WO2016169422A1 - Crystal form of a cyclin-dependent kinase inhibitor and the preparation method thereof - Google Patents

Abstract

Provided are the crystal form of a cyclin-dependent kinase inhibitor (CDK&6) and a preparation method thereof. In particular, provided are II-type crystals of 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl) amino)pyridino[2,3-d]pyrimidin-7(8H)-one (compound of formula (I)) and the preparation method thereof, the crystal having an X-ray powder diffraction pattern as shown in figure 1, a good chemical stability and crystal form stability, and using a low toxicity, low residual crystallization solvent, so as to be better used for clinical treatment.

Description

Crystalline form of cyclin-dependent protein kinase inhibitor and preparation method thereof Technical field

The present invention relates to 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d] Pyrimidine-7(8H)-one and its Form II. The compounds of formula (I) obtained by the process according to the invention are useful in the treatment of breast cancer.

Background technique

Breast cancer is one of the most common malignant tumors in women. It has a high incidence and is invasive, but the progress of the disease is slow. The China Population Association released the "China Breast Diseases Investigation Report" in Beijing on February 1, 2010. The report shows that The mortality rate of breast cancer in urban areas in China has increased by 38.91%. Breast cancer has become the most threatening disease for women. At least 156 kinds of breast cancer drugs are currently under research and market, 68% of which are targeted therapeutic drugs. Tumors were found to be abnormally associated with the cell cycle. Mutations in mitotic signaling proteins and defects in anti-mitotic signaling proteins in tumor cells lead to proliferation disorders. At the same time, most tumors have genomic instability (GIN) and genomic instability (CIN). These three basic cell cycle defects are caused directly or indirectly by the loss of control of CDKs. Cyclin Dependent Kinase (CDK) inhibitors are increasingly becoming a hot target.

There are many second-generation CDK inhibitors currently under development. The second-generation drugs of greatest concern include the CDK4&6 inhibitor PD-0332991 jointly developed by Pfizer and Onyx. It inhibits the phosphorylation of Rb by inhibiting the activity of CDK4&6, making E2F- The Rb complex is retained in the cytosol, blocking the initiation of the cell cycle. Clinical trial results (NCT00721409) showed that progression-free survival (PFS) was 7.5 months in patients treated with letrozole monotherapy, whereas no progress was observed in patients treated with letrozole and PD-0332991. The survival period was extended to 26.1 months. This remarkable advantage has received wide attention. In early 2013, after reviewing the interim results of this drug, the FDA thought it might be a breakthrough anticancer drug.

WO2014183520 discloses a CDK4&6 inhibitor similar in structure to PD-0332991, which has significant inhibitory activity and high selectivity for CDK4&6, including the following compounds:

However, WO 2014183520 does not delve into the crystalline form of the compound. It is well known to those skilled in the art that the crystalline structure of the pharmaceutically active ingredient often affects the chemical stability of the drug, and the crystallization conditions and storage conditions may cause changes in the crystal structure of the compound, sometimes accompanied by other Form of crystal form. In general, amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, and poor fluidity. Therefore, it is necessary to improve the various properties of the above compounds, and we need to further study to find new crystal forms with higher crystal purity and good chemical stability.

Summary of the invention

The present invention provides 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d A new crystalline form of pyrimidine-7(8H)-one (as shown in formula (I)).

A series of crystalline products obtained by the compound of the formula (I) under different crystallization conditions, the obtained crystalline product was subjected to X-ray diffraction and DSC detection, and it was found that the compound of the formula (I) can be obtained under the conventional crystallization conditions. A crystal form with good stability, we call it type II crystal. The DSC pattern of the type II crystal in the present application shows a melting endothermic peak near 294.42 ° C, and the X-ray powder diffraction pattern is shown in Fig. 1, using Cu-Ka radiation, at 2θ angle and interplanar spacing (d value) The X-ray powder diffraction pattern is represented by 5.84 (15.12), 6.16 (14.35), 10.75 (8.22), 12.56 (7.04), 12.96 (6.82), 16.25 (5.45), 17.24 (5.14), 18.97 (4.67). , 20.22 (4.39), 21.74 (4.08), 22.99 (3.87), and 25.85 (3.44) have characteristic peaks.

The invention also provides the preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridine [2,3 -d] A method of crystallizing Form II of pyrimidine-7(8H)-one, the method comprising the steps of:

1) adding a compound of the formula (I) of any crystal form or amorphous form to an appropriate amount of a solvent, adding an acid, dissolving the solution, and adding a base, which is selected from the group consisting of alcohols having a carbon number of 3 or less, Any one of a ketone or a nitrile or a mixed solvent thereof with water;

2) Filter the crystals, wash and dry.

In a preferred embodiment the acid is a mineral acid, preferably hydrochloric acid; the base is an inorganic base, preferably sodium hydroxide or potassium hydroxide.

