A method of preparing alvocidib malate

Abstract

The application provides a method for preparing alvocidib maleate, wherein crude alvocidib free base is refined, and the refined product is salted with maleic acid to obtain alvocidib maleate; the method is simple in process and convenient for industrialized mass production.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and specifically relates to a method for preparing avatrombopag maleate. Background Technology

[0002] Avatrombopag maleate (Formula I) is an oral thrombopoietin receptor agonist (TPO-RA) for chronic liver disease-related thrombocytopenia (CLD), indicated for adult patients with chronic liver disease-related thrombocytopenia who are scheduled for diagnostic procedures or surgery.

[0003] (Formula I) Summary of the Invention

[0004] This invention provides a method for preparing avatrombopag maleate, which involves purifying crude avatrombopag free base (compound of formula II), and then reacting the purified avatrombopag free base with maleic acid to form a salt, thereby obtaining avatrombopag maleate.

[0005] (Formula II)

[0006] A first aspect of the present invention provides a method for preparing avatrombopag maleate, comprising:

[0007] (1) Mix the crude avatrombopag free base with organic solvent A, and heat and stir to dissolve;

[0008] (2) Control the temperature of the solution obtained in step (1) to temperature T1, add organic solvent B, cool down to temperature T2 and stir to precipitate crystals, and separate the solid and liquid to obtain a solid;

[0009] (3) The solid obtained from solid-liquid separation in step (2) is mixed with organic solvent C, pulped at room temperature, and then subjected to solid-liquid separation to obtain the solid.

[0010] (4) Optionally, dry the solid obtained from the solid-liquid separation in step (3);

[0011] (5) Mix the solid obtained from solid-liquid separation in step (3) or the solid obtained from drying in step (4), maleic acid, and solvent D, and heat and stir to dissolve;

[0012] (6) The solution obtained in step (5) is hot filtered at a temperature of T3. The filtrate is cooled to crystallize, the solid and liquid are separated, and the solid is dried to obtain avatrombopag maleic acid.

[0013] In one embodiment of the present invention, organic solvent A is selected from one or more of DMF (N,N-dimethylformamide), DMA (N,N-dimethylacetamide), and DMSO (dimethyl sulfoxide). In another embodiment of the present invention, organic solvent A is DMF or DMA.

[0014] In one embodiment of the present invention, the mass-volume ratio of crude avatrombopag free base to organic solvent A is 1 g : (5-20) mL. In another embodiment of the present invention, the mass-volume ratio of crude avatrombopag free base to organic solvent A is 1 g : (5-15) mL. In yet another embodiment of the present invention, the mass-volume ratio of crude avatrombopag free base to organic solvent A is 1 g : (8-12) mL.

[0015] In one embodiment of the present invention, the temperature T1 is 60-75℃. In another embodiment of the present invention, the temperature T1 is 60-70℃. In yet another embodiment of the present invention, the temperature T1 is 65-75℃. In yet another embodiment of the present invention, the temperature T1 is 70-75℃.

[0016] In one embodiment of the present invention, organic solvent B is selected from one or more of acetone, ethyl acetate, dioxane, and tetrahydrofuran. In another embodiment of the present invention, organic solvent B is acetone or tetrahydrofuran. In one embodiment of the present invention, the volume ratio of organic solvent B to solvent A is 1:(1-3). In another embodiment of the present invention, the volume ratio of organic solvent B to solvent A is 1:2.

[0017] In one embodiment of the present invention, the temperature T2 is (-5)-15℃. In another embodiment of the present invention, the temperature T2 is (-5)-10℃. In yet another embodiment of the present invention, the temperature T2 is (-5)-5℃.

[0018] In one embodiment of the present invention, the organic solvent C is selected from one or more of acetone, ethyl acetate, dioxane, and tetrahydrofuran. In another embodiment of the present invention, the organic solvent C is acetone or tetrahydrofuran.

[0019] In one embodiment of the present invention, the solid obtained from solid-liquid separation in step (3) is dried as described in step (4) and then used in step (5). In another embodiment of the present invention, the solid obtained from solid-liquid separation in step (3) is used directly in step (5). In the present invention, the product after drying as described in step (4) is also referred to as the avatrombopag free base refined product. When the solid obtained from solid-liquid separation in step (3) is used directly in step (5), a small amount of the solid obtained from solid-liquid separation in step (3) can be taken first, and the content of avatrombopag free base in the undried solid obtained from solid-liquid separation in step (3) (i.e., wet product) can be determined by drying or content detection.

[0020] In one embodiment of the present invention, the drying in step (4) can be carried out by heating or not heating, and can be carried out by atmospheric pressure or reduced pressure; for example, atmospheric pressure drying at room temperature, reduced pressure drying at room temperature, atmospheric pressure drying above room temperature, and reduced pressure drying above room temperature; preferably, atmospheric pressure drying above room temperature or reduced pressure drying above room temperature. For example, it can be reduced pressure drying at 45-55°C for 12-18 hours.

