CN106883250B

CN106883250B - Preparation method of C-Met tyrosine kinase inhibitor

Info

Publication number: CN106883250B
Application number: CN201510934569.XA
Authority: CN
Inventors: 杨宝海; 朱强; 潘必高
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd
Current assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority date: 2015-12-15
Filing date: 2015-12-15
Publication date: 2021-05-18
Anticipated expiration: 2035-12-15
Also published as: WO2017101885A1; CN108473509A; CN106883250A

Abstract

The invention relates to a preparation method of a C-Met tyrosine kinase inhibitor. In particular to a compound 9- ((8-fluoro-6- (1-methyl-1H-pyrazol-4-yl) - [1,2,4] shown as a formula (I)]Triazolo [4,3-a]Pyridin-3-yl) -thio) -4-carboxylic acid methyl esterradical-2H- [1,4]Oxazino [3,2-c]The preparation method of the crystal form III of the mesylate of the quinoline-3 (4H) -ketone has the advantages of short process route, mild and controllable reaction conditions, small pollution, high product yield and high purity, and is very suitable for industrial production.

Description

Preparation method of C-Met tyrosine kinase inhibitor

Technical Field

The invention relates to the field of medicine production, and in particular relates to a preparation method of a mesylate crystal form III of 9- ((8-fluoro-6- (1-methyl-1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a ] pyridin-3-yl) -thio) -4-methyl-2H- [1,4] oxazino [3,2-c ] quinolin-3 (4H) -one.

Background

The 9- ((8-fluoro-6- (1-methyl-1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a ] pyridine-3-yl) -thio) -4-methyl-2H- [1,4] oxazino [3,2-C ] quinoline-3 (4H) -ketone (the compound of the formula (I) for short) is researched and developed by Jiangsu Hawson company, is a C-Met tyrosine kinase inhibitor, can effectively block an HGF/C-Met signal transduction pathway, and achieves the aim of treating abnormal cell growth (such as cancer) of mammals.

A compound of formula (I)

The mesylate crystal form III of the compound shown in the formula (I) has the characteristics of high solubility and good stability, and is particularly suitable for pharmaceutical preparations. CN 201410378371.3 discloses for the first time a process for the preparation of the mesylate salt form III of the compound of formula (I) by dissolving the compound of formula (I) in methanol in a HPLC vial, adding a solution of methanesulfonic acid, stirring at room temperature for about 2 days, and then drying in a vacuum oven at 100 ℃ for 1 day to give the mesylate salt form III of the compound of formula (I). The method has the advantages of long reaction time, increased cost of industrial production, low yield, reduced production efficiency and no contribution to industrial scale-up production.

Therefore, there is a need to develop a more economical and environmentally friendly industrial process for preparing the compound of formula (I) in crystalline form III.

Disclosure of Invention

The invention aims to overcome the defects in the prior art and provides a method for industrially producing the mesylate crystal form III of the compound shown in the formula (I).

A compound of formula (I)

The invention relates to a method for industrially producing a mesylate salt crystal form III of a compound shown as a formula (I), which comprises the following steps: the compound is obtained by salt-forming crystallization of a compound shown in a formula (I) and methanesulfonic acid in a dipolar aprotic solvent or a nonpolar solvent.

Preferably, the preparation method comprises the following steps: dissolving the compound of the formula (I) in a dipolar aprotic solvent or a nonpolar solvent, adding methanesulfonic acid, filtering, stirring the filtrate, and crystallizing to obtain the mesylate crystal form III of the compound of the formula (I).

Preferably, the molar ratio of compound of formula (I) to methanesulfonic acid is 1:1 to 10, more preferably 1:3 to 5, most preferably 1:3 to 4.

Preferably, the mass to volume (g/ml) ratio of the compound of formula (I) to the dipolar aprotic solvent is 1: 5-15, more preferably 1: 8-10, most preferably 1: 10.

Preferably, the mass to volume (g/L) ratio of the compound of formula (I) to the non-polar solvent is 1: 5-15, more preferably 1: 8-10, most preferably 1: 9.

