A compound, preparation method and application thereof

Abstract

The application belongs to the technical field of chemical medicines, and particularly relates to 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1H-quinolin-7-yl)oxy]butyl}oxy)benzene-1,2-dicarbonitrile, a preparation method and application thereof. H The 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1H-quinolin-7-yl)oxy]butyl}oxy)benzene-1,2-dicarbonitrile has a structure shown in formula I: formula I. The impurity in brexpiprazole contains the structure shown in formula I, the content of the impurity in brexpiprazole can be effectively detected by using the novel compound provided by the application as a standard sample, and the drug quality stability and drug safety can be effectively ensured.

Description

Technical Field

[0001] This invention belongs to the field of chemical and pharmaceutical technology, specifically relating to a 4,5-dichloro-3-hydroxy-6-({4-[(2-oxoylide-1H-quinolin-7-yl)oxy]butyl}oxy)benzene-1,2-dicarboxynitrile, its preparation method, and its application. Background Technology

[0002] Bripiprazole is a medication used to treat mental illnesses. It is primarily used to treat schizophrenia and other related mental disorders, helping patients improve their symptoms and quality of life. The importance of brripiprazole lies in its ability to effectively control symptoms such as hallucinations and delusions in patients with mental illness, reducing their social dysfunction. Bripiprazole is a novel multi-target mechanism of action drug for treating mental disorders. It has a regulatory effect on the monoaminergic neurotransmission system in the brain, acting as a partial agonist of serotonin receptor 5-HT1A and dopamine receptors D2 and D3, while also being a partial antagonist of serotonin receptors 5-HT2A and 5-HT2B, as well as adrenaline receptors α-1 and α-2.

[0003] Impurity control is a core guarantee for drug quality and medication safety. Impurities in biriperazole mainly arise from side reactions during synthesis, storage, and degradation reactions during use. Currently, there is limited research on the types and amounts of impurities in biriperazole. Summary of the Invention

[0004] In view of this, the present invention provides a 4,5-dichloro-3-hydroxy-6-({4-[(2-oxoylide-1H-quinolin-7-yl)oxy]butyl}oxy)benzene-1,2-dicarboxynitrile, its preparation method, and its application. The novel compound (4,5-dichloro-3-hydroxy-6-({4-[(2-oxoylide-1H-quinolin-7-yl)oxy]butyl}oxy)benzene-1,2-dicarboxynitrile) provided by the present invention is an impurity in bripiprazole. The content of impurities in bripiprazole can be detected by using the novel compound provided by the present invention as a standard sample.

[0005] To solve the above-mentioned technical problems, the present invention provides a 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-1-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl) 4-(2-oxo-1-yl)-yl)-yl)-yl)-yl) 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl) 4-(2-oxo-1 ... H -quinoline-7-yl)oxy]butyl]oxy)phenyl-1,2-dicarboxynitrile, having the structure shown in Formula I: Formula I.

[0006] The present invention also provides the 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-2 ...""" 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)"" 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-2 H The preparation method of quinolino-7-yl)oxy]butyl)oxy)phenyl-1,2-dicarboxynitrile includes the following steps: Compound A, compound B, a basic compound, a catalyst, and an organic solvent were mixed and subjected to a substitution reaction to obtain the 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-2 ... H -quinoline-7-yl)oxy]butyl]oxy)phenyl-1,2-dicarboxynitrile; The compound A is Where X includes -Cl, -Br, or -I; the compound B is .

[0007] Preferably, the alkaline compound includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, and cesium carbonate.

[0008] Preferably, the catalyst comprises one or more of potassium iodide, sodium iodide, potassium bromide, and sodium bromide.

[0009] Preferably, the organic solvent includes one or more of N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, and N,N-dimethylacetamide.

[0010] Preferably, the molar ratio of compound A to compound B is 1:1 to 3.

[0011] Preferably, the molar ratio of compound A to the basic compound is 1:1 to 5; The molar ratio of compound A to catalyst is 1:1 to 2.

[0012] Preferably, the mass ratio of compound A to the volume ratio of the organic solvent is 1 g: 5~15 mL.

[0013] Preferably, the temperature of the substitution reaction is 80~100℃, and the reaction time is 6~10h.

[0014] This invention also provides the application of 4,5-dichloro-3-hydroxy-6-({4-[(2-oxoylide-1H-quinolin-7-yl)oxy]butyl}oxy)benzene-1,2-dicarboxynitrile as described in the above technical solution or prepared by the above technical solution as a standard sample for impurities in bripiprazole.