[0021] In one embodiment of the present invention, solvent D is a combination of acetone, DMSO, and water. In another embodiment of the present invention, solvent D is a combination of acetone, DMSO, and water, with the volume ratio of acetone to water being (1-3):1, and the volume ratio of DMSO to water being (1-3):1. In yet another embodiment of the present invention, solvent D is a combination of acetone, DMSO, and water, with the volume ratio of acetone to water being (1.5-2.5):1, and the volume ratio of DMSO to water being (1.5-2.5):1.

[0022] In one embodiment of the present invention, the mass-to-volume ratio of the solid obtained in step (3) solid-liquid separation or the solid obtained in step (4) drying to solvent D is 1 g : (7-25) mL. In another embodiment of the present invention, the mass-to-volume ratio of the solid obtained in step (3) solid-liquid separation or the solid obtained in step (4) drying to solvent D is 1 g : (7-20) mL. In yet another embodiment of the present invention, the mass-to-volume ratio of the solid obtained in step (3) solid-liquid separation or the solid obtained in step (4) drying to solvent D is 1 g : (10-15) mL. It should be noted that when calculating the mass-to-volume ratio, if the solid obtained in step (3) solid-liquid separation (wet product) without drying is used, it needs to be converted according to the content of avatrombopag free base.

[0023] In one embodiment of the present invention, the molar ratio of the solid obtained in step (3) solid-liquid separation or the solid obtained in step (4) drying to maleic acid is 1:(1.1-2). In another embodiment of the present invention, the molar ratio of the solid obtained in step (3) solid-liquid separation or the solid obtained in step (4) drying to maleic acid is 1:(1.3-1.8). In yet another embodiment of the present invention, the molar ratio of the solid obtained in step (3) solid-liquid separation or the solid obtained in step (4) drying to maleic acid is 1:(1.5-1.8). Maleic acid is also known as maleic acid. It should be noted that when calculating the molar ratio, if the solid obtained in step (3) solid-liquid separation without drying (wet product) is used, it needs to be converted according to the content of avatrombopag free base.

[0024] In one embodiment of the present invention, the temperature T3 is 50-80℃. In another embodiment of the present invention, the temperature T3 is 50-70℃. In another embodiment of the present invention, the temperature T3 is 60-80℃. In yet another embodiment of the present invention, the temperature T3 is 55-75℃.

[0025] In one embodiment of the present invention, the temperature at which the filtrate is cooled and crystallized in step (6) is T4. In one embodiment of the present invention, temperature T4 is (-5)-15℃. In one embodiment of the present invention, temperature T4 is (-5)-10℃. In one embodiment of the present invention, temperature T4 is (-5)-5℃.

[0026] In one embodiment of the present invention, the drying in step (6) can be carried out by heating or not heating, and can be carried out by atmospheric pressure or reduced pressure; for example, atmospheric pressure drying at room temperature, reduced pressure drying at room temperature, atmospheric pressure drying above room temperature, and reduced pressure drying above room temperature; preferably, atmospheric pressure drying above room temperature or reduced pressure drying above room temperature. For example, it can be reduced pressure drying at 65-75°C for 12-36 hours.

[0027] In one specific embodiment of the present invention, solid-liquid separation can be performed by methods such as centrifugation or filtration. In another specific embodiment of the present invention, solid-liquid separation can be performed by filtration. In yet another specific embodiment of the present invention, solid-liquid separation can be performed by centrifugation.

[0028] A second aspect of the present invention provides a method for preparing a pharmaceutical composition containing avatrombopag maleate, comprising:

[0029] (a) Preparation of avatrombopag maleate according to the method described in the first aspect of the present invention.

[0030] (b) The avatrombopag maleate obtained in step (a) is mixed with a pharmaceutically acceptable carrier to obtain the pharmaceutical composition containing avatrombopag maleate.

[0031] Considering the influence of different seasons and times on room temperature, in this invention, "room temperature" refers to 10-30℃, preferably 15-25℃.

[0032] The terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “made of”.

[0033] "Percentage by volume" or "% (w / v)" or "% w / v" is a way of expressing mass-volume concentration, indicating the number of grams of solute contained in 100 ml of solution. For example, 20% (w / v) means that 100 ml of solution contains 20 g of solute.

[0034] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.

