Apremilast impurity and preparation method thereof
During the preparation of the Apste API, the amide cyclization reaction of the compound of formula I and 3-acetylaminophthalic anhydride was successfully prepared, which solved the problem of difficulty in controlling impurities in the prior art and ensured the safety of drug quality.
Patent Information
- Application Number
- CN202411647912.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-18
- Publication Date
- 2025-02-28
AI Technical Summary
The impurities generated in the preparation of Appster API in the prior art are difficult to effectively control, affecting the quality and safety of the drug.
The high-purity Apst impurity was prepared by amide cyclization reaction of the compound of formula I and 3-acetylaminophthalic anhydride in a solvent, and purified by column chromatography to obtain a product with a purity of more than 95%.
The preparation of high-purity apst impurities was achieved, and a reference product was provided for the study of impurities in apst, ensuring that the quality of the raw materials met the medicinal standards.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of medicines, and in particular relates to an apremilast impurity and a preparation method thereof. Background Art
[0002] Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis, with psoriatic rash and pain, swelling, tenderness, stiffness and movement disorders in the joints and surrounding soft tissues. Some patients may have sacroiliitis and (or) spondylitis, with a prolonged course and prone to relapse. Joint ankylosis may occur in the late stage. About 75% of patients have a rash before arthritis, about 15% have it at the same time, and about 10% have a rash after arthritis. The disease can occur at any age, with a peak age of 30 to 50 years old. There is no gender difference, but the spine is more likely to be affected in men.
[0003] Apremilast is a phosphodiester-4 (PDE-4) inhibitor, which is used to treat adult patients with active psoriatic arthritis. It was approved by the U.S. Food and Drug Administration (FDA) in March 2014. Evaluate Pharma predicts that the sales of Apremilast will reach US$1.219 billion in 2018. After the FDA approves the new indication of Apremilast, the industry expects the peak sales to exceed US$2 billion.
[0004] Therefore, quality control research on Apremilast is of great significance.
[0005] The structure of Apremilast is shown below:
[0006]
[0007] At present, Apremilast is mainly synthesized through the following routes:
[0008]
[0009] The applicant discovered that during the preparation of the API, an apremilast hydrolysis product of Formula II was produced, the structure of which is shown below:
[0010]
[0011] The compound of formula I further undergoes an amide cyclization reaction with SM2 to generate an apremilast impurity of formula II, the structure of which is shown below:
[0012] Summary of the invention
[0013] The technical problem to be solved by the present invention is to provide a new impurity of Apremilast and a preparation method thereof, so as to realize method development and content detection by using high-purity Apremilast impurity as a reference substance.
[0014] In order to solve the above technical problems, the present invention provides a compound of formula II:
[0015]
[0016] The present invention also provides a method for preparing a compound of formula II, characterized in that the compound of formula II is prepared by cyclizing the compound of formula I and 3-acetylaminophthalic anhydride:
[0017]
[0018] In certain embodiments of the present invention, the compound represented by Formula I and 3-acetylaminophthalic anhydride undergo amide cyclization reaction in a solvent under heating conditions to produce the compound represented by Formula II.
[0019] In certain embodiments of the present invention, the molar ratio of the compound represented by formula I to 3-acetylaminophthalic anhydride is 1:0.8 to 1:3, preferably 1:1 to 1:1.5. More specifically, the molar ratio of the compound represented by formula I to 3-acetylaminophthalic anhydride is 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5.
[0020] In certain embodiments of the present invention, the reaction is carried out in the presence of acetic acid.
[0021] In certain embodiments of the present invention, the weight-to-volume ratio of the compound represented by Formula I to acetic acid is 1:5 to 1:30 g / ml, preferably 1:10 to 1:20 g / ml. More specifically, the weight-to-volume ratio of the compound represented by Formula I to acetic acid is 1:10, 1:15, or 1:20 g / ml.
[0022] In certain embodiments of the present invention, the reaction temperature is from room temperature to the boiling point of the solvent, preferably from 40 to 100°C, preferably from 60 to 90°C.
[0023] In certain embodiments of the present invention, the reaction time is 1 to 48 hours, preferably 4 to 42 hours, preferably 8 to 36 hours, and preferably 12 to 24 hours.
[0024] In certain embodiments of the invention, the reaction is quenched by adding water and then extracted with an organic solvent.
[0025] In certain embodiments of the present invention, the extraction organic solvent is selected from one or more of ethyl acetate, dichloromethane, isopropyl acetate or 2-methyltetrahydrofuran.
