Rimetirol 1, 4-dioxane solvent compound and preparation method thereof

Abstract

The invention provides a solvent compound crystal which is formed by rosmeltirol and a 1, 4-dioxane solvent, and the molecular formula of the solvent compound crystal is C17H12Cl2N6O4.C4H8O2. The preparation process of the crystal form is simple, the operation is simple and convenient, the quality index of the obtained crystal form is basically kept unchanged in a stability acceleration experiment, the crystal form has good stability and is easy to store in the production circulation process, a good choice is provided for preparation of a medicinal preparation of the crystal form, and the crystal form has very important significance for medicine development.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical industry, and specifically relates to an antiviral drug resmetiro 1,4-dioxane solvent compound and a preparation method thereof. Background Art

[0002] Non-alcoholic steatohepatitis (NASH), also known as metabolic steatohepatitis, is common in middle-aged people, especially individuals with metabolic disorders such as obesity, insulin resistance, type 2 diabetes, and hyperlipidemia. If non-alcoholic steatohepatitis is not controlled, the condition may worsen and turn into cirrhosis or even liver cancer, seriously affecting health and even threatening life. There is still a lack of effective treatment drugs. Resmetirom (MGL-3196), a thyroid hormone receptor β (THR-β) agonist under development by the US biotechnology company Madrigal, achieved the primary endpoint and key secondary endpoints in a Phase III clinical trial for the treatment of patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and is expected to become the first successful treatment drug in the field of NASH.

[0003] The chemical name of Resmetiro is: 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, with the following structural formula:

[0004]

[0005] We all know that different crystalline forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., thus affecting the stability, bioavailability and efficacy of the drug. This phenomenon is particularly evident in oral solid preparations. PCT patent WO2014043706A reports the chemical synthesis route of resmetiro, using resmetiro N1 intermediate (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl)carbamic acid ethyl ester to add potassium acetate to N,N-dimethylacetamide solvent and heat to close the ring to obtain the target product resmetiro. Since sodium nitrite is used in the step of synthesizing resmetiro N1 intermediate, it is easy to produce nitrosamine impurities under the conditions of strong heating using DMAC in the subsequent reaction, which has a greater risk of radical poisoning. The patent also reports the crystalline form I of resmetiro and its ethanol solvate, methyl isobutyl ketone solvate, N,N-dimethylacetamide solvate and hydrate forms.

[0006] During the experimental research, the inventors found that resmetiro can form a 1,4-dioxane solvent compound, which has stable crystal properties, is conducive to purification, and is easy to industrially scale up production, which provides more options for the application of resmetiro. The present invention also provides a method for synthesizing a 1,4-dioxane solvent compound of resmetiro, which can significantly reduce the risk of nitrosamine impurities. Summary of the invention

[0007] In order to provide more options for the application of resmetiro, the purpose of the present invention is to provide a resmetiro 1,4-dioxane solvent compound and a preparation method thereof, which has a simple process route, low cost and is suitable for industrial production.

[0008] To achieve the purpose of the invention, the resmetirol 1,4-dioxane solvent compound crystal provided by the present invention is a solvent compound crystal formed by resmetirol and 1,4-dioxane solvent; one molecule of the resmetirol 1,4-dioxane solvent compound crystal contains one molecule of resmetirol and one molecule of dioxane, that is, the molar ratio is 1:1, and the molecular formula is: C 17 H 12 Cl2N6O4·C4H8O2.

[0009] The crystal form of the resmetirol 1,4-dioxane solvent compound crystal provided by the present invention is measured by using Cu-Kα ray X-ray powder diffraction Figure 2 Theta values ​​(±0.1°) have characteristic peaks at 6.9°, 14.9°, 22.5°, and 24.7°.

[0010] Furthermore, its X-ray powder diffraction Figure 2 Theta values ​​(±0.1°) have characteristic peaks at 11.7°, 12.1°, 13.8°, 17.4°, 19.0°, 20.0°, 23.6°, and 30.3°.

[0011] Furthermore, the differential scanning calorimetry analysis curve (DSC) of the crystalline form of the resmetiro 1,4-dioxane solvent compound crystals shows an endothermic peak when heated to 147°C to 175°C, with a peak value of 167.9±0.5°C, which is a desolvation peak; an endothermic peak appears when heated to 324°C to 340°C, with a peak value of 334.5±0.5°C, which is a melting point peak.

[0012] Furthermore, the thermogravimetric analysis curve (TGA) of the crystalline form of the resmetirole 1,4-dioxane solvent compound crystals shows a characteristic peak of weight loss when heated to about 150-175°C, with a weight loss of about 16.7%.

