Refining method of crude product of olpilcapone

Abstract

According to the refining method for the crude product of the olpilcapone, dimethyl sulfoxide and acetone are used as solvents, the use amount and the temperature of the solvents in the refining process are strictly controlled, the whole process is simple, the use amount of the solvents is small, the yield reaches 95% or above, the purity reaches 99.5% or above, all single impurities are smaller than 0.05%, and the refining method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for refining a crude opicapolone product. Background Art

[0002] Parkinson's disease (PD) is a chronic neurodegenerative disease that mainly affects the motor nervous system. The disease usually occurs in people over 60 years old, but can also occur in younger people. The main motor symptoms of Parkinson's disease include tremor, limb stiffness, bradykinesia, and abnormal gait. In addition, patients may also have non-motor symptoms such as loss of smell, depression, sleep problems, mental retardation, frequent urination, and intractable constipation. The treatment of Parkinson's disease usually adopts a comprehensive treatment strategy, including drug therapy, surgical treatment, botulinum toxin treatment, exercise therapy, psychological intervention, and care and nursing, among which drug therapy is the first choice and main means.

[0003] Opicapon is a third-generation COMT inhibitor, chemical name: 2,5-dichloro-3-[5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl]-4,6-dimethylpyridine-1-oxide, its chemical structure is as follows, it was approved by the US FDA in April 2020 as an adjunct therapy to levodopa / carbidopa for the treatment of Parkinson's disease and end-of-dose phenomenon (symptom fluctuations) in adults. In the BPARK-1 clinical trial, researchers compared the therapeutic effects of opicapon, entacapone and placebo as adjuncts to levodopa. The results showed that patients treated with 50 mg of opicapon and entacapone significantly reduced the number of episodes of off-periods after daily levodopa-related drug treatment compared with patients treated with placebo, and patients whose Parkinson's disease symptoms were fully controlled and without dyskinesias had an increase in the time they took their medication on time. Patients treated with opicapon had a greater reduction in the daily off-period after medication, even close to 2 hours.

[0004]

[0005] In addition, opicapol can increase the levels of levodopa that reach the brain and help reduce the dose of levodopa and its associated side effects. When used in combination with levodopa and the DDC inhibitor carbidopa, it can further reduce seizures in patients with Parkinson's disease.

[0006] Patent 111511735A discloses a method for preparing opicapone and its intermediates. The refining method is to suspend the crude opicapone in N,N-dimethylformamide and heat the reaction mixture at 60°C-65°C to obtain a clear solution. Then 500ml of methanol is added and the reaction mixture is cooled to room temperature. After stirring for 2-3 hours, the reaction mixture is filtered, the solid is washed with methanol, and vacuum dried at 50°C to obtain a refined opicapone. The yield and purity are low, the amount of solvent used is large, resulting in a large amount of waste liquid, which is not suitable for large-scale industrial production. Summary of the invention

[0007] The object of the present invention is to provide a method for refining crude opicapolone on the basis of the prior art.

[0008] The technical solution of the present invention is as follows:

[0009] A method for refining a crude opicapon product comprises the following steps: mixing the crude opicapon product with dimethyl sulfoxide, heating the mixture to 50-65°C to dissolve the mixture, slowly adding acetone, stirring the obtained mixed solution at 45-55°C, cooling the mixture to 20-30°C, stirring and crystallizing the mixture, filtering the mixture, washing the obtained filter cake, and drying the mixture to obtain a refined opicapon product.

[0010] For the present invention, the inventors have tried a large number of solvents to dissolve the crude opiate and refine the crude opiate. For example, the solvent may be, but is not limited to, dimethyl sulfoxide, dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methanol, ethanol, acetone, isopropanol and ethyl acetate. The results show that under the same conditions, only when dimethyl sulfoxide and acetone are used as solvents, the yield reaches more than 95%, the purity reaches more than 99.5%, and the content of other impurities is low during the refining process. When other solvents or several solvents are used, the yield and purity are greatly reduced during the refining process.

[0011] In the present invention, the mass volume ratio of crude opicapon to dimethyl sulfoxide is 1:2-6 g / mL, and may be but is not limited to 1:2 g / mL, 1:2.5 g / mL, 1:3 g / mL, 1:3.5 g / mL, 1:4 g / mL, 1:4.5 g / mL, 1:5 g / mL, 1:5.5 g / mL or 1:6 g / mL. In order to achieve better results, the mass volume ratio of crude opicapon to dimethyl sulfoxide is 1:2.5-3.5 g / mL. Further, the mass volume ratio of crude opicapon to dimethyl sulfoxide is 1:3 g / mL.