Preferably, the dipolar aprotic solvent is selected from acetone, acetonitrile, N-dimethylformamide or dimethylsulfoxide; more preferably N, N-dimethylformamide.

Preferably, the non-polar solvent is selected from dichloromethane, ethyl acetate or tetrahydrofuran; more preferably dichloromethane.

Preferably, the stirring temperature is from 0 ℃ to 50 ℃, more preferably from 20 ℃ to 30 ℃, most preferably from 20 ℃ to 25 ℃.

Preferably, the stirring time is 1-24 hours, and more preferably 7-10 hours.

Particularly preferably, the present invention provides a process for the industrial production of the mesylate salt form III of the compound of formula (I), comprising the steps of: adding a compound shown in the formula (I) and N, N-dimethylformamide into a reaction container, dropwise adding 3-4 equivalents of methanesulfonic acid, controlling the temperature to be 20-25 ℃, and stirring; filtering, and stirring the filtrate at 20-25 ℃ for reaction; filtering, and washing a filter cake by using N, N-dimethylformamide; and drying the filter cake at 105 ℃ in vacuum to obtain the mesylate crystal form III of the compound shown in the formula (I).

The invention has the following technical effects:

1. the mesylate crystal form III of the compound shown in the formula (I) prepared by the method has good stability, and influence factor tests show that the crystal form III sample does not generate crystal form transformation and chemical degradation when placed for 10 days under the conditions of high temperature (60 ℃), high humidity (25 ℃/RH 92.5%) and strong light.

2. The method has the advantages of short process route, mild and controllable reaction conditions, low pollution and suitability for industrial production;

3. the final product does not need to be refined and transformed after salifying, the required crystal form is directly obtained, the product yield is high, the purity is high, the product yield reaches more than 80%, and the purity reaches more than 99%.

Drawings

FIG. 1: an X-powder diffraction pattern of mesylate salt form III of 9- ((8-fluoro-6- (1-methyl-1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a ] pyridin-3-yl) -thio) -4-methyl-2H- [1,4] oxazino [3,2-c ] quinolin-3 (4H) -one.

Detailed Description

In order to make the technical problems, technical solutions and advantageous effects solved by the present invention more apparent, the present invention is further described in detail below with reference to the following embodiments. But is not intended to be limiting and all equivalent alterations in the field that are made in accordance with this disclosure are intended to be embraced by the present invention.

Example 1

Adding 9- ((8-fluoro-6- (1-methyl-1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a ] pyridine-3-yl) -thio) -4-methyl-2H- [1,4] oxazino [3,2-c ] quinolin-3 (4H) -one (450g) and N, N-dimethylformamide (4.5L) into a three-neck flask, dropwise adding methanesulfonic acid (373g), controlling the temperature to be 20-25 ℃, and stirring for 50-60 minutes; filtering, and stirring and reacting the filtrate for 7-8 hours at the temperature of 20-25 ℃; filtering, and washing a filter cake by using N, N-dimethylformamide (300 mL); and (3) drying the filter cake for 15-16 hours in vacuum at 105 ℃ to obtain the mesylate crystal form III (464g) of the 9- ((8-fluoro-6- (1-methyl-1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a ] pyridin-3-yl) -thio) -4-methyl-2H- [1,4] oxazino [3,2-c ] quinolin-3 (4H) -one, wherein the yield is 85.3%, the purity is 99.9%, and the X-powder diffraction pattern is shown in figure 1.

Example 2

Adding 9- ((8-fluoro-6- (1-methyl-1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a ] pyridin-3-yl) -thio) -4-methyl-2H- [1,4] oxazino [3,2-c ] quinolin-3 (4H) -one (450g) and dichloromethane (4.0L) into a three-necked bottle, dropwise adding methanesulfonic acid (373g), controlling the temperature to be 20-25 ℃, and stirring for 50-60 minutes; filtering, and stirring and reacting the filtrate for 7-8 hours at the temperature of 20-25 ℃; filtration and washing of the filter cake with dichloromethane (300 mL); and (3) drying the filter cake for 15-16 hours in vacuum at 100 ℃ to obtain the mesylate crystal form III (461g) of the 9- ((8-fluoro-6- (1-methyl-1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a ] pyridin-3-yl) -thio) -4-methyl-2H- [1,4] oxazino [3,2-c ] quinolin-3 (4H) -one, wherein the yield is 84.6%, the purity is 99.4%, and the X-powder diffraction pattern is basically shown in figure 1.