[0013] The second object of the present invention is to provide a method for preparing resmetiro 1,4-dioxane solvent compound crystals, which adopts the following technical scheme:

[0014] A method for preparing a resmetiro 1,4-dioxane solvent compound crystal comprises the following steps: mixing a resmetiro N1 intermediate (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl)ethyl carbamate with 1,4-dioxane, adding a carboxylate, and then heating to a certain temperature and stirring for reaction; after the reaction is completed, adding an acid to quench the reaction, and then adding water to dilute, or directly adding water to quench the reaction and dilute; stirring in the obtained dioxane-water mixed solvent system for a period of time, and then slowly cooling and crystallizing, filtering and drying to obtain a white to off-white solid, which is a 1,4-dioxane solvent compound; the reaction formula is as follows:

[0015]

[0016] Preferably, the carboxylate is selected from sodium acetate, potassium acetate, sodium propionate, potassium propionate, sodium butyrate, potassium butyrate, sodium isobutyrate, potassium isobutyrate, sodium isooctanoate or potassium isooctanoate; the reaction heating temperature is 60-110°C, preferably 90-101°C; the quenching acid is selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid; the pulping starting temperature in the crystallization step is 40-80°C, preferably 55-65°C; the pulping cooling temperature is -20-35°C, preferably 0-5°C.

[0017] The third object of the present invention is to provide a method for preparing resmetiro 1,4-dioxane solvent compound crystals, which adopts the following technical scheme:

[0018] A method for preparing crystals of a resmetiro 1,4-dioxane solvent compound comprises mixing resmetiro and 1,4-dioxane, heating to a certain temperature and stirring for a period of time, adding or not adding a solvent B, stirring in the obtained mixed solvent system or a single solvent for a period of time, slowly cooling to a certain temperature for crystallization, preserving and beating to obtain a suspension, filtering and drying to obtain the 1,4-dioxane solvent compound; the solvent B is selected from water, toluene, methyl tert-butyl ether, isopropyl ether, methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane or n-heptane; the heating temperature is 35-110°C, preferably 55-60°C; the cooling temperature is -20-30°C, preferably 0-5°C.

[0019] The present invention discovers a 1,4-dioxane solvent compound of resmetirox. The preparation process of the crystal form is simple and easy to operate. The quality indicators of the obtained crystal form remain basically unchanged in the accelerated stability test, which shows that the product 1,4-dioxane solvent compound has good stability, is easy to preserve during the production and circulation process, and provides a good choice for the preparation of its pharmaceutical preparation, which is of great significance to drug development. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] 1. Figure 1 is the XRPD pattern of 1,4-dioxane solvent compound of resmetiro;

[0021] 2. Figure 2 This is the DSC graph of the 1,4-dioxane solvent compound of resmetiro;

[0022] 3. Figure 3 This is the TGA diagram of the 1,4-dioxane solvent compound of resmetiro;

[0023] 4. Figure 4 This is an electron micrograph of a 1,4-dioxane solvent compound of resmetirol;

[0024] 5. Figure 5 This is an electron micrograph of Form I of resmetirole. DETAILED DESCRIPTION

[0025] The following is a detailed description of an embodiment of the present invention. This embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation method and a specific operation process are given, but the protection scope of the present invention is not limited to the following embodiment.

[0026] In the following examples, the test methods are usually carried out under conventional conditions or conditions recommended by the manufacturer. The resmetirol starting material is prepared according to the prior art, and its preparation method can refer to PCT patent WO2014043706A, and other raw materials and solvents are obtained from the market.

[0027] The X-ray powder diffraction pattern of the present invention is collected on a D8ADVANCE X-ray powder diffractometer, the detection and collection temperature is room temperature (about 25° C.), and the detection method parameters are as follows:

[0028]

[0029] The differential scanning calorimetry (DSC) diagram of the present invention was collected on TAQ2000, and the detection method parameters were as follows:

[0030]

[0031] The thermogravimetric analysis (TGA) graph of the present invention was collected on TAQ5000, and the detection method parameters were as follows:

[0032]

[0033]

[0034] Example 1

[0035]

