WO2016101868A1 - Β-crystalline form of naputinib tosylate, preparation method therefor and pharmaceutical composition containing same - Google Patents

Abstract

The present invention providesβ-crystalline form of 2 crystalline hydrate of compound N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-2-crotonamide tosylate, which has stable form and definite melting point, good chemical stability, resistance to high temperature and light, and is suitable for pharmaceutical use.

Description

β crystal form of naproxenil p-toluenesulfonate, preparation method thereof and pharmaceutical composition containing the same Technical field

The present invention belongs to the field of medical technology, and in particular to a novel crystalline form of naproxenil p-toluenesulfonate crystalline hydrate.

Background technique

Compound N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethyl) The base amino)-2-butenamide (napredniplatin) p-toluenesulfonate hydrate is suitable for the treatment of hyperproliferative diseases in mammals, such as cancer.

Formula 1)

The compound is an inhibitor of a tyrosine kinase such as an epidermal growth factor receptor and can be used to treat or prevent diseases associated with tyrosine kinases such as epidermal growth factor receptors, such as cancer, particularly non-small cell lung cancer, colorectal cancer, Refractory non-small cell lung cancer, ovarian cancer, pancreatic cancer, breast cancer, glioma, brain tumor or neck cancer.

Summary of the invention

One object of the present invention is to provide N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(two A new crystalline form of methylamino)-2-butenamide (napredniplatin) p-toluenesulfonate crystalline hydrate characterized by melting point, X-ray powder diffraction (XRD), differential scanning Calorimetric analysis (DSC), thermogravimetric analysis (TG), infrared spectroscopy (IR), and elemental analysis were performed, which have the properties required for the preparation of solid pharmaceutical formulations.

A second object of the present invention is to provide N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4- Process for the preparation of a new crystalline form of (dimethylamino)-2-butenamide (napredniplatin) p-toluenesulfonate crystal hydrate.

A further object of the present invention is to provide a solution comprising the N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]- A pharmaceutical composition of a new crystalline form of 4-(dimethylamino)-2-butenamide (napredniplatin) p-toluenesulfonate crystal hydrate.

The present inventors prepared the N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(two) In the process of methylamino)-2-butenamide (napredniplatin) p-toluenesulfonate crystal hydrate, the crude product is crystallized by recrystallization to obtain a new crystal form of two crystal waters. That is, the beta crystal form. By measuring and analyzing the melting point of the crystal, X-ray powder diffraction, DSC, TG, IR, elemental analysis, etc., it is confirmed that the obtained crystal is a novel crystal called N-[4-[(3-chloro) -4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-2-butenamide p-toluenesulfonate 2 The β crystal form of crystal water.

According to one aspect of the invention, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(two β crystal form of two crystalline hydrates of methylamino)-2-butenamide (naprednisol) p-toluenesulfonate, when subjected to X-ray powder diffraction using a Cu radiation source, the β crystal form The characteristic diffraction peaks at 5.0±0.2, 5.6±0.2, 17.4±0.2, 17.6±0.2, and 18.7±0.2 (°) at 2θ are included, and the relative intensities (I/I ₀ ) of these peaks are all greater than or equal to 15%. Further, the crystal may further comprise, in X-ray powder diffraction, 6.0±0.2, 10.1±0.2, 12.1±0.2, 15.6±0.2, 17.0±0.2, 21.8±0.2, 24.4±0.2, 25.0 at 2θ. Characteristic diffraction peaks of ±0.2, and 26.5 ± 0.2 (°), the relative intensities of these peaks are all greater than or equal to 7% (see Figure 1).

Where "±0.2" is the allowable measurement error range.

The beta crystal form of the invention can be characterized by an X-ray powder diffraction pattern. It is characterized in that its X-ray powder diffraction pattern has a characteristic peak represented by the above 2θ°, and its relative intensity is close to the following values:

The term "proximity" as used herein refers to the uncertainty of the relative intensity measurement. Those skilled in the art understand that the uncertainty of relative intensity is highly dependent on the measurement conditions. The uncertainty of the relative intensity is very dependent on the measurement conditions. The relative intensity value can vary, for example, within ±25% or preferably within ±10%.

