CN106029664A - Crystalline form of malate of tyrosine kinase inhibitor and preparation method therefor - Google Patents

Abstract

5‑(2‑diethylamino‑ethyl)‑2‑(5‑fluoro‑2‑oxo‑1,2‑dihydro‑indole‑3‑subunit useful as tyrosine kinase inhibitors -Methyl)-3-methyl-1,5,6,7-tetrahydro-pyrrole[3,2-c]pyridin-4-one L-malate (compound of formula (I)) type I crystal and its preparation method. The method comprises the step of crystallizing any crystalline and amorphous compound of formula (I) or its salt-forming raw material in a mixed solvent of an organic solvent preferably alcohol and water.

Description

A crystalline form of malate salt of a tyrosine kinase inhibitor and a preparation method thereof technical field

The present invention relates to a crystalline form of the malate salt of a tyrosine kinase inhibitor, in particular 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2 - Form I crystals of dihydro-indol-3-ylidene-methyl)-1,5,6,7-tetrahydro-pyrrole[3,2-c]pyridin-4-one L-malate salt.

Background technique

In recent years, with the advancement of molecular biology technology and the further understanding of tumor pathogenesis from the molecular level of cell receptors and proliferation regulation, treatments targeting cell receptors, key genes and regulatory molecules have begun to enter the clinic. People call it "molecular targeted therapy". These areas include targeted epidermal growth factor receptor (EGFR) blockers, monoclonal antibodies against certain specific cell markers, drugs against certain oncogenes and cytogenetic markers of cancer, anti-tumor vascular Generated drugs, anti-tumor vaccines and gene therapy, etc.

The anti-tumor mechanism of tyrosine kinase inhibitors (TKIs), which first entered the clinic, may be achieved through the following pathways: inhibiting the damage repair of tumor cells, arresting cell division in the G1 phase, inducing and maintaining apoptosis, and anti-angiogenesis Form etc. Overexpression of EGFR often indicates poor prognosis, rapid metastasis, resistance to chemotherapy drugs, hormone resistance, and short survival time. TKIs can also down-regulate the angiogenesis factors of tumor cells and inhibit the signal transduction of EGFR to tumor vascular endothelial cells. Two conduction pathways provide plausible evidence. The results of clinical trials show that multi-target inhibitors are superior to single-target inhibitors in treatment, and multi-target combined blockade of signal transduction is a new development direction for tumor treatment and drug development.

So far, the US FDA has approved 3 multi-target TKIs for marketing, such as: sorafenib (sorafenib), vandetanib (vandetanib) and Sunitinib (Sutent, SU-11248), of which Sunitinib was approved in January 2006 Listed for the treatment of GIST and advanced renal cancer. Since there are currently no clinically available drugs for the treatment of advanced GIST and few drugs for the treatment of kidney cancer except imatinib, the results of sunitinib are encouraging. WO2007085188 discloses a compound similar to Sunitinib, as shown in the following formula (I), which may be better applied For the treatment of the above tumors.

Those skilled in the art know that the crystal structure of the active ingredient used in medicine often affects the chemical stability of the drug. The difference in crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by other Morphological crystal form. Generally speaking, amorphous pharmaceutical 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-mentioned products, and we need to conduct in-depth research to find new crystal forms with high purity and good chemical stability.

Contents of the invention

The present invention provides 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indole-3-ylidene-methyl)-1 , a new crystalline form of 5,6,7-tetrahydro-pyrrole[3,2-c]pyridin-4-one L-malate (as represented by formula (I)).

A series of crystallization products of the compound shown in formula (I) obtained under different crystallization conditions, X-diffraction and DSC detection are carried out to the gained crystallization product, find that the compound shown in formula (I) can be obtained under the specific crystallization conditions of the present invention A new crystal form was obtained, which we called type I crystal. The DSC spectrum of the type I crystal in the present application shows that there is a melting endothermic peak near 240.64 ° C, and the X-ray powder diffraction spectrum is shown in Figure 1, using Cu-Ka radiation, with 2θ angle and interplanar spacing (d value) Represented X-ray powder diffraction pattern, wherein at 7.34(12.02), 10.09 (8.76), 11.06 (7.99), 12.25 (7.22), 13.03 (6.79), 14.69 (6.02), 15.11 (5.86), 15.42 (5.74), 16.00 (5.54), 17.17 (5.16), 17.72 (5.00), 19.86 (4.47), 20.35(4.36), 21.96(4.04), 22.77(3.90), 23.37(3.80), 25.33(3.51), 25.96(3.43), 26.52(3.36), 28.77(3.10), 30.17(2.96) and 31.65 (2.83) has characteristic peaks.