[0036] In a three-necked flask, resmetiro intermediate N1 (48.13 g, 100 mmol), 1,4-dioxane 240 mL, sodium acetate (9.84 g, 120 mmol) were added, stirred evenly, and then heated to 95-100° C. for reaction for 10-16 hours. After the reaction was completed, the mixture was cooled to 55-60° C. and 10% dilute hydrochloric acid (91.1 g, 250 mmol) was added. 480 mL of water was slowly added, and the mixture was stirred at this temperature for 1 hour. The mixture was slowly cooled to 0-5° C. for crystallization, and stirred at this temperature for 2-3 hours. The mixture was centrifuged and dried to obtain 46.09 g of resmetiro 1,4-dioxane solvent compound (purity 99.81%, yield 87.9%). 1 HNMR(DMSO-d6,500MHz)δ13.29(br,1H),12.25(s,1H),7.79(s,2H),7.44(s,1H),3.57(s,8H),3.02-3.10(m,1H),1.20(d,J=6.5Hz,6H)

[0037] In Example 1, sodium acetate can be replaced by potassium acetate, sodium propionate, potassium propionate, sodium butyrate, potassium butyrate, sodium isobutyrate, potassium isobutyrate, sodium isooctanoate or potassium isooctanoate; hydrochloric acid can be replaced by acetic acid, trifluoroacetic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid.

[0038] The X-ray powder diffraction data of the 1,4-dioxane solvent compound obtained in this example are shown in Table 1. Figure 1 , its DSC diagram is as follows Figure 2 , its TGA diagram is as follows Figure 3 .

[0039] Table 1

[0040]

[0041]

[0042] Example 2

[0043]

[0044] Resmetiro intermediate N1 (48.13 g, 100 mmol), 240 mL of 1,4-dioxane, and potassium acetate (11.78 g, 120 mmol) were added to a three-necked flask. After stirring evenly, the temperature was raised to 95-100° C. and the reaction was carried out for 10-16 hours. After the reaction was completed, the temperature was cooled to 55-60° C. and acetic acid (15.01 g, 250 mmol) was added. 480 mL of water was slowly added, and the mixture was stirred at this temperature for 1 hour. The mixture was slowly cooled to 0-5° C. for crystallization, and stirred at this temperature for 2-3 hours. The mixture was centrifuged and dried to obtain 47.80 g of resmetiro 1,4-dioxane solvent compound (purity 99.84%, yield 91.2%).

[0045] In Example 2, potassium acetate can be replaced by sodium acetate, sodium propionate, potassium propionate, sodium butyrate, potassium butyrate, sodium isobutyrate, potassium isobutyrate, sodium isooctanoate or potassium isooctanoate; acetic acid can be replaced by trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid.

[0046] Example 3

[0047]

[0048] Resmetiro intermediate N1 (48.13 g, 100 mmol), 240 mL of 1,4-dioxane, and potassium propionate (13.46 g, 120 mmol) were added to a three-necked flask. After stirring evenly, the temperature was raised to 95-100° C. and the reaction was carried out for 10-16 hours. After the reaction was completed, the temperature was cooled to 55-60° C. and acetic acid (15.01 g, 250 mmol) was added. 480 mL of water was slowly added, and the mixture was stirred at this temperature for 1 hour. The mixture was slowly cooled to 0-5° C. for crystallization, and stirred at this temperature for 2-3 hours. The mixture was centrifuged and dried to obtain 48.45 g of resmetiro 1,4-dioxane solvent compound (purity 99.92%, yield 92.5%).

[0049] In Example 3, potassium propionate can be replaced by sodium acetate, potassium acetate, sodium propionate, sodium butyrate, potassium butyrate, sodium isobutyrate, potassium isobutyrate, sodium isooctanoate or potassium isooctanoate; acetic acid can be replaced by trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid.

[0050] Example 4

[0051]

[0052] Add crude resmetiro (43.52 g, 100 mmol, purity 98.0%) and 240 mL of 1,4-dioxane into a three-necked flask, stir evenly and then heat to 55-60°C with stirring, slowly add 435 mL of water, keep warm and stir for 1 hour, slowly cool to 0-5°C for crystallization, keep warm and stir for 2-3 hours, centrifuge and dry to obtain 46.94 g of resmetiro 1,4-dioxane solvent compound (purity 99.87%, yield 91.4%).

[0053] Example 5

[0054]

[0055] Add crude resmetiro (43.52 g, 100 mmol, purity 98.0%) and 240 mL of 1,4-dioxane into a three-necked flask, stir evenly and heat to 55-60° C. with stirring, slowly add 435 mL of anhydrous ethanol, keep warm and stir for 1 hour, slowly cool to 0-5° C. for crystallization, keep warm and stir for 2-3 hours, centrifuge and dry to obtain 47.90 g of resmetiro 1,4-dioxane solvent compound (purity 99.79%, yield 93.2%).

[0056] In Example 5, ethanol can be replaced by water, toluene, methyl tert-butyl ether, isopropyl ether, methanol, isopropanol, n-butanol, tert-butanol, acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane or n-heptane.