The above β crystal form has an X-ray powder diffraction pattern shown in Fig. 1 .

The present invention employs differential scanning calorimetry (DSC) technique for N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl ]-4-(Dimethylamino)-2-butenamide (napredniplatin) is characterized by the β crystal form of two crystalline hydrates of p-toluenesulfonate (see Figure 2) with differential scanning The maximum endothermic heat is at 130 °C. The endothermic process appears as an endothermic peak on the DSC spectrum;

The present invention employs a thermogravimetric analysis technique for N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-( Dimethylamino)-2-butenamide (napredniplatin) is characterized by the β crystal form of two crystal hydrates of p-toluenesulfonate (see Figure 3), which is characterized by thermogravimetry (TG). It shows a weight loss of 2.8% at 195 ° C, indicating that crystal water is lost at this temperature.

The infrared spectrum of the β crystal form of the two crystalline hydrates of the present invention is shown in Figure 4, wherein at 3422, 3265, 3048, 2732, 1691, 1638, 1576, 1545, 1524, 1498, 1453, 1400, 1369, 1326 1,273, 1221, 1160, 1121, 1069, 1034, 1011, 952, 926, 883, 816, 779, 711, 684, 654, 569, 537 cm ^-1 have strong absorption peaks.

The elemental analysis data of the β crystal form of the present invention is in agreement with the theoretical value (within ±0.3% difference), and it was further confirmed that the compound contained two crystal waters (see the following table).

According to another aspect of the present invention, the above N-[4-[(3-chloro-4-fluorophenyl)ammonia]-7-[3-(ethoxyl) is prepared. Method for the β crystal form of 2 quinazolinyl]-4-(dimethylamino)-2-butenamide (napredniplatin) p-toluenesulfonate 2 crystal hydrates comprising: N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-2- a crude butenamide (napredniplatin) p-toluenesulfonate, added to a mixed solvent of a C1-C4 alkyl alcohol and water or added to a mixed solvent of a C3-C4 alkyl ketone and water, and heated to reflux to dissolve; After the solution was clarified, the temperature was lowered to precipitate a solid, and the solid was collected by filtration, and the collected solid was dried under reduced pressure to obtain a β crystal form. The alcohol is methanol, ethanol, propanol, isopropanol, butanol, preferably ethanol; the volume ratio of alcohol to water (V/V) is 1:1 to 10:1; the ketone is acetone, methyl Ethyl ketone, n-butyl ketone, etc., preferably acetone, the volume ratio of ketone to water (V/V) is 1:1 to 10:1; the ratio of the crude product to the solvent is weight (W/V) It is 1 (g): 5 to 30 (ml), preferably 1:12 (g/ml). The solution is preferably heated to 50 to 80 ° C, more preferably, the alcohol and water mixed solvent is heated to 70 ° C, and the ketone and water mixed solvent is heated to 60 ° C. According to this embodiment, the precipitation is carried out for 2 to 8 hours, more preferably 4 hours. The precipitation temperature is 0 to 40 ° C, preferably 5 to 15 ° C. After the solid solution is completely filtered, the drying temperature is 30 to 60 ° C, preferably 45 ° C. .

According to still another aspect of the present invention, there is provided a N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl group of the present invention] A pharmaceutical composition of β crystal form of two crystalline hydrates of 4-(dimethylamino)-2-butenamide (napredniplatin) p-toluenesulfonate. The composition contains the novel crystalline form of the compound and, optionally, a pharmaceutically acceptable carrier and/or excipient.

The above pharmaceutical composition can be further formulated into a form ready for administration according to a conventional formulation method, including an oral or parenteral administration form. In a form for administration, a therapeutically effective amount of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazoline should be included. Beta crystal form of p-toluenesulfonate of 4-(dimethylamino)-2-butenamide (napredniplatin). By "therapeutically effective amount" is meant that at this dose, the compounds of the invention are capable of ameliorating or alleviating the symptoms of the disease, or are capable of inhibiting or blocking the progression of the disease.

Those skilled in the art can readily select and determine the amount of various carriers and/or excipients based on experience and consideration of standard methods and references in the art.

