Purification method of ibrutinib

Abstract

The invention discloses a purification method of ibrutinib, and belongs to the field of chemical pharmacy. Comprising the following steps: (1) adding ibrutinib capsule contents into purified water, controlling the temperature at 23-27 DEG C, and adding an acid solution to adjust the pH value of a system; (2) stirring until the solution is clear, adding a protective agent and activated carbon, and decolorizing; (3) filtering the decolored solution; (4) adding an organic solvent into the filtrate at 23-27 DEG C, stirring for 15 minutes, dropwise adding alkali liquor to adjust the pH value to 8.0-9.0, crystallizing and growing crystals; (5) dropwise adding the alkali liquor for the second time to adjust the pH value to 9.5-10.5, and growing crystals; (6) filtering and washing after crystal growing; and (7) vacuum drying and discharging. According to the method, the active ingredient ibrutinib raw material medicine which does not meet the quality standard is treated and recycled, the cost is saved, meanwhile, the method can be suitable for preparing a high-content ibrutinib standard product, and the method is simple, energy-saving, environment-friendly and suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the field of chemical pharmacy, and particularly relates to a method for purifying ibrutinib. Background Art

[0002] Ibrutinib is an oral targeted BTK (Bruton's tyrosine kinase) inhibitor. Ibrutinib blocks the BCR pathway through the BTK target, affecting the growth and proliferation of malignant lymphocytes on the one hand, and destroying the adhesion and migration of B cells in lymphoid tissues on the other.

[0003] The chemical name of Ibrutinib is: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-D]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one. Molecular formula: C 25 H 24 N6O2, molecular weight 440.5, CAS: 936563-96-1, chemical structure formula is shown below.

[0004]

[0005] Ibrutinib structure The prior art for the preparation of ibrutinib mainly focuses on synthesis. Relevant technicians in the field disclosed a method in patent CN101610676A, which uses 4-phenoxybenzoic acid as a starting material, condenses it with malononitrile after chlorination, and then cyclizes it with hydrazine hydrate to obtain a pyrazole intermediate, which is then cyclized with formamide to obtain a 4-aminopyrazolo[3,4-d]pyrimidine mother nucleus, and then condenses it with a chiral alcohol through a Mitsunobu reaction, removes the BOC protecting group, and undergoes acryloylation to obtain a product. The route has many steps, the steps are complicated, the overall yield is low, and finally, ibrutinib is prepared by chromatography purification, which has a high industrial cost.

[0006] Patent CN112125913 A records a method for synthesizing high-purity ibrutinib: first react an acyl halide compound with an alkaline compound, then react with formula II for acylation, and finally crystallize to obtain high-purity ibrutinib. However, the product's single impurity content is up to 0.21%, which still has room for improvement, and a large amount of organic solvents are used in the process, which is not conducive to environmental protection.

[0007] Patent WO2014 / 022390A1 mentions a method for refining ibrutinib: using silica gel as a filler material for column chromatography separation, and using methanol: dichloromethane as an eluent. This method has a low yield and poor separation effect, and is not suitable for industrial production.

[0008] Patent CN106831788B is an improvement on WO2014 / 022390A1, using macroporous resin as filler material for column chromatography separation, and the eluents are ethyl acetate and petroleum ether. The yield is only 80%, the purity is 99.89%, and the process is cumbersome and the process time is long; both are not suitable for industrial production.

[0009] Therefore, it is necessary to develop a method for purifying ibrutinib to overcome the shortcomings of the prior art. Summary of the invention

[0010] In view of the above shortcomings, the present invention provides a method for purifying ibrutinib, which processes and recovers the active ingredient ibrutinib in a drug product that does not meet the quality standards, saves costs and can also be applied to the preparation of a high-content ibrutinib standard. The method is simple, energy-saving and environmentally friendly, and is suitable for large-scale industrial production.

[0011] To achieve the above purpose, the technical solution adopted by the present invention is as follows: A method for purifying ibrutinib comprises the following steps: (1) Add the contents of ibrutinib capsules to purified water, control the temperature at 23-27°C, and add acid to adjust the pH of the system to 1.0-3.0; the amount of purified water used is 2-4 times the weight of the ibrutinib contents, and the acid is acetic acid or hydrochloric acid.

