Preparation method of rosemeltirol intermediate

Abstract

The invention provides a method for preparing an intermediate of rosmeltirol. Belongs to the technical field of drug synthesis, and by optimizing the preparation process and under the catalysis of aluminum trichloride, the product is obtained with high yield through a Friedel-Crafts alkylation method with 2-chloropropane, so that not only is the cost reduced, but also the operation is safe and stable, and the industrial production is convenient.

Description

Technical Field

[0001] This invention pertains to drug synthesis methods in the field of pharmaceutical chemistry, specifically relating to a method for synthesizing a key intermediate of resimeltiro. Background Technology

[0002] Resmetirom is an orally selective thyroid hormone receptor (THR)-β agonist. On June 30, 2023, Madrigal Pharmaceuticals announced that it had submitted a rolling New Drug Application (NDA) to the FDA for resmetirom in the treatment of patients with non-alcoholic steatohepatitis (NASH) with liver fibrosis. Highly expressed in the human liver, THR-β regulates lipid metabolism, reducing LDL-C, triglycerides, and atherogenic lipoproteins. It can also reduce lipotoxicity and improve liver function by promoting fatty acid breakdown and stimulating mitochondrial biogeneration, thereby reducing liver fat. Therefore, THR-β agonists have the potential to regulate multiple liver metabolic pathways to treat NASH. The structure of resmetirom is shown below:

[0003]

[0004] Regarding the synthesis of resimeltiro, only two synthetic routes have been reported by the original research company, such as the route disclosed in WO2007009913. The key compound, 3,6-dichloro-4-isopropylpyridazine, is difficult to obtain commercially available. Conventional synthetic methods generally involve free radical reactions, requiring very high temperatures and typically employing strong oxidizing agents such as APS (ammonium persulfate), posing safety hazards and inconveniences for large-scale production.

[0005] Existing literature reports methods for obtaining the key compound 3,6-dichloro-4-isopropylpyridazine, including:

[0006]

[0007] Furthermore, CN116768802A discloses a method that uses 3-isopropylfuran-2,5-dione compound 1 as a starting material, reacts it with hydrazine hydrate to obtain 4-isopropyl-1,2-dihydropyridazine-3,6-dione compound 2, then chlorinates it to obtain 3,6-dichloro-4-isopropylpyridazine compound 3, and subsequently hydrolyzes it to obtain 6-chloro-4-isopropyldihydropyridazine n-3(4H)-one compound 3.

[0008] It is evident that existing synthetic techniques involve long routes, high costs, demanding conditions, and a lack of mild and controllable characteristics. Furthermore, some reagents pose safety risks and inconveniences during large-scale production. The resulting products also exhibit low purity. Therefore, it is necessary to find a synthetic method that is shorter, lower in cost, simpler to operate, and safer and more controllable. Summary of the Invention

[0009] To address the problems of existing technologies, this invention provides a novel route for synthesizing intermediates. This route reduces reaction steps and costs through catalytic reactions, while also being safe, stable, and convenient for industrial production. It operates under mild conditions, yields high purity, and is suitable for large-scale industrial production.

[0010] The intermediate is compound formula I.

[0011]

[0012] The preparation process includes the following synthetic route:

[0013]

[0014] Preferably, the synthesis process uses a catalyst, and the solvent is selected from one or more of isopropanol, dichloromethane, and tetrahydrofuran; more preferably, the catalyst includes aluminum trichloride.

[0015]

[0016] In another technical solution, the mass ratio of 3,6-dihydropyridazine to 2-chloropropane is 1-10:1-10. More preferably, the mass ratio is 1-5:1-5.

[0017] In another technical solution, the temperature of the above reaction system is ≤30℃, and an auxiliary agent is added to the reaction system. Further, the temperature of the reaction system is ≥0℃, and the auxiliary agent is pyridine sulfur trioxide.

[0018] The present invention also relates to a method for preparing resmetiro, wherein the method includes the preparation method described above.

[0019] Preferably, dichloropropane is added dropwise at low temperature, with the temperature controlled at 0-15°C, more preferably 0-10°C, and even more preferably 0-5°C.

[0020] Furthermore, after adding dichloropropane, the temperature is raised and stirred to ≥20°C; in another technical solution, the temperature is raised to room temperature. In yet another technical solution, the temperature is raised to below 30°C.

[0021] Furthermore, the stirring reaction time is ≥8h, preferably ≥10h.

[0022] Furthermore, the reaction solution was quenched with ice water, washed with saturated saline solution, and dried under reduced pressure.

[0023] In another technical solution, after the reaction is quenched, the phases will separate. The organic phase will be washed until neutral, preferably with saturated brine. Further, the organic phase will be dried under reduced pressure at 35°C.

[0024] All raw materials and reagents used in this invention are commercially available or prepared experimentally. Unless otherwise specified, all proportions in this invention are mass ratios, and room temperature refers to the range of 23-25°C.

