CN113214261A

CN113214261A - Purification method of ibrutinib crystal form A

Info

Publication number: CN113214261A
Application number: CN202010070739.5A
Authority: CN
Inventors: 王亚平; 竺伟
Original assignee: SYNCOZYMES (SHANGHAI) CO Ltd
Current assignee: SYNCOZYMES (SHANGHAI) CO Ltd
Priority date: 2020-01-21
Filing date: 2020-01-21
Publication date: 2021-08-06

Abstract

The invention discloses a purification method of an ibrutinib crystal form A, which realizes purification of the ibrutinib crystal form A by using crystal form transformation, and specifically comprises the steps of dissolving a crude product of the ibrutinib crystal form A, adding a seed crystal E to obtain an ibrutinib crystal form E, and dissolving and crystallizing the crystal form E to obtain the ibrutinib crystal form A with higher purity. The purification method of the ibrutinib crystal form A provided by the invention is simple in process and high in yield, and solves the problem of purification of impurities difficult to remove in the ibrutinib crystal form A.

Description

Purification method of ibrutinib crystal form A

The technical field is as follows:

the invention belongs to the technical field of crystal form medicines, and particularly relates to a purification method of ibrutinib crystal form A.

Background art:

ibrutinib (Ibrutinib) is a new drug for oral Bruton's Tyrosine Kinase (BTK) inhibitor, which irreversibly inhibits BTK by selectively covalent binding with the target protein BTK active site cysteine residue (Cys-481), thereby effectively preventing tumor migration from B cell to lymphoid tissue adapted to tumor growth environment. In 11 months 2013, the U.S. food and drug administration approved it for marketing for the treatment of Mantle Cell Lymphoma (MCL), a rare invasive blood cancer, and in 7 months 2014, the U.S. food and drug administration approved it for the treatment of Chronic Lymphocytic Leukemia (CLL). The product name is Imbruvica, and the chemical name is: 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one of the formula:

pharmacological research shows that different crystal forms have different solubility, dissolution rate and storage stability, and some crystal forms even have obvious changes, so that the requirements on the crystal form of a raw material medicament in the production process of the medicament are strict, and the convenient and stable acquisition of the crystal form required by the raw material medicament is very important.

PHARMACYCLICS discloses various crystal forms of the anticancer drug ibrutinib in patent CN104736178, wherein the crystal form a is the current medicinal crystal form.

The content of the crude drug of the ibrutinib crystal form A synthesized by the prior art is generally about 99 percent, the content of a single impurity can not stably reach the standard of the drug, and particularly the content of the impurity I and the impurity II exceeds 0.1 percent. The literature at present does not research a method for preparing high-purity ibrutinib crystal form A by using crystal form transformation.

The invention content is as follows:

the invention aims to provide a purification method of ibrutinib crystal form A, which is simple to operate and easy to industrialize, aiming at the defects of the prior art.

The invention provides a purification method of ibrutinib crystal form A, which specifically comprises the following steps: and converting the crude ibrutinib crystal form A containing the specific single impurity into a crystal form E, and dissolving and crystallizing the obtained crystal form E to obtain the ibrutinib crystal form A with higher purity.

Further, the 2theta values of the crystal form A are 5.7 degrees +/-0.1 degree, 13.6 degrees +/-0.1 degree, 16.1 degrees +/-0.1 degree, 18.9 degrees +/-0.1 degree, 21.3 degrees +/-0.1 degree and 21.6 degrees +/-0.1 degree.

Further, specific single impurities in the crude ibrutinib crystal form A product are impurity I and impurity II.

Further, the crude ibrutinib crystal form a is dissolved in dichloromethane.

Further, ibrutinib form a dissolved in dichloromethane was steamed with toluene, and the resulting liquid was cooled.

Further, seed crystals E were added to the cooled liquid and converted to crystalline form E of ibrutinib.

Further, ibrutinib form E is dissolved in dichloromethane and steamed with methanol.

Furthermore, water is added to separate out a solid, so that the ibrutinib crystal form A with higher purity is obtained.

The specific technical scheme is as follows: dissolving a crude ibrutinib crystal form A containing a specific single impurity in dichloromethane, washing with dilute hydrochloric acid, a sodium bicarbonate water solution and purified water respectively, concentrating an organic phase, steaming with toluene, cooling the obtained liquid, adding a crystal seed E for crystallization, dissolving the obtained ibrutinib crystal form E with dichloromethane, steaming with methanol, and adding water to precipitate a solid to obtain the ibrutinib crystal form A with higher purity.

The purification method of the crystal form A of ibrutinib adopted by the invention has the beneficial effects that the process is simple, the yield is high, the purification method is suitable for industrial production, the problem that single impurities are difficult to remove in the existing production process of the crystal form A of ibrutinib is solved, and the impurity control meets the requirements of ibrutinib raw material medicines.