[0026] In certain embodiments of the present invention, the organic phase obtained by extraction is washed with water and / or an inorganic base aqueous solution to a pH of about 7.
[0027] In certain embodiments of the present invention, the inorganic base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium carbonate or potassium bicarbonate.
[0028] In certain embodiments of the present invention, the organic phase is concentrated under reduced pressure to obtain an oily substance, i.e., a crude product of apremilast impurities, which is further purified by column chromatography to obtain a compound of formula II.
[0029] Furthermore, the compound shown in Formula I is obtained by using Apremilast as a raw material, heating and hydrolyzing in a solvent under the action of an acid.
[0030] In certain embodiments of the present invention, the compound represented by Formula I is prepared by using Apremilast as a raw material, using acetone or tetrahydrofuran as a solvent, and heating and hydrolyzing in the presence of dilute hydrochloric acid or dilute sulfuric acid aqueous solution.
[0031] In certain embodiments of the present invention, the hydrolysis reaction temperature is from room temperature to the boiling point of the solvent.
[0032] In certain embodiments of the present invention, the hydrolysis reaction temperature is slightly hot, that is, 5 to 30° C. higher than room temperature, preferably 10 to 20° C. higher than room temperature.
[0033] In certain embodiments of the present invention, the hydrolysis reaction time is 1 to 48 hours, preferably 4 to 42 hours, preferably 8 to 36 hours, and preferably 12 to 24 hours.
[0034] Furthermore, after the hydrolysis reaction is completed, water is added to quench the reaction, the solvent is evaporated and concentrated, the aqueous phase is extracted with an organic solvent, the organic phase is collected and concentrated to obtain the compound shown in Formula I.
[0035] The present invention also relates to the use of the compound of formula II in controlling the quality of Apremilast API and its preparation.
[0036] The advantages of the present invention are as follows: the present invention uses Apremilast as a raw material to prepare a new Apremilast impurity, solves the problem of Apremilast impurity and its preparation, the method can obtain high-purity Apremilast impurity with a purity of more than 95%, provides a reference substance for the study of impurities in Apremilast, and can detect the content of the Apremilast impurity in the raw material to ensure that the prepared raw material medicine meets the pharmaceutical standards. BRIEF DESCRIPTION OF THE DRAWINGS
[0037] Figure 1 is the impurity of formula II described in Example 1 1 HNMR spectrum.
[0038] Specific embodiment
[0039] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.
[0040] Embodiment 1:
[0041] The preparation method of the Apremilast impurity shown in Formula II:
[0042]
[0043] (1) 26 g of Apremilast (1.0 eq) and 130 mL of acetone were added to a 1000 mL three-necked bottle in sequence. After stirring, the solution became turbid. 130 mL of a 2 mol / L dilute hydrochloric acid solution was added to the reaction solution. The temperature was raised to 40±5° C. and the reaction was continued for 40 to 48 hours. After HPLC confirmed that the reaction of the raw materials was complete, the reaction was stopped. After adding water, the solution was concentrated under reduced pressure to remove acetone. The aqueous phase was extracted with ethyl acetate, separated, and the organic phase was concentrated under reduced pressure to obtain 23 g of the compound of formula I. The purity of the solution by HPLC was 99%.
[0044] (2) 6.5 g of compound B (1.0 eq), 4.8 g of 3-acetylaminophthalic anhydride (1.5 eq) and 130 mL of acetic acid were added to a 250 mL three-necked flask in sequence, and heated to 70-80° C. for reaction for 48 h. The reaction solution was added with water and extracted with ethyl acetate, and the organic phase was washed with water and sodium bicarbonate aqueous solution until pH=7, and concentrated under reduced pressure to obtain 8.1 g of an oily substance. The oily substance was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate=2 / 1) to obtain 4.9 g of a foamy light yellow solid, which was the apremilast impurity shown in formula II, with a purity of 98.2%. 1 HNMR Figure 1 ,Ms m / z is 606.2[M+H] + .
[0045] Embodiment 2:
[0046] (1) 30 g of Apremilast (1.0 eq) and 150 mL of tetrahydrofuran were added to a 1000 mL three-necked bottle in sequence. After stirring, the solution became turbid. 150 mL of a 1 mol / L dilute sulfuric acid aqueous solution was added to the reaction solution. The temperature was raised to 40±5° C. and the reaction was continued for 40 to 48 hours. After HPLC confirmed that the reaction of the raw materials was complete, the reaction was stopped. After adding water, the solution was concentrated under reduced pressure to remove acetone. The aqueous phase was extracted with ethyl acetate, separated, and the organic phase was concentrated under reduced pressure to obtain 25 g of the compound of formula I. The purity of the HPLC was 98.6%.