[0057] Example 6

[0058] The crystalline forms of 1,4-dioxane solvent compounds obtained in Example 1, Example 3, and Example 5 were subjected to an accelerated stability test. The test conditions were: 40°C ± 2°C, RH 75% ± 5%. The purity and moisture data of the products were measured as shown in Table 15. Under the accelerated conditions, the products showed very stable properties within 2 months.

[0059] Table 15 Accelerated stability test

[0060]

[0061] The test results show that the 1,4-dioxane solvent compound of the present invention is stable under the conditions of 40°C±2°C and RH75%±5% for 1 month and 2 months without crystal form change and chemical degradation.

Claims

1. Resmetiro and 1,4-dioxane solvent form a solvent compound crystal with the molecular formula: C 17 H 12 Cl2N6O4·C4H8O2.

2. The solvent compound crystal formed by resmetirol and 1,4-dioxane solvent according to claim 1, characterized in that The crystal form of the compound crystal has characteristic peaks at 6.9°, 14.9°, 22.5°, and 24.7° in the X-ray powder diffraction pattern 2Theta value (±0.1°) measured using Cu-Kα rays.

3. The solvent compound crystal formed by resmetirol and 1,4-dioxane solvent according to claim 2, characterized in that The crystal form of the compound crystals has characteristic peaks at 11.7°, 12.1°, 13.8°, 17.4°, 19.0°, 20.0°, 23.6°, and 30.3° in the X-ray powder diffraction pattern 2Theta value (±0.1°) measured using Cu-Kα rays.

4. The solvent compound crystal formed by resmetirol and 1,4-dioxane solvent according to claim 2 or 3, characterized in that The differential scanning calorimetry analysis curve of the crystal form of the compound crystal shows that an endothermic peak appears when heated to 147°C to 175°C, with a peak value of 167.9±0.5°C, which is a desolvation peak; an endothermic peak appears when heated to 324°C to 340°C, with a peak value of 334.5±0.5°C, which is a melting point peak.

5. The solvent compound crystal formed by resmetirol and 1,4-dioxane solvent according to claim 4, characterized in that The thermogravimetric analysis curve of the crystal form of the compound crystal shows a characteristic weight loss peak when heated to 150-175° C., with a weight loss of about 16.7%.

6. A method for preparing resmetiro 1,4-dioxane solvent compound crystals, characterized in that: The method comprises mixing (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxy-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl)carbamic acid ethyl ester with 1,4-dioxane, adding carboxylate, and then heating to a certain temperature and stirring for reaction. After the reaction is completed, cooling, adding acid to quench the reaction, and then adding water for dilution or directly adding water to quench the reaction and dilute; stirring in the obtained dioxane-water mixed solvent system for a period of time, slowly cooling for crystallization, filtering and drying to obtain a white to off-white solid, which is a 1,4-dioxane solvent compound; the reaction formula is as follows:

7. The method for preparing a resmetirol 1,4-dioxane solvent compound crystal according to claim 6, characterized in that: The carboxylate is selected from sodium acetate, potassium acetate, sodium propionate, potassium propionate, sodium butyrate, potassium butyrate, sodium isobutyrate, potassium isobutyrate, sodium isooctanoate or potassium isooctanoate; the reaction heating temperature is 60 to 110°C, preferably 90 to 101°C; the quenching acid is selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid; the reaction is cooled to 40 to 80°C after completion; and the crystallization temperature is -20 to 35°C.

8. The method for preparing a resmetirol 1,4-dioxane solvent compound crystal according to claim 7, characterized in that: The reaction heating temperature is 90-101°C, the cooling temperature after the reaction is completed is 55-65°C, and the crystallization temperature is 0-5°C.

9. A method for preparing resmetiro 1,4-dioxane solvent compound crystals, characterized in that: The crude product of resmetirol is mixed with 1,4-dioxane, heated to a certain temperature and stirred for a period of time, solvent B is added or not added, and after stirring for a period of time in the obtained mixed solvent system or single solvent, it is slowly cooled to a certain temperature for crystallization, and the suspension is obtained by heat preservation and slurrying, and filtered and dried to obtain 1,4-dioxane solvent compound; preferably, the solvent B is selected from water, toluene, methyl tert-butyl ether, isopropyl ether, methanol, ethanol, isopropanol, n-butanol, tert-butanol, acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane or n-heptane; the heating temperature is 35-110°C; the cooling temperature is -20-30°C.

10. The method for preparing a resmetirol 1,4-dioxane solvent compound crystal according to claim 9, characterized in that: The heating temperature is 55-60°C; the cooling temperature is 0-5°C.

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