Preparation method of citric acid ixazomib Form 2 crystal form

Abstract

The invention discloses a preparation method of citric acid ixazomib Form 2. The method comprises the following steps: preparing an amorphous form of citric acid ixazomib; and dissolving the citric acid ixazomib amorphous form with a solvent, and crystallizing at high temperature to obtain the citric acid ixazomib Form 2. The method is simple in post-treatment process, high in purity and yield, capable of effectively reducing solvent residues and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a method for preparing ixazomib citrate Form 2 crystal form. Background Technology

[0002] Ixazomib citrate is a third-generation protease inhibitor developed by Takeda Pharma of Japan, following bortezomib and carfilzomib. In 2015, it was approved by the U.S. Food and Drug Administration (FDA) for use in combination with lenalidomide and dexamethasone to treat multiple myeloma that has received at least one prior therapy. Its brand name is Ninlaro.

[0003] Ixazomib citrate has the chemical name 2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo-1,3,2-dioxoboronyl-4,4-diacetic acid, and its chemical structure is shown in the figure below:

[0004] Patent CN117964650B discloses a comparison of the dissolution curves of capsules prepared using the Form 2 crystal form and a reference reagent. The results show that they are basically consistent, thus inferring that the crystal form used in the marketed formulation of ixazomib citrate capsules is Form 2.

[0005] The original manufacturer's patent US8859504B2 discloses methods for preparing ixazomib citrate Form 1 and Form 2, using different cooling methods to prepare different crystal forms. Form 1 is prepared using natural cooling, while Form 2 is prepared using programmed cooling. During our research on the ixazomib citrate active pharmaceutical ingredient process, we reproduced the preparation method of this patent and discovered a problem: a large amount of solid precipitates within a short time, leading to solvent encapsulation. The resulting Form 2 crystal form has a high residual solvent content, failing to meet the ICH Q3C residual solvent guideline's acceptable limit of 5000 ppm for Class 3 solvents.

[0006] TEVA's patent US2021 / 0300950A1 also discloses a method for preparing ixazomib citrate Form 2 crystal form: First, after the reaction, the mixture is concentrated until spontaneous crystals are formed. Then, it is continuously diluted and concentrated, followed by a long period of low-temperature holding. Unstable solids are removed by filtration, and then the mixture is concentrated again to obtain the Form 2 crystal form. While this process can solve the problem of excessive solvent residue, it is extremely cumbersome, time-consuming, energy-intensive, and has a low yield, making it unsuitable for industrial production. Therefore, developing a method for preparing ixazomib citrate Form 2 crystal form with simple post-processing, high purity and yield, solvent residue meeting pharmaceutical standards, and suitability for industrial production is of great significance. Summary of the Invention

[0007] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a method for preparing ixazomib citrate Form 2 with high purity, high yield and solvent residue that meets pharmaceutical standards.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution: A method for preparing ixazomib citrate Form 2, characterized by comprising: Ixazomib citrate amorphous was dissolved in a mixed ester solvent (II), crystallized at 40-80°C, and cooled to room temperature to obtain ixazomib citrate Form 2.

[0009] Furthermore, in the preparation method of the present invention described above, the ester mixed solvent (II) is any two or more of ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl formate, methyl formate, propyl formate, isopropyl formate, butyl formate, isobutyl formate, and tert-butyl formate, preferably any two.

[0010] Furthermore, the volume ratio of any two ester solvents in the ester mixed solvent is 1:(1~4), preferably 1:(1~2).

[0011] It should be noted and understood that the so-called "any volume ratio of two ester solvents" includes the case of mixed solvents such as ethyl formate and ethyl acetate = 1:(1~2) or (1~2):1, and other mixed solvents are deduced by analogy.

[0012] Furthermore, in the preparation method of the present invention described above, the mass-to-volume ratio (g / mL) of the amorphous ixazomib citrate to the mixed solvent (II) is 1:(10-100), preferably 1:(15-40).

[0013] Furthermore, the preparation method of the present invention further includes the preparation of amorphous ixazomib citrate, wherein the preparation of amorphous ixazomib citrate comprises dissolving crude ixazomib citrate in solvent (I), removing solvent (I), and obtaining amorphous ixazomib citrate. Further, solvent (I) is any one or more of C1-C4 alcohols, tetrahydrofuran, acetone, dichloromethane, butanone, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, or dimethyl sulfoxide, preferably tetrahydrofuran.