[0015] This invention provides a 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-1-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl) 4-(2-oxo-1 ... 4-(2- H -quinoline-7-yl)oxy]butyl]oxy)phenyl-1,2-dicarboxynitrile, having the structure shown in Formula I: Formula I. Burepiperazole contains impurities with the structure shown in Formula I. Using the novel compound provided by this invention as a standard sample can effectively detect the content of impurities in burepiperazole, thus effectively ensuring drug quality stability and medication safety. Attached Figure Description

[0016] Figure 1 The 1H-NMR spectrum of the gray powder solid prepared in Example 1; Figure 2 The image shows the LC-MS spectrum of the gray powder solid prepared in Example 1. Detailed Implementation

[0017] This invention provides a 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-1-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl) 4-(2-oxo-1 ... 4-(2- H -quinoline-7-yl)oxy]butyl]oxy)phenyl-1,2-dicarboxynitrile, having the structure shown in Formula I: Formula I.

[0018] In this invention, the 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-1-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl) 4-(2-oxo-1 ... 5-dichloro H -quinoline-7-yl)oxy]butyl}oxy)benzene-1,2-dicarboxynitrile is a gray powder.

[0019] During the preparation of buriperazole, a compound with the structure shown in Formula I is generated. That is, the novel compound provided by the present invention is an impurity generated during the production of buriperazole.

[0020] The present invention also provides the 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-2 ...""" 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)"" 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-2 H The preparation method of quinolino-7-yl)oxy]butyl)oxy)phenyl-1,2-dicarboxynitrile includes the following steps: Compound A, compound B, a basic compound, a catalyst, and an organic solvent were mixed and subjected to a substitution reaction to obtain the novel compound. The compound A is Where X includes -Cl, -Br, or -I; the compound B is .

[0021] In this invention, the alkaline compound may include one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, and cesium carbonate, specifically sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, or cesium carbonate; in the embodiments of this invention, the alkaline compound is anhydrous potassium carbonate. In this invention, the alkaline compound provides an alkaline environment for the substitution reaction.

[0022] In this invention, the catalyst may include one or more of potassium iodide, sodium iodide, potassium bromide, and sodium bromide, specifically potassium iodide, sodium iodide, potassium bromide, or sodium bromide; in the embodiments of this invention, the catalyst is potassium iodide.

[0023] In this invention, the organic solvent includes one or more of N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, and N,N-dimethylacetamide, specifically N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, or N,N-dimethylacetamide.

[0024] In this invention, the molar ratio of compound A to compound B can be 1:1 to 3, specifically 1:1.5, 1:2 or 1:2.5.

[0025] In this invention, the molar ratio of compound A to the basic compound can be 1:1 to 5, specifically 1:2.5, 1:3 or 1:4.

[0026] In this invention, the molar ratio of compound A to catalyst can be 1:1 to 2, specifically 1:1.5.

[0027] In this invention, the mass ratio of compound A to the volume ratio of the organic solvent can be 1g:5~15mL, specifically 1g:8mL, 1g:10mL or 1g:13mL.

[0028] In this invention, the mixing can be carried out under stirring conditions; during the stirring process, nitrogen gas can be used for displacement, and the displacement can be performed 2 to 4 times, specifically 3 times. This invention removes oxygen from the reaction system through nitrogen displacement.

[0029] In this invention, the temperature of the substitution reaction can be 80~100℃, specifically 85℃, 90℃ or 95℃; the time of the substitution reaction can be 6~10h, specifically 7h, 8h or 9h.

[0030] This invention monitors the substitution reaction using TLC, and stops the reaction once the starting compound A has completely reacted. In this invention, the equation for the substitution reaction is shown in equation a: Formula a.

[0031] In this invention, the substitution reaction may further include: cooling the system after the substitution reaction to room temperature, adding water and stirring, followed by a first filtration; slurrying the solid obtained from the first filtration with anhydrous ethanol, followed by a second filtration; and drying the solid obtained from the second filtration to obtain the 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-2 ... 2-yl) 2-yl) 5-yl) 5-yl)" 2-yl) 5-yl)" 2-yl) 5-yl)" 2-yl)"" 2 H-quinoline-7-yl)oxy]butyl)oxy)phenyl-1,2-dicarboxynitrile. In this invention, the room temperature can be 20~35℃, or 25~30℃; the water added to the cooled system can be purified water; the volume ratio of water to the cooled system can be 1.8~2.2:1, specifically 2:1; the drying temperature can be 45~55℃, specifically 50℃; this invention does not have a special limitation on the drying time, as long as the solvent on the solid surface can be removed. This invention has no special requirements for the first filtration, the second filtration, and the pulping; conventional methods in the art can be used.

