WO2012055351A1

WO2012055351A1 - A crystal form of nilotinib hydrochloride and preparation method thereof

Info

Publication number: WO2012055351A1
Application number: PCT/CN2011/081324
Authority: WO
Inventors: 徐建康; 叶美其; 徐巧巧; 吴昊
Original assignee: 浙江九洲药业股份有限公司
Priority date: 2010-10-27
Filing date: 2011-10-26
Publication date: 2012-05-03
Also published as: CN102453024A; CN102453024B

Abstract

A crystal form of nilotinib hydrochloride with x-ray powder diffraction pattern in table 1is disclosed，and a preparation method of it is also provided in the present invention.

Description

The present invention claims to be submitted to the Chinese Patent Office on October 27, 2010, the application number is 201010531734.4, and the invention name is "a crystal form of nilotinib hydrochloride and its The priority of the Chinese Patent Application for the preparation of the present application is hereby incorporated by reference. Technical field

The invention relates to nilotinib, in particular to a crystal form of nilotinib hydrochloride and a preparation method thereof. Background technique

Nilotinib, English name Nilotinib, chemical name 4-mercapto-3-3 ((4-(3-pyridyl ¹ 3⁄4S -2-pyrimidinyl)amino)-N- ( 5-4 ( 4-曱) Base-111-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide, the structural formula of which is shown in formula II):

Nilotinib is a highly selective oral tyrosine kinase inhibitor developed by Novartis Pharmaceuticals of Switzerland. Its monohydrochloride monohydrate was approved by the US FDA in October 2007 under the trade name Tasigna (Dahina). ;), clinically used to treat blood cell chronic myeloid leukemia (CML) that is ineffective against imatinib mesylate. Nilotinib is improved by the molecular structure of imatinib. It has stronger selectivity for BCR-ABL kinase activity and 30 times stronger inhibition of tyrosine kinase than imatinib. Therefore, nilotinib can inhibit the kinase activity of the imatinib-resistant BCR-ABL mutant. Also. Nilotinib also replaces KIT (stem cell factor receptor) and PDGFR (human platelet-derived growth factor receptor) kinase activities. The preparation of hydrochloride, sulfate, phosphate and various crystal forms of nilotinib has been reported in the world patents WO2007015871 and WO2007015870.

The polymorphic state of solid drugs is an important part of the study of the presence of drugs, for most chemicals Polymorphism is generally present. Since these different crystalline substances affect the physical and chemical properties and biological activities of the drug, the presence of the drug crystal form should be considered in the study of the raw materials and formulation of the drug. For nilotinib, a crystalline form of a portion of nilotinib hydrochloride, such as nilotinib crystal form monohydrochloride single crystal form B, has been disclosed in the patent WO2007015871. The X-ray powder diffraction pattern of Form B has a maximum at the following 2 turns: 7.2. , 9.2. , 11.4. , 12.0. 12.3. 14.6°, 14.8°, 15.7°, 17.6°, 19.2°, 19.5°, 20.5°, 22.0°, 23.4°, 23.9°, 25.0°, 25.5. 25.9. , 27.0. . Since the solubility of the crystal form B is low, the use is greatly limited. Summary of the invention

The problem to be solved by the present invention is to provide a crystal form of nilotinib hydrochloride which has a better solubility in the crystal form of nilotinib hydrochloride prepared according to the present invention.

In order to solve the above technical problems, the present invention provides a crystal form of nilotinib hydrochloride, wherein the crystal form of the nilotinib hydrochloride has a structure represented by the formula (I).