[0047] (2) 13 g of compound B (1.0 eq), 6.4 g of 3-acetylaminophthalic anhydride (1.0 eq) and 130 mL of acetic acid were added to a 250 mL three-necked flask in sequence, and heated to 80-90° C. for reaction for 24 h. The reaction solution was added with water and extracted with ethyl acetate, and the organic phase was washed with water and sodium bicarbonate aqueous solution until pH=7, and concentrated under reduced pressure to obtain 17.0 g of an oily substance. The oily substance was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate=2 / 1) to obtain 10.1 g of a foamy light yellow solid, which was the apremilast impurity shown in formula II, with a purity of 97.2%.
[0048] Embodiment 3:
[0049] 10g of compound B (1.0eq), 4.9g of 3-acetylaminophthalic anhydride (1.0eq), and 100mL of acetic acid were added to a 250mL three-necked flask in sequence, and heated to 80-90°C for 24h. The reaction solution was extracted with ethyl acetate after adding water, and the organic phase was washed with water and sodium bicarbonate aqueous solution to pH = 7, and concentrated under reduced pressure to obtain 13.2g of oily substance. The oily substance was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 7.5g of foamy light yellow solid, which is the Apremilast impurity shown in formula II, with a purity of 97.1%.
[0050] The technical scheme of the present invention is further described in detail above in conjunction with specific embodiments. It should be understood that the above embodiments are only exemplary descriptions and explanations of the present invention, and should not be construed as limiting the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made based on the above contents of the present invention should be included in the scope of protection of the present invention.
Claims
1. A compound of formula II:
2. A method for preparing the compound of formula II according to claim 1, characterized in that: The compound shown in formula II is prepared by cyclizing the compound shown in formula I and 3-acetylaminophthalic anhydride:
3. The method according to claim 2, characterized in that The compound represented by formula I and 3-acetylaminophthalic anhydride undergo amide cyclization reaction in a solvent under heating conditions to obtain a compound represented by formula II; Preferably, the molar ratio of the compound represented by formula I to 3-acetylaminophthalic anhydride is 1:0.8 to 1:3, preferably 1:1 to 1:1.5; Preferably, the reaction is carried out under the action of acetic acid; Preferably, the weight-to-volume ratio of the compound represented by formula I to acetic acid is 1:5 to 1:30 g / ml, preferably 1:10 to 1:20 g / ml; Preferably, the reaction temperature is room temperature to the boiling point of the solvent, preferably 40 to 100°C, preferably 60 to 90°C; Preferably, the reaction time is 1 to 48 hours, preferably the reaction time is 4 to 42 hours, preferably the reaction time is 8 to 36 hours, and preferably the reaction time is 12 to 24 hours; Preferably, the reaction is quenched by adding water and then extracted with an organic solvent; Preferably, the extraction organic solvent is selected from one or more of ethyl acetate, dichloromethane, isopropyl acetate or 2-methyltetrahydrofuran; Preferably, the organic phase obtained by extraction is washed with water and / or an inorganic base aqueous solution to pH = 7; Preferably, the inorganic base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium carbonate or potassium bicarbonate; Preferably, the organic phase is concentrated under reduced pressure to obtain an oily substance, which is a crude product of Apremilast impurities, which is further purified by column chromatography to obtain a compound represented by Formula II.
4. The method according to claim 2, characterized in that: Furthermore, the compound shown in Formula I is obtained by using Apremilast as a raw material, heating and hydrolyzing in a solvent under the action of an inorganic acid.
5. The method according to claim 4, characterized in that The compound shown in formula I is obtained by using apremilast as a raw material, using acetone or tetrahydrofuran as a solvent, heating and hydrolyzing in the presence of dilute hydrochloric acid or dilute sulfuric acid aqueous solution.
6. The method according to claim 4, characterized in that Furthermore, after the reaction is completed, water is added to quench the reaction, the solvent is evaporated and concentrated, the aqueous phase is extracted with an organic solvent, the organic phase is collected and concentrated to obtain the compound shown in Formula I.
7. Use of the compound of formula II according to claim 1 in controlling the quality of Apremilast API and its preparation.