[0012] (2) Stir until the solution is clear, add a protective agent and activated carbon for decolorization; the protective agent is sodium metabisulfite or sodium sulfite; the amount of protective agent and activated carbon is 0.5%-1.0% of the weight of the ibrutinib content.

[0013] (3) Filtering the decolorized solution; (4) Add an organic solvent to the filtrate at 23-27°C and stir until the mixture is uniformly mixed. Add an alkali solution dropwise to adjust the pH to 8.0-9.0, crystallize, and grow the crystals. The organic solvent is methanol, ethanol, acetonitrile or acetone, and the growing time is 20-30 minutes.

[0014] (5) Add alkali solution for the second time to adjust the pH to 9.5-10.5 and grow the crystal; the growing time is 40-60 minutes.

[0015] (6) After the crystal growth is completed, filter and wash; the washing liquid used for washing is water and organic solvent in a weight ratio of 1:1, and wash twice with 1 volume.

[0016] The organic solvent is methanol, ethanol, acetonitrile or acetone; the organic solvent in the washing solution is consistent with the organic solvent in step (4).

[0017] (7) Vacuum drying and discharging.

[0018] The alkali solution for adjusting pH is NaOH solution.

[0019] Due to the adoption of the above invention, the present invention has the following technical advances compared with the prior art: 1. The method for purifying ibrutinib of the present invention is simple to operate, the obtained ibrutinib has high purity, the product quality and content are good, and the single impurity content is less than 0.1%.

[0020] 2. The present invention solves the problem that the quality of products such as ibrutinib capsules is degraded due to impurities and content during storage, and the effective ingredients cannot be recovered.

[0021] 3. The present invention uses the contents of ibrutinib capsules as raw materials to purify high-purity ibrutinib, the process is feasible, and the product is easy to filter and dry; the active ingredient ibrutinib raw material in the product is processed and recovered, which can be used to prepare high-purity ibrutinib standard products while saving costs.

[0022] 4. When dissolving ibrutinib, the present invention adjusts the pH to 1.0-3.0, which can ensure that the contents of the ibrutinib capsule can be well dissolved, and can also ensure its stability in the solution, while effectively improving the dissolution, complexation and decolorization effects of the product. When the weight ratio of the amount of purified water added to ibrutinib is 2-3:1, complete dissolution is guaranteed, while reducing the amount of solvent, and reducing the amount of subsequent protective agent and crystallization agent, thereby improving efficiency and reducing costs.

[0023] 5. The protective agent is added before decolorization in the present invention to ensure the stability of the system, and the feed liquid is dispersed and non-viscous during crystallization, thereby ensuring that Ibrutinib is crystallized as much as possible.

[0024] 6. The present invention adopts secondary crystallization, and by adjusting the pH, crystals are precipitated step by step, and various impurities remain in the system, ensuring that the obtained crystals have high purity and complete crystallization. During the secondary crystallization, the crystals that have not been precipitated during the first crystallization can be completely crystallized out, and it is ensured that the crystals have a certain growth process, thereby improving the yield of ibrutinib crystals. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The accompanying drawings are used to provide further understanding of the present invention and constitute a part of the specification. They are used to explain the present invention together with the embodiments of the present invention and do not constitute a limitation of the present invention.

[0026] Figure 1 This is the HPLC chart of the Ibrutinib API prepared in Example 1. (HPLC purity: 99.93%) DETAILED DESCRIPTION

[0027] The following is a description of the preferred embodiments of the present invention. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention. Example 1

[0028] (1) Take the contents of Ibrutinib capsules (equivalent to 10 g of Ibrutinib), add them to 30 mL of purified water, control the temperature at 25°C, and add glacial acetic acid to adjust the pH of the system to 1.0; (2) After stirring and dissolving, add 0.1g of protective agent sodium metabisulfite and 0.1g of activated carbon, and decolorize for 30 minutes; (3) filtering the decolorized solution in step 2; (4) Control the temperature at 25°C, add 30 mL of methanol to the filtrate, stir for 15 minutes, then add 20% NaOH to adjust the pH to 8.5, and grow the crystals for 30 minutes after crystallization; (5) Add 20% NaOH for the second time to adjust the pH to 10.0 and grow the crystal for 60 minutes; (6) After crystal growth, filter and wash the filter cake twice with 10 mL of 1:1 methanol-water mixture; (7) The mixture was dried under vacuum at 65° C. for 2 h, and 9.4 g of high-purity solid ibrutinib was obtained. Example 2