[0032] The present invention also provides the 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-2 ...""" 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)-2-yl)"" 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-2 H 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)oxy]butyl}oxy)phenyl-1,2-dicarboxynitrile or prepared by the method described in the above technical solution, is a quinoline-7-yl)oxy]butyl}oxy)phenyl-1,2-dicarboxynitrile. H The application of quinolin-7-yl)oxy]butyl}oxy)phenyl-1,2-dicarboxynitrile as a standard sample for impurities in bripiprazole. In this invention, the ,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-yl)-phenyl-1,2-dicarboxynitrile is described. H -quinoline-7-yl)oxy]butyl}oxy)phenyl-1,2-dicarboxynitrile can also be used as an impurity reference standard. This invention can utilize 5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-yl)-phenyl-1,2-dicarboxynitrile. H -quinoline-7-yl)oxy]butyl}oxy)benzene-1,2-dicarboxynitrile was used as a standard sample to test the content of impurities in bripiprazole; the test can be performed by high performance liquid chromatography.

[0033] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0034] Example 1 To a 1000 mL three-necked reaction flask, add compound A (20 g, 0.08 mmol), compound B (27.30 g, 0.12 mmol), anhydrous potassium carbonate (27.45 g, 0.2 mmol), potassium iodide (19.78 g, 0.12 mmol), and N,N-dimethylformamide (200 mL). Start stirring, purge with nitrogen three times, raise the temperature to 95 °C, and maintain the reaction temperature (substitution reaction) for 8 h. Monitor the reaction by TLC. Once the reactant compound A has completely reacted, stop the reaction. After stopping the reaction, lower the temperature of the system after the substitution reaction to 25 °C, slowly add purified water (400 mL), stir for 1 h, filter, collect the solid, and slurry the solid with anhydrous ethanol (100 mL) for 1 h. Filter again and dry the solid at 50 °C to obtain a gray powdery solid (4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1 ... H -quinoline-7-yl)oxy]butyl}oxy)phenyl-1,2-dicarboxynitrile).

[0035] The gray powdery solid prepared in Example 1 was subjected to NMR analysis, and the results showed that... 1 H-NMR spectrum as shown Figure 1 As shown, the specific results are as follows: 1 H NMR (600 MHz, DMSO- d 6) δ 1.78 (dq, J = 6.3, 12.9 Hz, 2H), 1.85 (dq, J = 6.4, 11.2 Hz, 2H), 3.86 (t, J = 6.1 Hz, 2H), 3.98 (t, J = 6.3 Hz, 2H), 6.20 (d, J = 9.4 Hz, 1H), 6.67 – 6.73 (m, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 9.5 Hz, 1H), 11.49 (s, 1H). The gray powder solid prepared in Example 1 was subjected to combined liquid chromatography-mass spectrometry (LC-MS) detection to obtain the LC-MS spectrum, as shown below. Figure 2 As shown, Figure 2 The image below is a magnified view of a portion of the image above.

[0036] according to Figure 1 and Figure 2 The results show that the gray powder solid prepared in Example 1 is (4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1)-)-( ...-dichloro-3-hydroxy-6-({4-[(2-oxo-1)-)-(4-dichloro-3-hydroxy-6-({4-[(2-oxo-1) H-quinoline-7-yl)oxy]butyl}oxy)benzene-1,2-dicarboxynitrile.

[0037] Example 2 To a 1000 mL three-necked reaction flask, add compound A (20 g, 0.08 mmol), compound B (27.30 g, 0.12 mmol), anhydrous potassium carbonate (27.45 g, 0.2 mmol), potassium iodide (19.78 g, 0.12 mmol), and N-methylpyrrolidone (200 mL). Start stirring, purge with nitrogen three times, raise the temperature to 95 °C, and maintain the reaction temperature (substitution reaction) for 8 h. Monitor the reaction by TLC. Once the reactant compound A has completely reacted, stop the reaction. After stopping the reaction, lower the temperature of the system after the substitution reaction to 25 °C, slowly add purified water (400 mL), stir for 1 h, filter, collect the solid, and slurry the solid with anhydrous ethanol (100 mL) for 1 h. Filter again and dry the solid at 50 °C to obtain a gray powdery solid (4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1 ... H -quinoline-7-yl)oxy]butyl}oxy)phenyl-1,2-dicarboxynitrile).

[0038] Comparative Example 1 (different from Example 1 in terms of the types of basic compounds and organic solvents) Compound A (20 g, 0.08 mmol), compound B (27.30 g, 0.12 mmol), triethylamine (20.24 g, 0.2 mmol), potassium iodide (19.78 g, 0.12 mmol), and 1,4-dioxane (200 mL) were added to a 1000 mL three-necked reaction flask. Stirring was started, and nitrogen was purged three times. The temperature was raised to 95 °C and maintained for 8 h. The reaction was monitored by TLC. When the reaction ceased, it was stopped. After stopping the reaction, the temperature of the system was lowered to 25 °C, and purified water (400 mL) was slowly added. The mixture was stirred for 1 h, filtered, and the solid was collected. The solid was then slurried with anhydrous ethanol (100 mL) for 1 h, filtered, and dried at 50 °C to obtain a gray powder.