The present invention also provides the preparation of 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indole-3-ylidene-methyl) - Method for type I crystallization of 1,5,6,7-tetrahydro-pyrrole[3,2-c]pyridin-4-one L-malic acid. The method comprises the steps of:

(1) L-malic acid and 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene- Methyl)-1,5,6,7-tetrahydro-pyrrole [3,2-c] pyridin-4-one, or the compound shown in any crystalline or amorphous formula (I) is dissolved in an organic solvent and Crystallization in a mixed solvent of water, the organic solvent is selected from one or more of alcohols, ketones, nitriles, ethers or tetrahydrofuran with carbon atoms less than or equal to 3;

(2) The crystals are filtered and washed, and dried.

In a preferred embodiment of the present invention, in step (1), the organic solvent is alcohols, preferably methanol, ethanol, isopropanol.

The method of recrystallization is not particularly limited, and a usual recrystallization operation method can be used. For example, the compound represented by the raw material formula (I) can be heated and dissolved in a solvent and then slowly cooled and crystallized. After the crystallization is completed, the desired crystal can be obtained by filtering and drying. It should be noted that the filtered crystals are usually vacuum-dried under reduced pressure at a temperature of about 30-100°C, preferably 40-60°C, to achieve the effect of removing the recrystallization solvent.

By means of differential scanning calorimetry (DSC) and X-ray diffraction pattern determination, the crystal form of the obtained compound crystal represented by formula (I) was studied, and the solvent residue of the obtained crystal was detected at the same time.

Compound I type crystals shown in formula (I) prepared according to the method of the present invention do not contain or only contain low levels of residual solvents, and meet the limit requirements of the relevant pharmaceutical product residual solvents stipulated in the National Pharmacopoeia, so the crystals of the present invention can be compared. It is best used as a pharmaceutical active ingredient.

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

Description of drawings

The X-ray powder diffraction pattern of compound I crystal shown in Fig. 1 formula (I).

The DSC spectrogram of compound I crystal shown in Fig. 2 formula (I).

detailed description

The present invention will be explained in more detail below in conjunction with the examples. The examples of the present invention are only used to illustrate the technical solutions of the present invention, and do not limit the essence and scope of the present invention.

The test equipment used in the experiment

1. DSC spectrum

Instrument model: Mettler Toledo DSC ^1Stare System

Purge gas: Nitrogen

Heating rate: 10.0°C/min

Temperature range: 40-300°C

2. X-ray diffraction spectrum

Instrument model: Bruker D8Focus X-ray powder diffractometer

Rays: monochromatic Cu-Kα rays (λ=1.5406)

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

Voltage: 40KV, Current: 40mA

Example 1

Get (1.0g, 1.84mmol) the compound shown in formula (I) (prepared according to the method disclosed in WO2007085188) and join in a 250ml single-necked bottle, add 50ml ethanol, 50ml water, heat to dissolve, then cool to room temperature, stand for crystallization, Suction filtration and vacuum drying afforded 0.64 g of solid with a yield of 64.0%. The X-ray diffraction spectrum of the crystalline sample is shown in FIG. 1 , and the peak list of the X-ray diffraction spectrum is shown in Table 1. The crystallization at about 7.34 (12.02), 10.09 (8.76), 11.06 (7.99), 12.25 (7.22), 13.03 (6.79), 14.69 (6.02), 15.11 (5.86), 15.42 (5.74), 16.00 (5.54), 17.17 (5.16), 17.72(5.00), 19.86(4.47), 20.35(4.36), 21.96(4.04), 22.77(3.90), 23.37(3.80), 25.33(3.51), 25.96(3.43), 26.52(3.36), 28.77 There are characteristic peaks at (3.10), 30.17 (2.96) and 31.65 (2.83). The DSC spectrum is shown in Figure 2, which is sharp.

Table 1, the peak list of X-ray diffraction spectrum

Example 2

Take (1.0g, 1.84mmol) compound represented by formula (I) and add it to a 250ml single-necked bottle, add 74ml ethanol, 37ml water, heat to dissolve, then cool to room temperature, stand for crystallization, suction filter, and vacuum dry to obtain a solid 0.33g, yield 33.0%. Its X-diffraction and DSC patterns are researched and compared, and it is confirmed that the product is I crystal form.

Example 3

Take (1.0g, 1.84mmol) the compound represented by formula (I) and add it to a 250ml single-necked bottle, add 50ml methanol and 50ml water, heat to dissolve, then cool to room temperature, stand for crystallization, suction filter, and vacuum dry to obtain a solid 0.42g, yield 42.0%. Its X-diffraction and DSC patterns are researched and compared, and it is confirmed that the product is I crystal form.