[0012] In the present invention, the mass volume ratio of crude opicapone to acetone is 1:15-35 g / mL, and may be but is not limited to 1:15 g / mL, 1:20 g / mL, 1:25 g / mL, 1:30 g / mL or 1:35 g / mL. In order to achieve better results, the mass volume ratio of crude opicapone to acetone is 1:20-30 g / mL. Further, the mass volume ratio of crude opicapone to acetone is 1:30 g / mL.

[0013] In the present invention, the crude opicapolone is mixed with dimethyl sulfoxide, and the temperature is raised to 50-65°C to dissolve it. When dissolving, the temperature can be but is not limited to 50°C, 52°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 62°C or 65°C. Preferably, the temperature is 52-62°C, and more preferably, the temperature is 55-60°C.

[0014] In the present invention, the obtained mixed solution is stirred at 45-55° C., and during stirring, the temperature may be but is not limited to 45° C., 46° C., 47° C., 48° C., 49° C., 50° C., 51° C., 52° C., 53° C., 54° C. or 55° C., preferably, the temperature is 48-52° C., and more preferably, the temperature is 50-51° C. The stirring time is 1-3 hours, preferably 2 hours.

[0015] In the present invention, during the stirring crystallization, the temperature is 20-30° C., and the temperature may be but is not limited to 20° C., 21° C., 22° C., 23° C., 24° C., 25° C., 26° C., 27° C., 28° C., 29° C. or 30° C., preferably, the temperature is 23-27° C., and more preferably, the temperature is 25° C. The stirring time is 2-5 hours, preferably 3 hours.

[0016] In the present invention, the drying temperature is 40-50°C, and the temperature may be but is not limited to 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C or 50°C. Preferably, the temperature is 45°C; the drying time is 4-8 hours, preferably 6 hours.

[0017] When the obtained filter cake is washed, the solvent is acetone. The mass volume ratio of the crude opiate to acetone is 1:2-5 g / mL, and can be but not limited to 1:2 g / mL, 1:2.5 g / mL, 1:3 g / mL, 1:3.5 g / mL, 1:4 g / mL, 1:4.5 g / mL or 1:5 g / mL. In order to achieve better results, the mass volume ratio of the crude opiate to acetone is 1:2.5-3.5 g / mL, and further, the mass volume ratio of the crude opiate to acetone is 1:3 g / mL.

[0018] Adopt the technical scheme of the present invention, the advantages are as follows:

[0019] The invention provides a method for refining a crude opicapolone product. Dimethyl sulfoxide and acetone are used as solvents, and the amount and temperature of the solvents are strictly controlled during the refining process. The whole process is simple, the amount of solvent used is small, the yield reaches more than 95%, the purity reaches more than 99.5%, all single impurities are less than 0.05%, and the method is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is the HPLC liquid phase diagram of the refined opicapolone in Example 1;

[0021] Figure 2 This is the HPLC liquid phase diagram of the refined opicapolone in Comparative Example 1. DETAILED DESCRIPTION

[0022] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0023] Example 1

[0024] Mix 10g of crude opiate and 30mL of dimethyl sulfoxide in a 500mL reaction bottle, stir and heat to 58°C to dissolve it, slowly add 300mL of acetone, and keep the resulting mixed solution at 51°C with stirring for 2 hours, then cool to 25°C and stir and crystallize for 3 hours. Filter, wash the filter cake once with 30mL of acetone to obtain a yellow solid. Dry in a vacuum oven at 45°C for 6 hours to obtain 9.62g of yellow solid, which is the refined opiate, with a yield of 96.2%, a purity of 99.924%, and all impurities less than 0.05%. The relevant HPLC spectrum is shown in Figure 1 shown.

[0025] Example 2

[0026] 10g of crude opiate and 50mL of dimethyl sulfoxide were mixed in a 500mL reaction bottle, stirred and heated to 55°C to dissolve, 200mL of acetone was slowly added, and the resulting mixed solution was kept warm and stirred at 50°C for 2 hours, then cooled to 25°C and stirred for crystallization for 3 hours. Filter, wash the resulting filter cake once with 30mL of acetone to obtain a yellow solid. Dry in a vacuum oven at 45°C for 6 hours to obtain 9.51g of yellow solid, which is the refined opiate, with a yield of 95.1%, a purity of 99.908%, and all single impurities less than 0.05%.

[0027] Example 3

[0028] 10 kg of crude opiate and 30 L of dimethyl sulfoxide were mixed in a 500 L reactor, stirred and heated to 60 ° C to dissolve, 300 L of acetone was slowly added, and the resulting mixed solution was kept warm and stirred at 51 ° C for 2 hours, then cooled to 25 ° C, and stirred and crystallized for 3 hours. Filter, wash the filter cake once with 30 L of acetone to obtain a yellow solid. Dry in a vacuum oven at 45 ° C for 6 hours to obtain 9.70 kg of yellow solid, which is the refined opiate, with a yield of 97.0%, a purity of 99.982%, and all single impurities less than 0.05%.