[0039] Comparative Example 2 (No catalyst added compared to Example 1) Compound A (20 g, 0.08 mmol), compound B (27.30 g, 0.12 mmol), anhydrous potassium carbonate (27.45 g, 0.2 mmol), and N,N-dimethylformamide (200 mL) were added to a 1000 mL three-necked reaction flask. Stirring was started, and nitrogen was purged three times. The temperature was raised to 95 °C and maintained for 8 h. The reaction was monitored by TLC. Once the reactant compound A had reacted completely, the reaction was stopped. After stopping the reaction, the temperature of the system was lowered to 25 °C, and purified water (400 mL) was slowly added. The mixture was stirred for 1 h, filtered, and the solid was collected. The solid was then slurried with anhydrous ethanol (100 mL) for 1 h, filtered, and dried at 50 °C to obtain a gray powder.

[0040] Comparative Example 3 (different from Example 1 in terms of organic solvent) To a 1000 mL three-necked reaction flask, add compound A (20 g, 0.08 mmol), compound B (27.30 g, 0.12 mmol), anhydrous potassium carbonate (27.45 g, 0.2 mmol), potassium iodide (19.78 g, 0.12 mmol), and dimethyl sulfoxide (200 mL). Start stirring, purge with nitrogen three times, raise the temperature to 95 °C, and maintain the reaction temperature for 8 h. Monitor the reaction by TLC. Once the reactant compound A has reacted completely, stop the reaction. After stopping the reaction, lower the system temperature to 25 °C, slowly add purified water (400 mL), stir for 1 h, filter, collect the solid, and slurry the solid with anhydrous ethanol (100 mL) for 1 h. Filter again and dry the solid at 50 °C to obtain a gray powder.

[0041] The purity of the gray powder solids prepared in Examples 1-2 and Comparative Examples 1-3 was determined by high performance liquid chromatography (HPLC), and the results are listed in Table 1. The yields were also calculated and are listed in Table 1.

[0042] Table 1. Purity and yield of the products prepared in Examples 1-2 and Comparative Examples 1-3

[0043] As can be seen from Table 1, the preparation method provided by the present invention can prepare 4,5-dichloro-3-hydroxy-6-({4-[(2-oxoylide-1H-quinolin-7-yl)oxy]butyl}oxy)benzene-1,2-dicarboxynitrile with high purity and high yield.

[0044] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-1-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl) 4-(2-oxo-1 ... H -quinoline-7-yl)oxy]butyl]oxy)phenyl-1,2-dicarboxynitrile, characterized in that... It has the structure shown in Equation I: Equation I.

2. The 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl) ... 4, 5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-yl)-yl)-yl)-yl)-yl)-yl)-yl)) H The method for preparing quinolino-7-yl)oxy]butyl)oxy)phenyl-1,2-dicarboxynitrile, characterized in that, Includes the following steps: Compound A, compound B, a basic compound, a catalyst, and an organic solvent were mixed and subjected to a substitution reaction to obtain the 4,5-dichloro-3-hydroxy-6-({4-[(2-oxo-1-yl)-2 ... H -quinoline-7-yl)oxy]butyl]oxy)phenyl-1,2-dicarboxynitrile; The compound A is Where X includes -Cl, -Br, or -I; the compound B is .

3. The preparation method according to claim 2, characterized in that, The alkaline compound includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, and cesium carbonate.

4. The preparation method according to claim 2, characterized in that, The catalyst includes one or more of potassium iodide, sodium iodide, potassium bromide, and sodium bromide.

5. The preparation method according to claim 2, characterized in that, The organic solvent includes one or more of N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane and N,N-dimethylacetamide.

6. The preparation method according to claim 2, characterized in that, The molar ratio of compound A to compound B is 1:1 to 3.

7. The preparation method according to claim 2, 3, 4 or 6, characterized in that, The molar ratio of compound A to the basic compound is 1:1 to 5; The molar ratio of compound A to catalyst is 1:1 to 2.

8. The preparation method according to claim 2 or 5, characterized in that, The mass ratio of compound A to the volume ratio of the organic solvent is 1 g: 5~15 mL.

9. The preparation method according to any one of claims 2 to 6, characterized in that, The substitution reaction is carried out at a temperature of 80-100°C for 6-10 hours.

10. The application of 4,5-dichloro-3-hydroxy-6-({4-[(2-oxoylide-1H-quinolin-7-yl)oxy]butyl}oxy)benzene-1,2-dicarboxynitrile as described in claim 1 or prepared by the method described in any one of claims 2 to 9 as a standard sample for impurities in bripiprazole.

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