[0029] (1) Take the contents of Ibrutinib capsules (equivalent to 10 g of Ibrutinib API), add them to 30 mL of purified water, control the temperature at 25°C, and add glacial acetic acid to adjust the pH of the system to 1.0; (2) After stirring and dissolving, add 0.05g of protective agent sodium metabisulfite and 0.05g of activated carbon, and decolorize for 30 minutes; (3) filtering the decolorized solution in step 2; (4) Control the temperature at 25°C, add 30 mL of ethanol to the filtrate, stir for 15 minutes, then add 20% NaOH to adjust the pH to 8.0, and grow the crystals for 30 minutes after crystallization; (5) Add 20% NaOH for the second time to adjust the pH to 9.5 and grow the crystal for 60 minutes; (6) After crystal growth, filter and wash the filter cake twice with 10 mL of 1:1 ethanol water; (7) The mixture was dried under vacuum at 65°C for 2 h, and 9.1 g of high-purity solid ibrutinib was obtained. Example 3

[0030] (1) Take the contents of Ibrutinib capsules (equivalent to 10 g of Ibrutinib), add them to 30 mL of purified water, control the temperature at 25°C, and add glacial acetic acid to adjust the system pH to 1.0; (2) After stirring and dissolving, add 0.08g of sodium metabisulfite and 0.08g of activated carbon as protective agents and decolorize for 30 minutes; (3) filtering the decolorized solution in step 2; (4) Control the temperature at 25°C, add 30 mL of acetone to the filtrate, stir for 15 minutes, then add 20% NaOH to adjust the pH to 9.0, and grow the crystals for 30 minutes after crystallization; (5) Add 20% NaOH for the second time to adjust the pH to 10.5 and grow the crystal for 60 minutes; (6) After crystal growth, filter and wash the filter cake twice with 10 mL of 1:1 acetone water; (7) The mixture was dried under vacuum at 65°C for 2 h, and 9.2 g of high-purity solid ibrutinib was obtained.

[0031] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein with equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the scope of protection of the claims of the present invention.

Claims

1. A method for purifying ibrutinib, characterized in that: The following steps are involved: (1) Add the contents of Ibrutinib capsules into purified water, control the temperature at 23-27°C, and add acid to adjust the pH of the system to 1.0-3.0; (2) Stir until the solution is clear, add protective agent and activated carbon for decolorization; (3) Filtering the decolorized solution; (4) adding an organic solvent to the filtrate at 23-27°C and stirring until the mixture is uniformly mixed, adding alkaline solution dropwise to adjust the pH to 8.0-9.0, crystallizing, and growing crystals; (5) Add alkali solution for the second time to adjust the pH to 9.5-10.5 and grow the crystal; (6) Filter and wash after crystal growth; (7) Vacuum drying and discharging.

2. The method for purifying ibrutinib according to claim 1, characterized in that: In step (1), the amount of purified water used is 2-4 times the weight of the contents of the ibrutinib capsules, and the acid is acetic acid or hydrochloric acid.

3. The method for purifying ibrutinib according to claim 1, characterized in that: In step (2), the protective agent is sodium metabisulfite or sodium sulfite; the amount of the protective agent and activated carbon is 0.5%-1.0% of the weight of the contents of the ibrutinib capsule.

4. The method for purifying ibrutinib according to claim 1, characterized in that: In step (4), the organic solvent is methanol, ethanol, acetonitrile or acetone, and the crystal growing time is 20-30 minutes.

5. The method for purifying ibrutinib according to claim 1, characterized in that: The crystal growing time in step (5) is 40-60 minutes.

6. The method for purifying ibrutinib according to claim 1, characterized in that: The washing liquid used in step (6) is water and an organic solvent in a weight ratio of 1:1, and washing is performed twice with 1 volume.

Images