CN112679473B

CN112679473B - Lenatinib intermediate crystal, preparation method and application thereof

Info

Publication number: CN112679473B
Application number: CN201910993519.7A
Authority: CN
Inventors: 王高; 马小波; 潘钧铸; 王晶翼
Original assignee: Sichuan Kelun Pharmaceutical Research Institute Co Ltd
Current assignee: Sichuan Kelun Pharmaceutical Research Institute Co Ltd
Priority date: 2019-10-18
Filing date: 2019-10-18
Publication date: 2024-03-05
Anticipated expiration: 2039-10-18
Also published as: CN112679473A

Abstract

The present application relates to lenatinib intermediate crystals, a preparation method and uses thereof. In particular to form II of intermediate a compound 6-amino-4- (3-chloro-4- (pyridin-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile, which comprises diffraction peaks at diffraction angles 2θ of 6.3, 7.8, 14.0, 15.1, 17.1, 18.8, 21.5, 22.2, 23.4 and 27.5 degrees in an XRPD pattern. The intermediate crystal form II of the invention is used for preparing lenatinib, which can obviously reduce the solvent consumption, shorten the reaction time, improve the yield and obviously reduce the residual quantity of the intermediate A in the final product.

Description

Lenatinib intermediate crystal, preparation method and application thereof

Technical Field

The invention relates to the field of medicine synthesis, in particular to a crystal of a lenatinib intermediate 6-amino-3-cyano quinoline derivative, a preparation method and application thereof in preparation of lenatinib.

Background

Lenatinib maleate (Neratinib Maleate) was originally developed by wheatstone corporation as an orally active, irreversible pan-human Epidermal Growth Factor Receptor (EGFR) inhibitor capable of inhibiting HER1, HER2 and HER4 receptors and their associated tyrosine kinases. The method is used for assisting in treating early HER2 over-expression and amplified breast cancer adult patients, prevents the signaling of the epidermal growth factor receptors HER1, HER2 and HER4 from being transferred, and achieves the purpose of resisting cancer.

In the reported synthesis of lenatinib maleate, the intermediate 6-amino-3-cyanoquinoline derivative (intermediate a) is basically used, its chemical name being: 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile (CAS number 848139-78-6) is subjected to chemical reaction to obtain the lenatinib, and then is further reacted with maleic acid to obtain the lenatinib maleate. The structural formula of the intermediate A is shown as follows:

chinese patent application CN 1761644A discloses a method for synthesizing lenatinib using intermediate a. Adding the solution of the intermediate A into the solution of 4-N, N-dimethyl amino crotonyl chloride hydrochloride, and controlling the end point of the reaction to be that the residual amount of the intermediate A is less than or equal to 0.5 percent. The reaction for preparing the lenatinib needs to use a large amount of organic solvent, and after the reaction is finished, more antisolvent needs to be added to precipitate and separate the product from the system. And the intermediate A has a genotoxicity warning structure, so that the residual quantity in the medicine needs to be controlled at a very low level, and the residual quantity of the intermediate A after the reaction is finished is relatively high, an additional purification process is required, and the yield is lost and meanwhile, the requirement of environmental protection is not met.

Chinese patent application CN 101203494A discloses intermediate a and further a process for synthesizing lenatinib from intermediate a, the synthetic route is as follows:

the patent reports that intermediate A is obtained by adopting a continuous feeding mode, and N- [4- [ 3-chloro-4- (2-pyridylmethoxy) aniline ] -3-cyano-7-ethoxy-6-quinolyl ] acetyl (compound B) is obtained under the condition of methanesulfonic acid/ethanol; the ethanol solution of the compound B is not separated, then hydrochloric acid aqueous solution is added into a reaction system, acetyl is removed under a hydrochloric acid/water/ethanol system, and hydrochloride of the intermediate A is obtained through crystallization, centrifugation and washing; the hydrochloride salt of intermediate a is then dissolved in a sodium carbonate/water/methanol solution and dried by centrifugation to give the free intermediate a.

The route in this patent application for the synthesis of lenatinib from intermediate a is similar to CN 1761644A, with the same problems.

The following drawbacks are common in the synthesis of lenatinib from intermediate a reported in the prior art: (1) A large amount of solvent is needed, more antisolvents are needed in the post-treatment process, the cost is high, and pollution is easy to cause; (2) The residue of the intermediate A in the final product is larger, the intermediate A needs to be removed by an additional refining step, the yield is lower, and the operation steps are increased; and (3) the reaction time is long, and the energy consumption is increased.

Therefore, it is important to develop an improved synthesis method for preparing lenatinib, which can reduce the use amount of organic solvents and the impurity residue.

Disclosure of Invention

In view of this, the present application aims to solve the above-mentioned technical problems. For this purpose, the invention provides crystals of 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile (intermediate A), a preparation method and use thereof.