The present invention N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)- The application range of 2-butenamide (napredniplatin) p-toluenesulfonate β crystal form is consistent with naproxenil p-toluenesulfonate for the treatment of hyperproliferative diseases, preferably the hyperproliferative diseases For cancer, including but not limited to non-small cell lung cancer, colorectal cancer, refractory non-small cell lung cancer, pancreatic cancer, ovarian cancer, breast cancer, glioma, brain cancer or cervical cancer.

The present invention produces N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazoline Beta crystal form of p-toluenesulfonate, which has a stable morphology and a defined melting point, good chemical stability and high temperature resistance. And light, this new crystalline form of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4- (Dimethylamino)-2-butenamide (napredniplatin) p-toluenesulfonate has the properties required for the preparation of solid preparations, and is convenient to store, simple in production operation, and easier to control in quality.

DRAWINGS

1 is an X-ray diffraction spectrum of a β crystal form obtained in Example 2 of the present invention;

2 is a DSC spectrum of a β crystal form obtained in Example 2 of the present invention;

Figure 3 is a TG spectrum of the β crystal form obtained in Example 2 of the present invention;

4 is an IR spectrum of a β crystal form obtained in Example 2 of the present invention;

Fig. 5 is an HPLC chart of the β crystal form obtained in Example 2 of the present invention.

detailed description

All materials and reagents are commercially available.

Crude preparation:

N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-2- Butenamide (Naproxil) is based on N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine, and is similar to the method of WO2007085638. To prepare, the salt forming process refers to the preparation method of the patent WO2012121764.

Preparation of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamine Α-form and β-form of 2-butenamide (napredniplatin) p-toluenesulfonate

[Example 1]

200 g of crude naproxenil p-toluenesulfonate was added to the reaction flask, and 2400 ml of a mixed solvent of acetone and water (V/V = 12:1) was added, and the mixture was heated to reflux at 60 ° C under stirring. After dissolving, stirring for 10 min, and then cooling to 5-15 ° C, until the solid precipitated and stirred for 4 h, suction filtration, and the filter cake was rinsed with acetone. The filter cake was blast dried at 45 ° C and dried with phosphorus pentoxide. A white solid 163 g was obtained in a yield of 81.5%. The moisture was measured by a Karl Fischer analyzer to be 3.3%. The obtained compound was 1.5 water of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4- (Dimethylamino)-2-butenamide p-toluenesulfonate crystal form a.

[Embodiment 2]

200 g of naproventil p-toluenesulfonate was added to the reaction flask, and 1600 ml of a mixed solvent of acetone and water (V/V = 10:1) was added, and the mixture was heated to reflux at 60 ° C with stirring. After dissolving, stirring for 10 min, and then cooling to 5-15 ° C, until the solid precipitated and stirred for 4 h, suction filtration, and the filter cake was rinsed with acetone. The filter cake was blast dried at 45 ° C and dried with phosphorus pentoxide. The white solid was obtained in 154 g, yield 77.0%. The moisture was measured by a Karl Fischer meter to be 4.4%. The obtained compound was N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4- (Dimethylamino)-2-butenamide p-toluenesulfonate crystal form β.

Test conditions for the sample of the example:

(1) XRD:

Testing equipment: Empyean X-ray diffractometer

Detection conditions: Cu target Kα ray, voltage 40kV, current 40mA, divergence slit 1/32°, anti-scatter slit 1/16°, anti-scatter slit 7.5mm, 2θ range: 3°-50°, step size 0.02 °, each step of stay time 40S.

Test basis: Appendix IXFX ray powder diffraction method of the People's Republic of China (2010 edition 2)

Test results: as shown in Figure 1.

(2) DSC:

Testing equipment: Germany NETZSCH DSC 204F1 differential scanning calorimeter

Detection conditions: atmosphere: N2 (purity: ≥ 99.99%), 20 ml / min

Scanning procedure: The temperature was raised from room temperature to 180 ° C at 10 ° C / min, and the temperature rise curve was recorded.

Test sample quality: Sample 1: 2.27 mg (using an aluminum sample pan)

Test basis: General rules for thermal analysis methods of JY/T 014-1996

Test results: as shown in Figure 2.