Example 4

Take (1.0g, 1.84mmol) compound shown in formula (I) and join in 250ml one-necked bottle, add 60ml isopropanol, 60ml water, heat to dissolve, then cool to room temperature, stand for crystallization, suction filter, vacuum dry, 0.31 g of solid was obtained, yield 31.0%. Its X-diffraction and DSC patterns are researched and compared, and it is confirmed that the product is I crystal form.

Example 5

Take (1.0g, 1.84mmol) the compound represented by formula (I) and add it to a 250ml single-necked bottle, add 50ml acetone, 50ml water, heat to dissolve, then cool to room temperature, stand for crystallization, suction filter, and vacuum dry to obtain a solid 0.35g, yield 35.0%. Its X-diffraction and DSC patterns are researched and compared, and it is confirmed that the product is I crystal form.

Example 6

Take (1.0g, 1.84mmol) the compound represented by formula (I) and add it to a 250ml single-necked bottle, add 60ml acetonitrile, 60ml water, heat to dissolve, then cool to room temperature, stand for crystallization, suction filter, and vacuum dry to obtain a solid 0.37g, yield 37.0%. Its X-diffraction and DSC patterns are researched and compared, and it is confirmed that the product is I crystal form.

Example 7

Take (1.0g, 1.84mmol) compound represented by formula (I) and add it to a 250ml single-necked bottle, add 50ml tetrahydrofuran, 50ml water, heat to dissolve, then cool to room temperature, stand for crystallization, suction filter, and vacuum dry to obtain a solid 0.34g, yield 34.0%. Its X-diffraction and DSC patterns are researched and compared, and it is confirmed that the product is I crystal form.

Example 8

The type I crystalline product samples obtained in Example 1 were placed open and flat respectively to investigate the stability of the samples under heating (40° C., 60° C.) and high humidity (RH75%, RH90%) conditions. The investigation sampling time was 5 days and 10 days, and the HPLC detection purity is shown in Table 2.

The stability of compound I type crystalline sample shown in table 2, formula (I)

The results of the stability investigation show that the type I crystalline sample of compound shown in formula (I) is placed under the condition of being exposed, and the stability comparison under high temperature and high humidity conditions finds that high humidity and high temperature have little influence on the quality of the product. It shows that it has better stability.

Example 9

The Type I crystal of the compound represented by formula (I) prepared according to the method in Example 1 was ground, heated and tableted. The research results showed that the crystal form was stable. For detailed experimental data, see Table 3 below.

Table 3. Special stability research of compound I crystal form shown in formula (I)

Claims (5)

1. The I types crystallization of compound as shown in formula (I), it is characterised in that：Radiated using Cu-Ka, obtain the X-ray powder diffraction collection represented with 2 θ angles and interplanar distance, the crystallization has X-ray powder diffraction collection as shown in Figure 1, wherein in about 7.34 (12.02), 10.09 (8.76), 11.06 (7.99), 12.25 (7.22), 13.03 (6.79), 14.69 (6.02), 15.11 (5.86), 15.42 (5.74), 16.00 (5.54), 17.17 (5.16), 17.72 (5.00), 19.86 (4.47), 20.35 (4.36), 21.96 (4.04), 22.77 (3.90), 23.37 (3.80), 25.33 (3.51), 25.96 (3.43), 26.52 (3.36), 28.77 (3.10), there is characteristic peak 30.17 (2.96) and 31.65 (2.83),
2. The method that one kind prepares the I types crystallization of the compound as claimed in claim 1 as shown in formula (I), methods described comprises the steps：

   1) by L MALIC ACID and 5- (2- diethylin-ethyl) -2- (fluoro- 2- oxos -1 of 5-, 2- Dihydro-indole -3- ylidene-memyls) -1,5,6,7- tetrahydrochysenes-pyrroles [3,2-c] pyridine -4- ketone, or the one or more that compound shown in any crystal formation or unformed formula (I) is less than or equal in 3 alcohols, ketone, nitrile, ethers or tetrahydrofuran in organic solvent and the in the mixed solvent crystallization of water, the organic solvent selected from carbon number；

   2) filtering for crystallizing and wash, dry.
3. Method according to claim 2, it is characterised in that in step 1) described in organic solvent be preferably alcohols, further preferred methanol, ethanol, isopropanol.
4. A kind of pharmaceutical composition, its I types crystallization for containing the compound as claimed in claim 1 as shown in formula (I) and pharmaceutically acceptable carrier.
5. Purposes of the pharmaceutical composition in the medicine for preparing the treatment disease relevant with EGFR-TK as described in the I types crystallization of the compound according to claim 1 shown in formula (I) or claim 4；The preferred tumour of disease, more preferably non-small cell lung cancer, liver cancer, gastrointestinal stromal tumors or kidney.