[0035] "Pharmaceutical acceptable" means that compounds, materials, compositions, and / or dosage forms are suitable for use in contact with human and animal tissues, within the limits of reliable medical judgment, without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0036] This invention provides a method for preparing avatrombopag maleic acid, which involves refining crude avatrombopag free base, and then reacting the refined avatrombopag free base with maleic acid to form a salt, thereby obtaining avatrombopag maleic acid. This method is simple and suitable for large-scale industrial production. In particular, the preferred solvent D in the salt-forming step can improve the yield of the salt-forming step. Detailed Implementation

[0037] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0038] Example 1

[0039] 21.6 L of DMA and 2.16 kg of crude avatrombopag base were added to a reaction vessel. Under a nitrogen atmosphere, the reaction solution was heated and stirred until dissolved. 10.8 L of acetone was added dropwise to the reaction vessel, controlling the addition temperature at 65-75℃. After the addition was complete, the reaction solution was stirred for 5-10 min, and the temperature was gradually lowered to 0±5℃, stirring to induce crystallization. The mixture was centrifuged, the reaction vessel wall was rinsed with acetone, and the centrifuged filter cake was washed and centrifuged until dry. 25.78 L of acetone and the centrifuged filter cake were added to the reaction vessel, and the mixture was stirred at room temperature for 1-2 h. The mixture was centrifuged, the reaction vessel wall was rinsed with acetone, and the centrifuged filter cake was washed and centrifuged until dry. The centrifuged filter cake was dried under reduced pressure at 50±5℃ for 16-18 h to obtain the purified avatrombopag base.

[0040] Add 9.7 L of dimethyl sulfoxide, 9.7 L of acetone, and 1.95 kg of purified avatrombopag base to a reaction vessel and stir. Heat the reaction solution to 50-55°C and add maleic acid dropwise (0.56 kg of maleic acid dissolved in 4.87 kg of purified water), controlling the addition temperature at 50-70°C. After the addition is complete, maintain the temperature at 60-70°C and filter the reaction solution while hot. Stir the filtrate at 60-70°C for 0.5-1 h, then cool to 35-55°C. Once solid precipitation is observed, gradually cool to 0±5°C and stir to induce crystallization. Centrifuge, rinse the reaction vessel wall with an appropriate amount of acetone, and wash the filter cake. Centrifuge until dry. Add 19.33 L of acetone and the centrifuged filter cake to the reaction vessel, stir, and slurry at room temperature for 1-2 h. Centrifuge, rinse the reaction vessel wall with an appropriate amount of acetone, and wash the filter cake. Centrifuge until dry. The centrifuged filter cake was dried under reduced pressure for about 24 hours to obtain avatrombopag maleate product.

[0041] Example 2

[0042] 203.30 kg of DMA and 21.63 kg of crude avatrombopag base were added to a reaction vessel. Under a nitrogen atmosphere, the reaction solution was heated and stirred until dissolved. 84.82 kg of acetone was added dropwise to the reaction vessel, controlling the adding temperature at 65-75℃ and the adding time at 0.5-2 h. After the addition was complete, the reaction solution was stirred for 5-10 min, gradually cooled to 0±5℃, and stirred to induce crystallization for about 3 h. The mixture was centrifuged, the reaction vessel wall was rinsed with acetone, and the filter cake was washed and centrifuged until dry. 203.60 kg of acetone and the filter cake were added to the reaction vessel, and the mixture was stirred at room temperature for 2-3 h. The mixture was centrifuged, the reaction vessel wall was rinsed with acetone, and the filter cake was washed and centrifuged until dry. The filter cake was dried under reduced pressure at 50±5℃ for 16 h to obtain the purified avatrombopag base, with a yield of approximately 95%.

[0043] Add 107.10 kg of dimethyl sulfoxide, 76.70 kg of acetone, and 19.46 kg of purified avatrombopag base to a reaction vessel and stir. Heat the reaction solution to 50-55°C and add maleic acid dropwise (5.57 kg of maleic acid dissolved in 48.65 kg of purified water), controlling the addition temperature at 50-70°C. After the addition is complete, maintain the temperature at 60-70°C and filter the reaction solution while hot. Stir the filtrate at 60-70°C for 1-2 hours, then cool to 35-55°C. Once solid precipitation is observed, gradually cool to 0±5°C and stir to induce crystallization. Centrifuge, rinse the reaction vessel wall with an appropriate amount of acetone, and wash the filter cake. Centrifuge until dry. Add 152.65 kg of acetone and the centrifuged filter cake to the reaction vessel, stir, and slurry at room temperature for 2-3 hours. Centrifuge, rinse the reaction vessel wall with an appropriate amount of acetone, and wash the filter cake. Centrifuge until dry. The centrifuged filter cake was dried under reduced pressure at 70±5℃ for 16-24 hours to obtain avatrombopag maleate product with a yield close to 100% and a purity close to 100%.