(3) TG:

Testing equipment: Germany NETZSCH company TG209 thermogravimetric analyzer

Test conditions: atmosphere: air, 20ml/min

Scanning procedure: room temperature ~ 700 ° C, heating rate: 10 ° C / min.

Test basis: General rules for thermal analysis methods of JY/T 014-1996

Test results: as shown in Figure 3.

(4) Infrared spectrum:

Testing equipment: FT-IR NICOLET6700 (Germany)

Detection conditions: potassium bromide tableting method

Test basis: GB/T 6040-2002 General rules for infrared spectrum analysis

Test results: as shown in Figure 4.

(5) HPLC

Testing equipment: Agilent 1260series (USA)

Detection conditions:

Column: Waters C18

Mobile phase A: acetonitrile-mobile phase B (70:30)

Mobile phase B: 0.05 mol/l ammonium dihydrogen phosphate solution (pH = 7.3)

Column temperature: 30 ° C detection wavelength: 247 nm.

Test basis: "Chinese Pharmacopoeia" two appendix VD high performance liquid chromatography

Test results: Figure 5

[Other Embodiments]

20 g of naproxenil p-toluenesulfonate crude was added to the reaction flask, and the following experiments were carried out with reference to the experimental procedures of Examples 1 and 2:

N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-2- Ding Study on the stability of the crystal form of the enamide (naprednisol) p-toluenesulfonate

[Example 3]

The obtained crystal forms α and β were investigated for stability (10-day accelerated test), and the water, purity, and maximum heterogeneity of the new crystal form were observed at 40 ° C, 60 ° C, humidity 75%, 92.5%, and light conditions. The total impurity was compared with the data for 0 days, and the results showed that the obtained crystal form was stable. And the free base (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino) The degradation of 2-butene amide at 60 ° C indicates that high temperature has an effect on the stability of the free base.

Table 1 Test results of factors affecting crystal form α

Table 2 Test results of influencing factors of crystal form β

Table 3 Test results of factors affecting free base

Preparation method of free base: the free base is based on N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine, and the method similar to patent WO2007085638 is used. preparation.

Preparation of solid pharmaceutical preparations

[Example 4] Preparation of solid pharmaceutical preparation

Prescription 1:

Process: The above ingredients are mixed according to a conventional preparation method and directly compressed.

Prescription 2:

Method: Naphthinib p-toluenesulfonate 2 crystal hydrate β crystal form and mannitol, lactose, crospovidone are uniformly mixed by equal multiplication method, and pre-formed HPMC solution is added to make soft material. 20 mesh sieve granules, dried at 60 ° C for 30 minutes, 18 mesh sieve granules, added micro-silica gel, mixed evenly, and filled into 2 ^# capsules.

Prescription 3:

Process: The above ingredients are mixed according to a conventional preparation method and directly compressed.

[Example 5] Controlled factors of influencing factors

Three batches of samples were prepared according to the procedures of Formulations 1-3 in Example 4. After passing the basic project, the light, high temperature and high humidity tests were carried out respectively to examine the appearance properties, content and dissolution of the samples. The results of the influencing factors indicate that the sample is stable under high temperature and light conditions and can be used as a reference formulation and process for the formulation, but the prescription 3 is easy to absorb moisture under the conditions of 25 ° C, RH 75%, 25 ° C, and RH 92.5%. It is easy to produce degradation products.

Table 4

Survey indicator		Prescription 1	Prescription 2	Prescription 3
Dissolution	it is good	it is good	difference
Compressibility	it is good	/	better
Disintegration	it is good	better	difference

The purpose of developing the crystal form is mainly to solve the problem of dissolution and increase the dissolution. According to the 2010 edition of the Pharmacopoeia dissolution test, the dissolution of prescriptions 1 to 2 was above 80% in 15 minutes. The prescription 3 has a dissolution rate of less than 70% in 15 minutes. Under the premise of consistent excipients, the indicators of prescription 1 are better than prescription 3, so the products of β crystal form and free base are not only different in melting point, solubility, crystal solubility, etc. The stability of the latter and the dissolution of the preparation The test indexes such as compressibility and disintegration degree are not as good as the crystal form of the two crystalline hydrates of naproxenil p-toluenesulfonate of the present invention.