Drawings

FIG. 1 HPLC chart of crude ibrutinib form A in example 1

FIG. 2 XPRD diagram of crystalline form E of ibrutinib in example 2

FIG. 3 XPRD drawing of purified ibrutinib form A from example 2

FIG. 4 HPLC profile of purified ibrutinib form A from example 2

Detailed Description

The technical content of the present invention is further described below with reference to specific examples for better understanding of the content of the present invention, but the scope of the present invention is not limited thereto.

Example 1 preparation of crude Ibrutinib form A

To a 250mL reaction flask was added 6.0g of Compound I and 90mL of dichloromethane at room temperature. Slowly dripping 4.23g N N-diisopropylethylamine into the reaction under the protection of nitrogen, controlling the temperature to be 0-10 ℃, and stirring for 0.5 h; dripping 1.10g of acryloyl chloride into the reaction system, and stirring for reaction for 1 hour; then adding 60mL of water, stirring, standing, separating liquid, and concentrating the organic phase under reduced pressure until the organic phase is dry; adding 40mL of methanol, heating to 45-50 ℃, stirring to dissolve, cooling to 0-10 ℃, and stirring for 0.5 h; filtering, washing a filter cake with 10mL of methanol/water to obtain 7.5g of wet product, and drying in a vacuum oven at 45 ℃ until the weight is constant to obtain crude ibrutinib crystal form A product. The HPLC chart is shown in figure 1.

Example 2 purification of crystalline form a of ibrutinib

Dissolving 10g of crude ibrutinib crystal form A product in 100mL of dichloromethane at room temperature, then washing with 100mL of 0.5N diluted hydrochloric acid, 100mL of saturated sodium bicarbonate aqueous solution and 100mL of purified water respectively, concentrating an organic phase, steaming with 100mL of toluene to a small volume, cooling the obtained liquid, adding a seed crystal E, dissolving the obtained ibrutinib crystal form E with 40mL of dichloromethane, steaming with 30mL of methanol to remove the dichloromethane, and adding water to precipitate 8.33g of ibrutinib crystal form A solid with the purity of 99.85%. The XPRD pattern of the crystal form E is shown in an attached figure 2, the XPRD pattern of the crystal form A is shown in an attached figure 3, and the HPLC pattern of the purified crystal form A is shown in an attached figure 4.

Example 3 purification of crystalline form a of ibrutinib

Dissolving 100g of crude ibrutinib crystal form A product in 600mL of dichloromethane at room temperature, then washing with 600mL of 0.5N diluted hydrochloric acid, 600mL of saturated sodium bicarbonate aqueous solution and 600mL of purified water respectively, concentrating an organic phase, steaming with 200mL of toluene to a small volume, cooling the obtained liquid, adding a seed crystal E, dissolving the obtained ibrutinib crystal form E with 400mL of dichloromethane, steaming with 150mL of methanol to remove the dichloromethane, and adding water to precipitate 84.2g of solid ibrutinib crystal form A with the purity of 99.81%.

Example 4 purification of crystalline form a of ibrutinib

Dissolving 500g of crude ibrutinib crystal form A product in 2L of dichloromethane at room temperature, then washing with 2L of 0.5N diluted hydrochloric acid, 2L of saturated sodium bicarbonate water solution and 2L of purified water respectively, concentrating an organic phase, steaming with 400mL of toluene to a small volume, cooling the obtained liquid, adding a seed crystal E, dissolving the obtained ibrutinib crystal form E with 1L of dichloromethane, steaming with 500mL of methanol to remove dichloromethane, and adding water to precipitate 423g of solid ibrutinib crystal form A with the purity of 99.81%.

Example 5 purification of crystalline form a of ibrutinib

Dissolving 1kg of crude ibrutinib crystal form A product in 5L of dichloromethane at room temperature, then washing with 5L of 0.5N diluted hydrochloric acid, 5L of saturated sodium bicarbonate aqueous solution and 5L of purified water respectively, concentrating an organic phase, steaming with 5L of toluene to a small volume, cooling the obtained liquid, adding a seed crystal E, dissolving the obtained ibrutinib crystal form E with 2L of dichloromethane, steaming with 2L of methanol to remove the dichloromethane, and adding water to precipitate 0.86kg of solid ibrutinib crystal form A with the purity of 99.73%.

Claims

1. The purification method of the ibrutinib crystal form A is characterized in that an ibrutinib crystal form A crude product containing a specific single impurity is converted into a crystal form E, and the obtained crystal form E is dissolved and crystallized to obtain the ibrutinib crystal form A with higher purity.

2. The purification method of ibrutinib form a as claimed in claim 1, wherein the specific impurities contained in the crude ibrutinib form a are impurity I and impurity II.