[0029] Comparative Example 1

[0030] Mix 25g of crude opiate and 250mL of N,N-dimethylformamide in a 250mL three-necked flask, stir and heat to 62°C to obtain a clear solution, add 500mL of methanol, cool the mixture to 25°C, stir for 3 hours, filter, and rinse the filter cake with 50mL of methanol to obtain a yellow solid. Dry in a vacuum oven at 50°C for 6 hours to obtain 20.5g of yellow solid, which is opiate refined product, with a yield of 82%, a purity of 95.481%, and a maximum single impurity of 2.113%. The relevant HPLC spectrum is shown in Figure 2 shown.

[0031] Comparative Example 2

[0032] 10g of crude opicapone and 30mL of N-methylpyrrolidone were mixed in a 500mL three-necked flask, stirred and heated to 58°C to obtain a clear solution, 300mL of acetone was added, and the resulting mixed solution was kept warm and stirred at 51°C for 2 hours, then cooled to 25°C and stirred for crystallization for 3 hours. Filter, wash the resulting filter cake once with 30mL of acetone to obtain a yellow solid. Dry in a vacuum drying oven at 45°C for 6 hours to obtain 8.5g of yellow solid, which is the refined opicapone, with a yield of 85%, a purity of 93.283%, and a maximum single impurity of 3.369%.

[0033] Comparative Example 3

[0034] 10g of crude opiate and 30mL of dimethyl sulfoxide were mixed in a 500mL three-necked flask, stirred and heated to 58°C to obtain a clear solution, 300mL of methanol was added, and the resulting mixed solution was kept warm and stirred at 51°C for 2 hours, then cooled to 25°C, stirred for 3 hours, filtered, and the filter cake was rinsed with 30mL of methanol to obtain a yellow solid. Drying in a vacuum drying oven at 45°C for 6 hours, 9.08g of yellow solid was obtained, which was the refined opiate, with a yield of 90.8%, a purity of 96.921%, and a maximum single impurity of 0.764%.

[0035] Comparative Example 4

[0036] 10g of crude opiate and 30mL of dimethyl sulfoxide were mixed in a 500mL three-necked flask, stirred and heated to 58°C to obtain a clear solution, 100mL of acetone was added, the resulting mixed solution was kept stirred at 51°C for 2 hours, then cooled to 25°C, stirred for 3 hours, filtered, and the filter cake was washed with 30mL of acetone to obtain a yellow solid. Drying in a vacuum drying oven at 45°C for 6 hours, 9.28g of yellow solid was obtained, which was the refined opiate, with a yield of 92.8%, a purity of 98.868%, and a maximum single impurity of 0.175%.

[0037] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for refining crude opicapolone, characterized in that: The method comprises the following steps: mixing crude opiate with dimethyl sulfoxide, heating to 50-65°C to dissolve it, slowly adding acetone, stirring the obtained mixed solution at 45-55°C, cooling to 20-30°C, stirring and crystallizing, filtering, washing the obtained filter cake, and drying to obtain opiate fine product.

2. The method for refining crude opiate according to claim 1, characterized in that: The mass volume ratio of the crude opicapolone to dimethyl sulfoxide is 1:2-6 g / mL.

3. The method for refining crude opicapolone according to claim 2, characterized in that: The mass volume ratio of the crude opicapolone to dimethyl sulfoxide is 1:3-5 g / mL, preferably 1:3 g / mL.

4. The method for refining crude opicapolone according to claim 1, characterized in that: The mass volume ratio of the crude opicapolone to acetone is 1:15-35 g / mL.

5. The method for refining crude opicapolone according to claim 4, characterized in that: The mass volume ratio of the crude opicapolone to acetone is 1:20-30 g / mL, preferably 1:30 g / mL.

6. The method for refining crude opicapolone according to claim 1, characterized in that: When dissolving, the temperature is 52-62°C, preferably 55-60°C.

7. The method for refining crude opicapolone according to claim 1, characterized in that: During stirring, the temperature is 48-52°C, preferably 50-51°C, and the stirring time is 1-3 hours, preferably 2 hours.

8. The method for refining crude opicapolone according to claim 1, characterized in that: During the stirring crystallization, the temperature is 23-27°C, preferably 25°C; the stirring time is 2-5 hours, preferably 3 hours.

9. The method for refining crude opicapolone according to claim 1, characterized in that: The drying temperature is 40-50°C, preferably 45°C; the drying time is 4-8 hours, preferably 6 hours.

10. The method for refining crude opicapolone according to claim 1, characterized in that: When the obtained filter cake is washed, the solvent is acetone; the mass volume ratio of the crude opicapolone to acetone is 1:2-5 g / mL; preferably 1:2.5-3.5 g / mL; more preferably 1:3 g / mL.

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