The crystal form of the nilotinib hydrochloride salt was expressed using Cu-Κα radiation, using a crystal plane spacing d, a Bragg angle 2Θ, and a relative intensity, and having an X-ray diffraction chart as shown in Table 1:

Table 1 Nilotinib hydrochloride crystal form X-ray diffraction chart

2 Θ angle (°) interplanar spacing d ( A ) relative intensity (%)

4.987 17.7060 15.1

8.430 10.4795 100

11.309 7.8179 25.6

14.403 6.1447 10.4

17.219 5.1456 18.8 19.225 4.6128 37.0

25.544 3.4842 87.0 The present invention also provides a method for preparing a crystal form of nilotinib hydrochloride according to Table 1, which comprises: a) dissolving nilotinib free base in an organic solvent to obtain a first solution;

b) adding the first solution to an ether hydrochloric acid solution for reaction;

c) filtering the product obtained by the reaction and drying to obtain a crystal form of nilotinib hydrochloride.

Preferably, the organic solvent is selected from the group consisting of an alcohol organic solvent, a hydrocarbon-based organic solvent, an ether organic solvent, a ketone organic solvent, an ester organic solvent, or a mixed solvent of an alcohol solvent and a hydrocarbon-based solvent. .

Preferably, the ether in the hydrochloric acid solution of the ether is diethyl ether, phenylpropyl ether, isopropyl ether, decyl tert-butyl ether. Preferably, the ratio of the amount of the substance of the nilotinib free base to the hydrochloric acid in the hydrochloric acid solution of the ether is 1: 0.95 to 1: 1.2.

Preferably, the step b) comprises:

Bl) adding the first solution to the ether hydrochloric acid solution;

B2) Insulation.

Preferably, before the step b), the step of cooling the ether hydrochloric acid solution to 5 ° C ~ -50 ° C is further included.

Preferably, the dropping time in the step bl) is not more than 10 hours.

Preferably, the holding time in the step b2) is not more than 12 hours.

Preferably, the step c) comprises:

Cl) filtering the product obtained by the reaction;

C2) drying the filtered product under vacuum;

C3) Dry the dried product at 40 ° C ~ 60 ° C.

The present invention provides a crystal form of nilotinib hydrochloride having an X-ray diffraction pattern as shown in Table 1, and a preparation method thereof, compared with the prior art, the present invention The prepared nilotinib hydrochloride has a higher solubility. DRAWINGS

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray diffraction pattern of the crystal form of nilotinib hydrochloride prepared in Example 1 of the present invention; and Figure 2 is an X-ray diffraction pattern of the crystal form of nilotinib hydrochloride prepared in Example 2 of the present invention. detailed description

In order to further understand the invention, the preferred embodiments of the present invention are described in the accompanying drawings.

this invention

The crystal form of nilotinib hydrochloride represented by the formula (I) was irradiated with Cu-Κα, and the X-ray diffraction patterns expressed by the interplanar spacing d, the Bragg angle 2 Θ and the relative intensity are shown in Table 1.

The invention also provides a preparation method of the crystal form of nilotinib hydrochloride hydrochloride shown in Table 1, which comprises:

a) taking nilotinib free base dissolved in an organic solvent to obtain a first solution;

According to the present invention, when the crystal form of the nilotinib hydrochloride is prepared, the nilotinib free base is used as a raw material, and the nilotinib free base is dissolved in an organic solvent to obtain a first solution. The organic solvent is selected from the group consisting of an alcohol organic solvent, a hydrocarbon-based organic solvent, an ether organic solvent, a ketone organic solvent, an ester organic solvent, or a mixed solvent of an alcohol solvent and a hydrocarbon-based solvent. Specific examples of the alcohol organic solvent may be decyl alcohol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol, but are not limited thereto. Specific examples of the halogenated hydrocarbon organic solvent may be dichlorosilane, chloroform, 1,2-dichloroethylene, but are not limited. Here. Specific examples of the ether organic solvent may be tetrahydrofuran, diethyl ether, diisopropyl ether, benzoin ether or mercapto tert-butyl ether, but are not limited thereto. Specific examples of the ketone organic solvent may be acetone, decyl isobutyl ketone, butanone, decyl butyl ketone, but are not limited thereto. Specific examples of the ester organic solvent may be ethyl acetate, isobutyl acetate, butyl acetate, and isopropyl acetate, but are not limited thereto, and the organic solvent is preferably a mixed solution of decyl alcohol and dichlorosilane. The volume ratio of sterol to dichloromethane in the mixed solution is preferably 1:99 to 99:1, more preferably 1:9 to 1:1.