[0025] The beneficial effects of this invention are:

[0026] 1) The improved Friedel-Crafts alkylation method ensures higher yield and product purity while reducing costs.

[0027] 2) The steps have been optimized, the reaction route has been shortened, the catalyst used is readily available, and under specific conditions, the use of by-products and harmful reagents has been avoided;

[0028] 3) The conditions are mild, making it suitable for large-scale CNC and industrial production. Attached Figure Description

[0029] Figure 1 This is the HPLC spectrum of compound I in Example 1 of the present invention;

[0030] Figure 2 The NMR spectrum of compound I in Example 2 of this invention; Detailed Implementation

[0031] Example 1:

[0032] 1480 g (1 eq) of 3,6-dichloropyridazine and 10 L of DCM (dichloromethane) were added to a 20 L three-necked flask. 1330 g (1.2 eq) of aluminum trichloride was slowly added under stirring at 0 °C until the solution became clear. Then, 785 g (1.1 eq) of 2-chloropropane was slowly added dropwise under stirring at 0-5 °C, controlling the dropping rate and temperature. After the addition was complete, the temperature was raised to 30 °C and the reaction was stirred for 12 h. After the reaction was complete, the reaction solution was quenched with ice water. After separation, the organic phase was washed with saturated brine until neutral, dried over anhydrous sodium sulfate, and dried under reduced pressure at 35 °C to obtain 1710 g of compound 1 (identification spectrum see [reference]). Figure 1 It is a brown solid with a yield of 90%, a purity of 99.65%, and a single impurity content of ≤0.05%.

[0033] Example 2:

[0034] Add 1580 g of 3,6-dichloropyridazine and 12 L of DCM (dichloromethane) to a 20 L three-necked flask. Slowly add 1430 g of aluminum trichloride and 450 g of sulfur trioxide pyridine while stirring at 5 °C. Stir until the solution is clear. Then, slowly add 835 g of 2-chloropropane dropwise while stirring at 0-5 °C, controlling the dropping rate and temperature. After the addition is complete, raise the temperature to room temperature and stir for 10 h. After the reaction is complete, quench the reaction solution with ice water. After separation, wash the organic phase with saturated brine until neutral, dry with anhydrous sodium sulfate, and dry under reduced pressure at 35 °C to obtain 1796 g of compound 1 (see identification chromatogram for details). Figure 2 Brown solid, yield 92%, purity 99.69%, single impurity content ≤0.05%.

[0035] Example 3:

[0036] The solvent was replaced with tetrahydrofuran, and the other conditions were the same as in Example 1, to obtain compound I (identification spectrum same as in Example 1), with a yield of 86.6% and a purity of 98.21%.

[0037] Example 4:

[0038] The solvent was replaced with tetrahydrofuran, and the other conditions were the same as in Example 2, to obtain compound I (identification spectrum as in Example 2), with a yield of 90% and a purity of 96.21%.

[0039] Example 5:

[0040] After the addition of 2-chloropropane, the reaction temperature was raised to 30°C, and the reaction was stirred for 8 hours. The remaining conditions were the same as in Example 2, and compound I was obtained (identification spectrum was the same as in Example 2), with a yield of 89% and a purity of 98.9%.

[0041] The above experimental results show that by optimizing the preparation process, a product with high purity was obtained. In particular, Examples 1 and 2, as the optimal implementation schemes, demonstrated the characteristics of high purity and high yield. Under certain conditions (with the addition of special additives), the reaction conditions were milder. The synergistic effect of the additives seems to be related to the solvent as well, and has a certain degree of randomness, possibly related to weak oxidizing properties.

[0042] The specific embodiments described above do not constitute a limitation on the scope of protection of the present invention. Those skilled in the art can make various changes and applications to the present invention based on the above description.

Claims

1. A method for preparing a key intermediate of resmemetiro, wherein the intermediate is a compound of formula I. Its features The following synthetic routes are included:

2. The method according to claim 1, characterized in that: The synthesis process uses a catalyst, which includes aluminum trichloride, and the reaction solvent is selected from one or more of isopropanol, dichloromethane, and tetrahydrofuran.

3. The method according to claim 1, characterized in that: The mass ratio of 3,6-dihydropyridazine to 2-chloropropane is 1-10:1-10.

4. The method according to claim 3, characterized in that, The mass ratio of 3,6-dihydropyridazine to 2-chloropropane is 1-5:1-5.

5. The method according to claim 1, characterized in that, The reaction system temperature is ≤30℃, and auxiliary agents are also added to the reaction system.

6. The method according to claim 5, wherein the reaction system temperature is ≥0℃, and the auxiliary agent is pyridine sulfur trioxide.

7. The method according to claim 1, characterized in that... After the reaction was complete, ice water was added to quench the reaction, and the solution was washed and dried under reduced pressure.

8. A method for preparing resmetrol, wherein the method comprises the preparation method according to any one of claims 1-6.

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