary evaporated to obtain crude product. The crude product was dissolved with THF and then MTBE was added to crystallize. The crystallization temperature was 25-30℃ and the volume ratio of THF to MTBE was 1:1-2. (3) After filtering and drying the reaction product of step (2), the resmetiro impurity B is obtained. The structural formulas of resimeltiro impurity B and 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-nitrile are as follows: Impurity B: 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide; 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile.

2. The synthesis method according to claim 1, characterized in that: The specific operation method of step (1) is as follows: Under room temperature conditions, add 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile, THF, and 0.2M NaOH aqueous solution sequentially to a single-necked flask; heat the reaction solution to 50-60℃, and react until HPLC analysis shows 2-(3,5-dichloro-4-((5-isopropyl-6-oxo)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile. The remaining 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile) was completely eliminated; the equivalence ratio of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-onitrile) to NaOH was 1:1, and the solvent system for the above reaction consisted of THF and water.

3. The synthesis method according to claim 1, characterized in that: The specific method of step (2) is as follows: at room temperature, the reaction solution of step (1) is quenched by adding 0.2M HCl; NaCl solid is added to separate the reaction solution into layers, the upper organic phase is taken, and the aqueous phase is extracted with THF 2-3 times; the organic phases are combined, and the excess water in the organic phase is removed with an appropriate amount of Na2SO4 and filtered; the organic phase is concentrated to obtain a reddish-brown viscous solid, THF is added under stirring at room temperature to completely dissolve the crude product, and MTBE is slowly added dropwise, at which point a reddish-brown solid is precipitated.

4. The synthesis method according to claim 1, characterized in that: The specific method of step (3) is as follows: filter the reaction solution of step (2), wash the filter cake with MTBE, and dry it in a hot air drying oven to obtain a reddish-brown solid, which is the resimetiro impurity B.

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