According to the present invention, a specific example of the hydrochloric acid hydrochloric acid solution may be an ether hydrochloric acid solution, a phenyl ether ether hydrochloric acid solution, a isopropyl ether hydrochloric acid solution, or a mercapto tert-butyl ether hydrochloric acid solution, but is not limited thereto. The ratio of the amount of the nilotinib free base to the hydrochloric acid in the hydrochloric acid solution of the ether is preferably 1: 0.95 to 1: 1.2, more preferably 1: 0.95 - 1: 1.05, more preferably 1: 0.98 ~ 1: 1.02.

According to the present invention, before the step b), the step of cooling the hydrochloric acid hydrochloric acid solution to 10 ° C to -50 ° C is further included. Preferably, the hydrochloric acid hydrochloric acid solution is cooled to 5 ° C to -50 °C, more preferably cooled to 0 ° C ~ -50 ° C.

According to the invention, said step b) preferably comprises:

Bl) adding the first solution to the ether hydrochloric acid solution;

B2) Insulation.

According to the present invention, in the step bl), the dropping time when the first solution is added dropwise to the hydrochloric acid hydrochloric acid solution is preferably controlled to not more than 10 hours, more preferably to 1 hour to 5 hours. The holding time in the step b2) is preferably not more than 12 hours, more preferably not more than 5 hours, more preferably not more than 1 hour.

According to the invention, said step c) comprises:

Cl) filtering the product obtained by the reaction;

C2) drying the filtered product under vacuum;

C3) Dry the dried product at 40 ° C ~ 60 ° C.

For the filtration method, filtration can be carried out according to a method well known to those skilled in the art, and the present invention is not particularly limited. Drying can be carried out using a vacuum dryer well known to those skilled in the art, the drying temperature is preferably carried out at normal temperature, and the drying time is preferably at least 20 min, more preferably at least 30 min. More preferably, it is 1 hour - 3 hours, More preferably, it is 1 hour. The drying temperature is preferably 40 ° C to 60 ° C, more preferably 42 ° C to 58 ° C, still more preferably 45 V to 55 ° C.

The effects of the present invention are described below by way of specific examples, but the scope of the present invention is not limited by the following examples.

In the following examples:

X-ray diffraction experiments were performed using a Japanese Science D/MAX-2200 diffractometer:

Target: Cu-Κα (λ=1·5405 A), 2Θ=2°~70°;

Step angle: 0.04°;

Tube pressure: 40KV;

Tube flow: 40mA;

Scanning speed: 10 min

Step size: 0.033°.

Example 1

In a clean and dry 500 mL four-necked flask, 10 g of nilotinib free base monomer, 50 mL of sterol, and 400 mL of dichloromethane were added, and the mixture was stirred, heated to reflux, dissolved, and filtered to obtain a first solution, which was first. The solution was transferred to a dropping funnel.

A mixed solution of 6.3 mL of a hydrazino-t-butyl ether hydrochloride solution having a hydrochloric acid concentration of 3.0 mol. L" ¹ and 400 ml of decyl tert-butyl ether was prepared.

The mixed solution was cooled to 2 ° C with ice brine, and the dissolved nilotinib free base was added dropwise under a nitrogen atmosphere, and the mixture was dropped at 1.5 hours, and the temperature was kept at 4 ° C during the dropwise addition. Heat for another 1.2 hours, keep warm, and filter.

The wet product was rinsed with 20 ml of decyl tert-butyl ether, drained, placed in a vacuum oven, dried without vacuuming for 1 hour, and then warmed to 50 ° C to dry, to obtain a dry product: llg, yield: 100 %;

The X-ray diffraction pattern of the crystalline form of nilotinib hydrochloride prepared in this example is shown in Fig. 1. Example 2

In a clean and dry 500 mL four-necked flask, 10 g of nilotinib free base monomer, sterol 100mL, dichlorosilane 150mL, start stirring, heated to reflux to dissolve transparent, filtered to obtain the first solution, the first solution was transferred to the dropping funnel;

A mixed solution of 6.3 mL of decyl tert-butyl ether hydrochloride solution having a hydrochloric acid concentration of 3.0 molL and 120 ml of decyl tert-butyl ether was prepared.