Example 3

Adding 9- ((8-fluoro-6- (1-methyl-1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a ] pyridin-3-yl) -thio) -4-methyl-2H- [1,4] oxazino [3,2-c ] quinolin-3 (4H) -one (2.3kg) and N, N-dimethylformamide (22.0L) into a three-neck flask, dropwise adding methanesulfonic acid (1.5kg), controlling the temperature to be 20-25 ℃, and stirring for 50-60 minutes; filtering, and stirring and reacting the filtrate for 9-10 hours at the temperature of 20-25 ℃; filtering, washing the filter cake with N, N-dimethylformamide (1.0L); and (3) drying the filter cake for 15-16 hours in vacuum at 105 ℃ to obtain the mesylate crystal form III (2.35kg) of 9- ((8-fluoro-6- (1-methyl-1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a ] pyridin-3-yl) -thio) -4-methyl-2H- [1,4] oxazino [3,2-c ] quinolin-3 (4H) -one, wherein the yield is 84.7%, the purity is 99.5%, and the X-powder diffraction pattern is basically shown in figure 1.

EXAMPLE 4 product stability study

The mesylate salt form III sample prepared in example 1 was left open to the atmosphere for 10 days under high temperature, high humidity and light conditions, and the appearance of the crystal was observed periodically and the content of the mesylate salt of the compound of formula (I) in the sample was examined for changes, the results of which are shown in table 1.

Table 1 the results of the examination under different influence factors are as follows:

the result shows that the appearance and the content of the crystal form III of the mesylate prepared by the method do not have physical change and chemical change, which shows that the crystal form III of the mesylate prepared by the method has stable and controllable quality, is convenient to store and transport and meets the requirement of medical use.

Claims

1. A process for the preparation of the mesylate salt form III of the compound of formula (I), characterized in that it is prepared by salting out the crystals of the compound of formula (I) in a dipolar aprotic solvent or a nonpolar solvent,

wherein the dipolar aprotic solvent is selected from N, N-dimethylformamide;

the non-polar solvent is selected from dichloromethane;

the preparation method comprises the following steps: dissolving the compound of formula (I) in a dipolar aprotic solvent or a nonpolar solvent, adding methanesulfonic acid, filtering, and stirring the filtrate for crystallization.

2. The process according to claim 1, wherein the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:1 to 10.

3. The process according to claim 1, wherein the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:3 to 5.

4. The process according to claim 1, wherein the molar ratio of the compound of formula (I) to methanesulfonic acid is 1:3 to 4.

5. The process according to claim 1, wherein the mass to volume ratio of the compound of formula (I) to the dipolar-aprotic solvent is 1 g: 5-15 ml.

6. The process according to claim 1, wherein the mass to volume ratio of the compound of formula (I) to the dipolar-aprotic solvent is 1 g: 8-10 ml.

7. The process according to claim 1, wherein the mass to volume ratio of the compound of formula (I) to the dipolar-aprotic solvent is 1 g: 10 ml.

8. The preparation method according to claim 1, wherein the mass-to-volume ratio of the compound of formula (I) to the nonpolar solvent is 1 g: 5-15 ml.

9. The preparation method according to claim 1, wherein the mass-to-volume ratio of the compound of formula (I) to the nonpolar solvent is 1 g: 8-10 ml.

10. The preparation method according to claim 1, wherein the mass-to-volume ratio of the compound of formula (I) to the nonpolar solvent is 1 g: 9 ml.

11. The method according to claim 1, wherein the stirring temperature is 0 ℃ to 50 ℃.

12. The method according to claim 1, wherein the stirring temperature is 20 ℃ to 30 ℃.

13. The method according to claim 1, wherein the stirring temperature is 20 ℃ to 25 ℃.

14. The preparation method according to claim 1, wherein the stirring time is 1 to 24 hours.

15. The preparation method according to claim 1, wherein the stirring time is 7 to 10 hours.