[0014] The beneficial technical effects of the present invention are that the preparation method of ixazomib citrate Form 2 crystal form provided by the present invention has simple post-processing steps, high purity and yield, effectively reduces solvent residue, and meets pharmaceutical standards, making it suitable for industrial production. Attached Figure Description

[0015] Figure 1 The image shows the X-ray powder diffraction (XRD) pattern of amorphous ixazomib citrate obtained in Example 1. Figure 2 The image shows the X-ray powder diffraction (XRD) pattern of the isazomib citrate Form 2 crystal obtained in Example 1. Detailed Implementation

[0016] The following examples are provided to further illustrate and understand the spirit of the present invention, but do not limit the scope of protection of the present invention in any way. Example 1

[0017] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0018] 10g of amorphous ixazomib citrate was dissolved in a mixed solvent of 150mL ethyl acetate and methyl acetate (V... 乙酸乙酯 / V 乙酸甲酯 =1:1) Dissolve in water, crystallize at 60~65℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 9.64g of ixazomib citrate Form 2, with a yield of 96.4% and a purity of 99.98%. Residual solvents: ethyl acetate 2000ppm, methyl acetate 1950ppm, tetrahydrofuran 80ppm. Example 2

[0019] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0020] 10g of amorphous ixazomib citrate was dissolved in 250mL of a mixed solvent of ethyl acetate and methyl acetate (V...乙酸乙酯 / V 乙酸甲酯 =1:1) Dissolve in water, crystallize at 50~55℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 9.59g of ixazomib citrate Form 2, with a yield of 95.9% and a purity of 99.96%. Residual solvents: ethyl acetate 2000ppm, methyl acetate 1980ppm, tetrahydrofuran 100ppm. Example 3

[0021] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0022] 10g of amorphous ixazomib citrate was dissolved in a mixed solvent of 400mL ethyl acetate and methyl acetate (V... 乙酸乙酯 / V 乙酸甲酯 =1:1) Dissolve in water, crystallize at 40~45℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 9.55g of ixazomib citrate Form 2, with a yield of 95.5% and a purity of 99.97%. Residual solvents: ethyl acetate 2000ppm, methyl acetate 2000ppm, tetrahydrofuran 110ppm. Example 4

[0023] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0024] 10g of amorphous ixazomib citrate was dissolved in a mixed solvent of 400mL ethyl acetate and propyl acetate (V... 乙酸乙酯 / V 乙酸丙酯 =1:1) Dissolve in water, crystallize at 75~80℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 9.38g of ixazomib citrate Form 2, with a yield of 93.8% and a purity of 99.97%. Residual solvents: ethyl acetate 2000ppm, propyl acetate 2200ppm, tetrahydrofuran 60ppm. Example 5

[0025] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0026] 10g of amorphous ixazomib citrate was dissolved in a mixed solvent of 400mL ethyl acetate and isopropyl acetate (V... 乙酸乙酯 / V 乙酸异丙酯=1:1) Dissolve in water, crystallize at 70~75℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 9.40g of ixazomib citrate Form 2, with a yield of 94.0% and a purity of 99.97%. Residual solvents: ethyl acetate 2300ppm, isopropyl acetate 2400ppm, tetrahydrofuran 80ppm. Example 6

[0027] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0028] 10g of amorphous ixazomib citrate was dissolved in a mixed solvent of 300mL ethyl acetate and methyl formate (V... 乙酸乙酯 / V 甲酸甲酯 =1:1) Dissolve in water, crystallize at 40~45℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 9.62g of isazomib citrate Form 2, with a yield of 96.2% and a purity of 99.97%. Residual solvents: ethyl acetate 1800ppm, methyl formate 1000ppm, tetrahydrofuran 90ppm. Example 7

[0029] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0030] 10g of amorphous ixazomib citrate was dissolved in a mixed solvent of 300mL ethyl acetate and ethyl formate (V... 乙酸乙酯 / V 甲酸乙酯 =1:1) Dissolve in water, crystallize at 40~45℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 9.51g of isazomib citrate Form 2, with a yield of 95.1% and a purity of 99.98%. Residual solvents: ethyl acetate 1850ppm, ethyl formate 1300ppm, tetrahydrofuran 90ppm. Example 8

[0031] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0032] 10g of amorphous ixazomib citrate was dissolved in 300mL of a mixed solvent of ethyl acetate and propyl formate (V... 乙酸乙酯 / V 甲酸丙酯=1:1) Dissolve in water, crystallize at 50~55℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 9.56g of isazomib citrate Form 2, with a yield of 95.6% and a purity of 99.98%. Residual solvents: ethyl acetate 2000ppm, propyl formate 2300ppm, tetrahydrofuran 70ppm. Example 9

[0033] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0034] 10g of amorphous ixazomib citrate was dissolved in a mixed solvent of 300mL ethyl acetate and isopropyl formate (V... 乙酸乙酯 / V 甲酸异丙酯 =1:1) Dissolve in water, crystallize at 50~55℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 9.44g of ixazomib citrate Form 2, with a yield of 94.4% and a purity of 99.97%. Residual solvents: ethyl acetate 2400ppm, isopropyl formate 2200ppm, tetrahydrofuran 80ppm. Example 10

[0035] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0036] 10g of amorphous ixazomib citrate was dissolved in a mixed solvent of 300mL ethyl formate and ethyl acetate (V... 甲酸乙酯 / V 乙酸乙酯 =1:2) Dissolve in water, crystallize at 45~50℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 9.61g of ixazomib citrate Form 2, with a yield of 96.1% and a purity of 99.96%. Residual solvents: ethyl acetate 2700ppm, ethyl formate 1300ppm, tetrahydrofuran 90ppm. Example 11