The above description of the preferred embodiments of the present invention is not intended to limit the invention, and various modifications and changes can be made by those skilled in the art without departing from the spirit of the invention. .

Claims (8)

1. Compound (1) N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethyl Beta crystal form of amino)-2-butenamide p-toluenesulfonate, which is N-[4-[(3-chloro-4-fluorophenyl)amino]-containing 2 water of crystallization 7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-2-butenamide p-toluenesulfonic acid salt hydrate having a 2θ° of 5.0±0.2, 5.6 ± 0.2, 6.0 ± 0.2, 10.1 ± 0.2, 12.1 ± 0.2, 15.6 ± 0.2, 17.0 ± 0.2, 17.4 ± 0.2, 17.6 ± 0.2, 18.7 ± 0.2, 21.8 ± 0.2, 24.4 ± 0.2, 25.0 ± 0.2, and 26.5 X-ray powder diffraction pattern of characteristic peaks represented by ±0.2

   
2. N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(II) according to claim 1 The β crystal form of methylamino)-2-butenamide p-toluenesulfonate, characterized in that the relative intensity I/I ₀ of 2θ° is about the following values:

   
3. N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl] according to any one of claims 1-2 The beta form of -4-(dimethylamino)-2-butenamide p-toluenesulfonate characterized in that the maximum endothermic transition of the DSC scan of the alpha form is about 130 °C.
4. N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl] according to any one of claims 1-2 Beta crystal form of 4-(dimethylamino)-2-butenamide p-toluenesulfonate characterized by thermogravimetry showing a weight loss of 2.8% at 195 °C.
5. N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl] according to any one of claims 1-2 β crystal form of -4-(dimethylamino)-2-butenamide p-toluenesulfonate characterized by an infrared absorption spectrum measured by KBr tableting at about 3422, 3265, 3048, 2732 1691, 1638, 1576, 1545, 1524, 1498, 1453, 1400, 1369, 1326, 1273, 1221, 1160, 1121, 1069, 1034, 1011, 952, 926, 883, 816, 779, 711, 684, 654, There is an absorption peak at 569, 537 cm ^-1 .
6. Preparation of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(II) according to claim 1. A method for the beta crystal form of methylamino)-2-butenamide p-toluenesulfonate, comprising the steps of:

   1) N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino) a crude 2-methylbutyramide p-toluenesulfonate, added to a mixed solvent of a C ₁ -C ₄ alkyl alcohol and water or added to a mixed solvent of a C ₃ -C ₄ alkyl ketone and water, and heated to reflux to dissolve ;

   Wherein the alkyl alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol, and the volume ratio of alcohol to water is 1:1 to 10:1;

   The alkyl ketone is selected from the group consisting of acetone, methyl ethyl ketone and n-butanone, and the volume ratio of ketone to water is 1:1 to 10:1;

   The ratio of the crude product to the solvent is 1 to g (g): 5 to 30 (ml), and the heating temperature is 50 to 80 ° C;

   2) After the solution is clarified, the temperature is lowered to precipitate a solid, and the solid is collected by filtration, and the collected solid is dried under reduced pressure to obtain a β crystal form;

   The precipitation is carried out for 2 to 8 hours, the precipitation temperature is 0 to 40 ° C, and the filtration is completed and filtered, and the drying temperature is 30 to 60 ° C.
7. The preparation method according to claim 6, wherein the alkyl alcohol in the step 1) is ethanol, the alkyl ketone is acetone, and the weight-to-volume ratio of the crude product to the solvent is 1:12 (g/ml), and the alcohol and water mixed solvent. Heat to 70 ° C, ketone and water mixed solvent heated to 60 ° C;

   In step 2), the precipitation time is 4 hours, the precipitation temperature is 5 to 15 ° C, and the drying temperature is 45 ° C.
8. Containing N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(II) according to claim 1 A pharmaceutical composition of the beta form of methylamino)-2-butenamide p-toluenesulfonate.

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