In a preferred embodiment the solvent described in step 1) is methanol, ethanol, isopropanol, acetone, acetonitrile or methanol/water, ethanol/water, acetone/water, acetonitrile/water, isopropanol/water; Ethanol.

The method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method. For example, the compound represented by the starting material (I) can be slowly cooled and crystallized by heating in an organic solvent, and after completion of crystallization, it can be dried by filtration to obtain a desired crystal. It is to be noted that the crystals to be filtered are usually subjected to vacuum drying under reduced pressure at a temperature of about 30 to 100 ° C, preferably 40 to 60 ° C, to obtain an effect of removing the recrystallization solvent.

The crystal form of the obtained compound of the formula (I) was examined by differential scanning calorimetry (DSC) and X-ray diffraction pattern measurement, and the solvent residue of the obtained crystal was examined.

The compound of the formula II type represented by the formula (I) prepared according to the method of the present invention does not contain or contains only a low content of residual solvent, and meets the requirements of the national pharmacopoeia for the residual solvent of the pharmaceutical product, so that the crystal of the present invention can be compared. It is used as a pharmaceutical active ingredient.

Studies have shown that the type II crystal of the compound of the formula (I) prepared by the present invention has good stability under the conditions of illumination, high temperature and high humidity, and the crystal form stability is good under the conditions of grinding, pressure and heat. It can meet the medicinal requirements of production, transportation and storage. The production process is stable and repeatable and controllable, and can be adapted to industrial production.

DRAWINGS

Figure 1 is an X-ray powder diffraction pattern of the compound II type crystal represented by the formula (I).

Figure 2 is a DSC chart of the compound type II crystal of the formula (I).

detailed description

The invention is explained in more detail below with reference to the embodiments, which are intended to illustrate the technical scope of the invention and not to limit the scope and scope of the invention.

Test instrument used in the experiment

1, DSC spectrum

Instrument model: MettlerToledo DSC 1Staree System

Purge gas: nitrogen

Heating rate: 10.0 ° C / min

Temperature range: 40-350 ° C

2. X-ray diffraction spectrum

Instrument model: Bruker D8Focus X-ray powder diffractometer

Ray: Monochrome Cu-Kα ray (λ=1.5406)

Scanning mode: θ/2θ, scanning range: 2-40°

Voltage: 40KV, current: 40mA

Example 1

(1.0 g, 2.24 mmol) of the compound of the formula (I) (prepared according to the method provided in WO2014183520) was added to a 250 ml Erlenmeyer flask, 40 ml of ethanol was added thereto, stirred at room temperature, and then diluted with hydrochloric acid (219 mg, 6.01 mmol). (dissolved in 4 ml of water), heated to 60 ° C, dissolved, added dropwise to a sodium hydroxide solution (576 mg, 14.40 mmol) (dissolved in 40 ml of water), and then cooled to room temperature overnight. The solid was dried to 0.88 g, and the yield was 88.0%. The X-ray diffraction spectrum of the crystal sample is shown in Fig. 1. The crystals are at about 5.84 (15.12), 6.16 (14.35), 10.75 (8.22), 12.56 (7.04), 12.96 (6.82), 16.25 (5.45), 17.24 (5.14), 18.97 (4.67), 20.22 (4.39), 21.74. (4.08), 22.99 (3.87), and 25.85 (3.44) have characteristic peaks. The DSC spectrum is shown in Figure 2. There is a sharp melting endotherm peak of 294.42 ° C. This crystal form is defined as Form II.

Example 2

(1.0 g, 2.24 mmol) of the compound of the formula (I) (prepared as in Example 1) was added to a 250 ml Erlenmeyer flask, and 40 ml of methanol was added thereto, stirred at room temperature, and then diluted with hydrochloric acid (219 mg, 6.01 mmol) ( Dissolved in 4ml water), heated to 60 ° C, dissolved, dripped into hydrogen and oxygen The sodium solution (576 g, 14.40 mmol) (dissolved in 40 ml of water) was cooled to room temperature and stirred overnight. The solid was dried to 0.86 g, and the yield was 86.0%. The X-ray diffraction and DSC spectra were compared by study to confirm that the product was Form II.

Example 3

(1.0 g, 2.24 mmol) of the compound of the formula (I) (prepared as in Example 1) was added to a 250 ml Erlenmeyer flask, 40 ml of isopropanol was added, stirred at room temperature, and then dilute hydrochloric acid (219 mg, 6.01 mmol) was added dropwise. (dissolved in 4 ml of water), heated to 60 ° C, dissolved, dropped into a sodium hydroxide solution (576 mg, 14.40 mmol) (dissolved in 40 ml of water), and cooled to room temperature overnight. The solid was dried to 0.90 g, and the yield was 90.0%. The X-ray diffraction and DSC spectra were compared by study to confirm that the product was Form II.