The mixed solution was cooled to 4 ° C with iced water, and the dissolved nilotinib free base was added dropwise under a nitrogen atmosphere, and the mixture was dropped at 1.5 hours, and the temperature was kept at 4 ° C during the dropwise addition. Heat for another 1.2 hours, keep warm, and filter.

The wet product was rinsed with 20 ml of decyl tert-butyl ether, drained, placed in a vacuum oven, dried under vacuum for 1 hour, and dried at 55 ° C to obtain a dry product: 9 g, yield: 81.6 %;

The X-ray diffraction pattern of the crystal form of nilotinib hydrochloride prepared in this example was measured as shown in Fig. 2. Solubility experiment:

In a water bath of 25 ° C ± 5, the new crystal form of the product nilotinib hydrochloride according to Example 1 and the crystal form B prepared according to the method described in International Patent WO2007015870 were separately subjected to solvent equilibrium experiments with 1 mL of decyl alcohol and ethyl acetate. After at least 20 hours, the solution was filtered, dried in air for 10 minutes, and after evaporation of the solvent in vacuo, the approximate dissolution in the solvent was determined by gravimetric analysis. The results are shown in Table 2 below.

Table 2 Equilibrium experiment results with solvent at 25 ° C

As can be seen from Table 2, the crystal form prepared by the present invention has a solubility of 25% in sterol compared to Form B.

The novel crystal form and preparation method of nilotinib hydrochloride provided by the present invention are described in detail above. The above description of the embodiments is merely to assist in understanding the method of the present invention and its core idea. It should be noted that those skilled in the art will be able to devote themselves to the principles of the present invention without departing from the principles of the invention. A number of modifications and variations of the present invention are possible, and such modifications and modifications are also intended to fall within the scope of the appended claims.

Claims

Right to demand

It is characterized in that the crystal form of the nilotinib hydrochloride is Cu-Κα radiation, and the X-ray diffraction pattern expressed by the interplanar spacing d, the Bragg angle 2Θ and the relative intensity is as follows:

The method for preparing a crystal form of nilotinib hydrochloride according to claim 1, wherein: a) taking nilotinib free base dissolved in an organic solvent to obtain a first solution;

The preparation method according to claim 2, wherein the organic solvent is selected from the group consisting of an alcohol organic solvent, a hydrocarbon-based organic solvent, an ether organic solvent, a ketone organic solvent, and an ester organic solvent. A mixed solvent of an alcohol solvent and a hydrocarbon-based solvent.

The process according to claim 2, wherein the ether in the hydrochloric acid solution of the ether is diethyl ether, phenylpropyl ether, isopropyl ether or decyl tert-butyl ether.

The preparation method according to claim 2, wherein the nilotinib free base The ratio of the amount of the hydrochloric acid in the hydrochloric acid solution of the ether is 1: 0.95-1: 1.2.

The preparation method according to any one of claims 2 to 5, wherein the step b) comprises:

Bl) adding the first solution to the ether hydrochloric acid solution;

B2) Insulation.

7. The preparation method according to claim 6, wherein the step b) further comprises the step of cooling the hydrochloric acid hydrochloric acid solution to 5 V - 50 V.

8. The preparation method according to claim 7, wherein the dropping time in the step bl) is not more than 10 hours.

9. The preparation method according to claim 6, wherein the holding time in the step b2) is not more than 12 hours.

The preparation method according to any one of claims 2 to 5, wherein the step c) comprises:

Cl) filtering the product obtained by the reaction;

C2) drying the filtered product under vacuum;

C3) Dry the dried product at 40 ° C ~ 60 ° C.

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