[0044] Example 3

[0045] Avatrombopag maleate tablets are prepared using avatrombopag maleate as the active ingredient; the tablet core excipients of the avatrombopag maleate tablets include lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silica, and magnesium stearate; the coating is a pharmaceutical film coating premix (gastric-soluble type).

[0046] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing description of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing avatrombopag maleate, comprising: (1) Mix the crude avatrombopag free base with organic solvent A, and heat and stir to dissolve; (2) Control the temperature of the solution obtained in step (1) to temperature T1, add organic solvent B, cool down to temperature T2 and stir to precipitate crystals, and separate the solid and liquid to obtain a solid; (3) The solid obtained from solid-liquid separation in step (2) is mixed with organic solvent C, pulped at room temperature, and then subjected to solid-liquid separation to obtain the solid. (4) Optionally, dry the solid obtained from the solid-liquid separation in step (3); (5) Mix the solid obtained from solid-liquid separation in step (3) or the solid obtained from drying in step (4), maleic acid, and solvent D, and heat and stir to dissolve; (6) The solution obtained in step (5) is hot filtered at a temperature of T3. The filtrate is cooled to crystallize, the solid and liquid are separated, and the solid is dried to obtain avatrombopag maleic acid.

2. The method according to claim 1, characterized in that, In step (1), Organic solvent A is selected from one or more of DMF, DMA, and DMSO; preferably, organic solvent A is DMF or DMA. The mass-volume ratio of crude avatrombopag free base to organic solvent A is 1 g : (5-20) mL; preferably, the mass-volume ratio of crude avatrombopag free base to organic solvent A is 1 g : (5-15) mL; preferably, the mass-volume ratio of crude avatrombopag free base to organic solvent A is 1 g : (8-12) mL.

3. The method according to claim 1, characterized in that, In step (2), Temperature T1 is 60-75℃; preferably, temperature T1 is 60-70℃; preferably, temperature T1 is 65-75℃; preferably, temperature T1 is 70-75℃. Organic solvent B is selected from one or more of acetone, ethyl acetate, dioxane, and tetrahydrofuran; preferably, organic solvent B is acetone or tetrahydrofuran; The volume ratio of organic solvent B to solvent A is 1:(1-3); preferably, the volume ratio of organic solvent B to solvent A is 1:

2. The temperature T2 is (-5)-15℃; preferably, the temperature T2 is (-5)-10℃; preferably, the temperature T2 is (-5)-5℃.

4. The method according to claim 1, characterized in that, In step (3), The organic solvent C is selected from one or more of acetone, ethyl acetate, dioxane, and tetrahydrofuran; preferably, the organic solvent C is acetone or tetrahydrofuran.

5. The method according to claim 1, characterized in that, The solid obtained from solid-liquid separation in step (3) is dried as described in step (4) and then used in step (5).

6. The method according to claim 1, characterized in that, In step (5), solvent D is a combination of acetone, DMSO, and water; Preferably, the solvent D is a combination of acetone, DMSO and water, with the volume ratio of acetone to water being (1-3):1 and the volume ratio of DMSO to water being (1-3):

1. Preferably, solvent D is a combination of acetone, DMSO and water, with the volume ratio of acetone to water being (1.5-2.5):1 and the volume ratio of DMSO to water being (1.5-2.5):

1.

7. The method according to claim 1, characterized in that, In step (5), The mass-to-volume ratio of the solid obtained in step (3) solid-liquid separation or the solid obtained in step (4) drying to solvent D is 1 g : (7-25) mL; preferably, the mass-to-volume ratio of the solid obtained in step (3) solid-liquid separation or the solid obtained in step (4) drying to solvent D is 1 g : (7-20) mL; preferably, the mass-to-volume ratio of the solid obtained in step (3) solid-liquid separation or the solid obtained in step (4) drying to solvent D is 1 g : (10-15) mL; The molar ratio of the solid obtained in step (3) solid-liquid separation or the solid obtained in step (4) drying to maleic acid is 1:(1.1-2); preferably, the molar ratio of the solid obtained in step (3) solid-liquid separation or the solid obtained in step (4) drying to maleic acid is 1:(1.3-1.8); preferably, the molar ratio of the solid obtained in step (3) solid-liquid separation or the solid obtained in step (4) drying to maleic acid is 1:(1.5-1.8).

8. The method according to claim 1, characterized in that, In step (6), the temperature T3 is 50-80℃; Preferably, the temperature T3 is 50-70℃; Preferably, the temperature T3 is 60-80℃; Preferably, the temperature T3 is 55-75℃.

9. A method for preparing a pharmaceutical composition containing avatrombopag maleate, comprising: (a) Preparation of avatrombopag maleate according to any one of claims 1-7, (b) The avatrombopag maleate obtained in step (a) is mixed with a pharmaceutically acceptable carrier to obtain the pharmaceutical composition containing avatrombopag maleate.