Example 4

(1.0 g, 2.24 mmol) of the compound of the formula (I) (prepared as in Example 1) was added to a 250 ml Erlenmeyer flask, 40 ml of acetone was added, and the mixture was stirred at room temperature, then dilute hydrochloric acid (219 mg, 6.01 mmol) was added dropwise. Dissolved in 4 ml of water), heated to 60 ° C, dissolved, added dropwise to a sodium hydroxide solution (576 mg, 14.40 mmol) (dissolved in 40 ml of water), and cooled to room temperature overnight. The solid was dried to 0.86 g, and the yield was 86.0%. The X-ray diffraction and DSC spectra were compared by study to confirm that the product was Form II.

Example 5

(1.0 g, 2.24 mmol) of the compound of the formula (I) (prepared as in Example 1) was added to a 250 ml Erlenmeyer flask, 40 ml of acetonitrile was added, stirred at room temperature, and then diluted with dilute hydrochloric acid (219 mg, 6.01 mmol). Dissolved in 4 ml of water), heated to 60 ° C, dissolved, added dropwise to a sodium hydroxide solution (576 mg, 14.40 mmol) (dissolved in 40 ml of water), and cooled to room temperature overnight. The solid was dried to 0.60 g, and the yield was 60.0%. The X-ray diffraction and DSC spectra were compared by study to confirm that the product was Form II.

Example 6

(1.0 g, 2.24 mmol) of the compound of the formula (I) (prepared as in Example 1) was added to a 250 ml Erlenmeyer flask, 40 ml of tetrahydrofuran was added thereto, stirred at room temperature, and then diluted with hydrochloric acid (219 mg, 6.01 mmol) ( Dissolved in 4 ml of water), heated to 60 ° C, dissolved, added dropwise to a sodium hydroxide solution (576 mg, 14.40 mmol) (dissolved in 40 ml of water), and cooled to room temperature overnight. The solid was dried to 0.76 g, and the yield was 76.0%. The X-ray diffraction and DSC spectra were compared by study to confirm that the product was Form II.

Example 7

The sample of the type II crystal product obtained in Example 1 was separately placed in an open position, and the stability of the sample under illumination (4500 Lux), heating (40 ° C, 60 ° C), and high humidity (RH 75%, RH 90%) was examined. The sampling time was 5 days and 10 days, and the purity of HPLC was shown in Table 1.

Comparison of the stability of the crystalline form of the compound II shown in Table 1 and formula (I)

The results of the stability investigation showed that the crystalline sample of the compound type II represented by the formula (I) had good stability under light, high temperature and high humidity conditions under open conditions.

Example 8

The compound of the formula II (I) obtained by the method of Example 1 was subjected to grinding, heating and tableting, and the results showed that the crystal form was stable. For detailed experimental data, see Table 2 below.

Table 2. Study on the special stability of the crystal form of compound II represented by formula (I)

Claims (7)

A type II crystal of a compound of the formula (I), characterized in that an X-ray powder diffraction pattern represented by a 2θ angle and a crystal plane spacing is obtained using Cu-Ka radiation, the crystal having the structure shown in FIG. X-ray powder diffraction pattern, which is about 5.84 (15.12), 6.16 (14.35), 10.75 (8.22), 12.56 (7.04), 12.96 (6.82), 16.25 (5.45), 17.24 (5.14), 18.97 (4.67), 20.22 (4.39), 21.74 (4.08), 22.99 (3.87), and 25.85 (3.44) have characteristic peaks,

A method of preparing a Form II crystal of a compound of formula (I) according to claim 1, the method comprising the steps of: 1) adding a compound of the formula (I) of any crystal form or amorphous form to an appropriate amount of a solvent, adding an acid, dissolving the solution, and adding a base, which is selected from the group consisting of alcohols having a carbon number of 3 or less, Any one of a ketone or a nitrile or a mixed solvent thereof with water; 2) Filter the crystals, wash and dry. The production method according to claim 2, wherein the acid is a mineral acid, preferably hydrochloric acid. The process according to claim 2, wherein the base is an inorganic base, preferably sodium hydroxide or potassium hydroxide. The method according to claim 2, wherein the solvent in the step 1) is methanol, ethanol, isopropanol, acetone, acetonitrile or tetrahydrofuran; or methanol/water, ethanol/water, acetone/water, acetonitrile/ Water, isopropanol/water, tetrahydrofuran/water; preferably ethanol. A pharmaceutical composition comprising the compound of formula (I) according to claim 1. Form II crystals of the substance and a pharmaceutically acceptable carrier. Use of the type II crystal of the compound of formula (I) according to claim 1 or the pharmaceutical composition of claim 6 for the preparation of a medicament for treating a disease associated with cyclin-dependent protein kinase (CDK4&6) The disease is preferably breast cancer.

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