[0037] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0038] 10g of amorphous ixazomib citrate was dissolved in a mixed solvent of 300mL ethyl acetate and ethyl formate (V... 乙酸乙酯 / V 甲酸乙酯=1:2) Dissolve in water, crystallize at 45~50℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 9.48g of ixazomib citrate Form 2, with a yield of 94.8% and a purity of 99.97%. Residual solvents: ethyl acetate 1900ppm, ethyl formate 2500ppm, tetrahydrofuran 70ppm. Example 12

[0039] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0040] 10g of amorphous ixazomib citrate was dissolved in 300mL of a mixed solvent of methyl acetate and ethyl formate (V... 乙酸甲酯 / V 甲酸乙酯 =1:2) Dissolve and crystallize at 45~50℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 9.52g of ixazomib citrate Form 2, with a yield of 95.2% and a purity of 99.97%. Residual solvents: methyl acetate 2200ppm, ethyl formate 2600ppm, tetrahydrofuran 90ppm. Example 13

[0041] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0042] 10g of amorphous ixazomib citrate was dissolved in 300mL of a mixed solvent of methyl acetate and propyl acetate (V... 乙酸丙酯 / V 乙酸甲酯 =1:2) Dissolve in water, crystallize at 50~55℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 97.1g of ixazomib citrate Form 2, with a yield of 97.1% and a purity of 99.96%. Residual solvents: methyl acetate 2800ppm, propyl acetate 2800ppm, tetrahydrofuran 100ppm. Example 14

[0043] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0044] 10g of amorphous ixazomib citrate was dissolved in 300mL of a mixed solvent of ethyl formate and propyl formate (V... 甲酸乙酯 / V 甲酸丙酯=1:1) Dissolve in water, crystallize at 45~50℃ for 3h, then slowly cool to room temperature, filter, and dry under reduced pressure to obtain 95.5g of ixazomib citrate Form 2, with a yield of 95.5% and a purity of 99.96%. Residual solvents: ethyl formate 3100ppm, propyl formate 3000ppm, tetrahydrofuran 120ppm. Comparative Example

[0045] Add 15g of crude ixazomib citrate and 300mL of tetrahydrofuran to the reaction flask, stir at room temperature until dissolved, and then concentrate under reduced pressure at 40-45℃ to obtain amorphous ixazomib citrate.

[0046] 10g of amorphous ixazomib citrate was dissolved in 300mL of a single solvent, crystallized at 50-60℃ for 3h, then cooled, filtered, and dried under reduced pressure to obtain ixazomib citrate Form 2. The HPLC purity, yield, and solvent residue of ixazomib citrate Form 2 prepared with different single solvents are detailed in the table below: solvent HPLC purity (%) Yield (%) Solvent residue Ethyl acetate 99.97 95.1 Ethyl acetate: 11800 ppm; Tetrahydrofuran: 4600 ppm Methyl acetate 99.96 94.8 Methyl acetate: 9000ppm; Tetrahydrofuran: 3900ppm Propyl acetate 99.96 95.7 Propyl acetate: 10700ppm; Tetrahydrofuran: 6100ppm Isopropyl acetate 99.94 96.2 Isopropyl acetate: 7800 ppm; Tetrahydrofuran: 6400 ppm Ethyl formate 99.97 93.4 Ethyl formate: 1000ppm; Tetrahydrofuran: 6400ppm Isopropyl formate 99.95 93.5 Isopropyl formate: 9300 ppm; Tetrahydrofuran: 3400 ppm .

Claims

1. A method for preparing ixazomib citrate Form 2, characterized in that, include: Ixazomib citrate amorphous was dissolved in a mixed ester solvent (II), crystallized at 40-80°C, and cooled to room temperature to obtain ixazomib citrate Form 2.

2. According to the preparation method of claim 1, the ester mixed solvent (II) is any two or more of ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, ethyl formate, methyl formate, propyl formate, isopropyl formate, butyl formate, isobutyl formate, and tert-butyl formate.

3. The preparation method according to claim 2, wherein the ester mixed solvent is composed of two ester solvents.

4. In the preparation method according to claim 3, the volume ratio of any two ester solvents in the ester mixed solvent is 1:(1~4), preferably 1:(1~2).

5. The preparation method according to any one of claims 1-4, wherein the mass-volume ratio (g / mL) of the amorphous ixazomib citrate to the mixed solvent (II) is 1:(10-100), preferably 1:(15-40).

6. The preparation method according to claim 1 further includes the preparation of ixazomib citrate amorphous, comprising dissolving crude ixazomib citrate in solvent (I), removing solvent (I), and obtaining ixazomib citrate amorphous.

7. The preparation method according to claim 6, wherein the solvent (Ⅰ) is any one or more of C1-C4 alcohols, tetrahydrofuran, acetone, dichloromethane, butanone, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, or dimethyl sulfoxide.

8. The preparation method according to claim 7, wherein the solvent is tetrahydrofuran.

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