In a first aspect the invention provides crystalline form II of 6-amino-4- (3-chloro-4- (pyridin-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile (intermediate a), which crystalline form II of intermediate a comprises characteristic peaks at diffraction angles (2Θ) of 6.3, 7.8, 14.0, 15.1, 17.1, 18.8, 21.5, 22.2, 23.4 and 27.5 degrees in a powder X-ray diffraction (XRPD) pattern, wherein the error range of the 2Θ values is ± 0.2 degrees.

Specifically, the XRPD pattern of form II of intermediate a includes diffraction peaks having diffraction angles (2θ) of 6.3, 7.8, 8.2, 11.2, 13.6, 14.0, 15.1, 15.8, 17.1, 18.8, 20.1, 21.5, 22.2, 23.4, 24.2, 27.0, 27.5, 28.6, and 32.1 degrees, wherein the error range of 2θ values is ± 0.2 degrees.

More specifically, the XRPD pattern of form II of intermediate a includes diffraction peaks having diffraction angles (2θ) of 6.3, 7.8, 8.2, 11.2, 12.7, 13.6, 14.0, 15.1, 15.8, 16.3, 17.1, 18.8, 19.3, 20.1, 21.5, 22.2, 22.6, 22.8, 23.4, 23.7, 24.2, 25.1, 27.0, 27.5, 28.6, 29.3, and 32.1 degrees, wherein the error range of the 2θ values is ± 0.2 degrees.

More specifically, the diffraction peaks and corresponding relative intensities in the XRPD pattern of form II of intermediate a are as follows:

wherein the error range of the 2 theta value is + -0.2 degrees.

Preferably, form II of intermediate a has a XPRD pattern substantially the same as that shown in fig. 1.

More preferably, the XRPD pattern of form II of intermediate a is as shown in figure 1.

In a second aspect the present invention provides a process for the preparation of crystalline form II of 6-amino-4- (3-chloro-4- (pyridin-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile, the process comprising the steps of: reacting N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide with 3-chloro-4- (pyridine-2-methoxy) aniline at 70 to 90 ℃ in a reaction solvent under methanesulfonic acid conditions, adding an aqueous solution of an alkaline salt to the reaction system to alkaline the pH value of the reaction solution, and filtering to obtain an N- [4- [ 3-chloro-4- (2-pyridylmethoxy) aniline ] -3-cyano-7-ethoxy-6-quinolinyl ] acetyl wet product; suspending the wet product in water, adding hydrochloric acid to react at 80-85 ℃, and filtering after the reaction is completed to obtain hydrochloride of 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile; and (3) re-suspending the hydrochloride in a mixed solution of potassium carbonate aqueous solution and alcohol, stirring for 0.5-12 h at room temperature, filtering, and drying to obtain the crystal form II.

Preferably, the reaction solvent is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.

Preferably, the pH value to alkaline means that the pH value is 7-12, preferably 8.

Preferably, the alkaline salt in the aqueous solution of the alkaline salt is selected from the group consisting of carbonates, bicarbonates and hydroxides of alkali metals; preferably selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide.

Preferably, in the mixed solution of the aqueous potassium carbonate solution and the alcohol, the alcohol is selected from methanol, ethanol and isopropanol; wherein, the volume ratio of the aqueous solution of potassium carbonate to the alcohol is 3:4.

preferably, the drying temperature is from 40 to 70 ℃, more preferably about 50 ℃.

Preferably, the hydrochloride of the intermediate A is obtained by reacting the wet product with hydrochloric acid, filtering and washing, wherein the washing reagent used in the washing is a mixed solvent of water and alcohol, and the alcohol comprises methanol, ethanol and isopropanol, but is not limited thereto, wherein the content of the alcohol is more than 40vol%, for example, 50vol%.

In a third aspect the present invention provides a process for the preparation of lenatinib or a pharmaceutically acceptable salt thereof comprising the step of preparing lenatinib from said crystalline form II of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile.

In a fourth aspect the invention provides crystalline form I of 6-amino-4- (3-chloro-4- (pyridin-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile (intermediate a), which crystalline form I of intermediate a mainly comprises characteristic peaks at diffraction angles (2θ) of 12.8, 16.0, 16.2, 16.4, 19.0, 20.5, 20.9, 23.2, 23.7, 25.5, 26.2 and 26.7 degrees in a powder X-ray diffraction (XRPD) pattern, wherein the error range of the 2θ values is ± 0.2 degrees.

Specifically, the XRPD pattern of form I of intermediate a includes diffraction peaks having diffraction angles (2θ) of 9.4, 11.4, 12.8, 16.0, 16.2, 16.4, 19.0, 19.6, 20.5, 20.9, 22.4, 23.2, 23.7, 25.5, 26.2, 26.7, 28.1, 28.5, 30.5, 31.1, 33.2, 34.7, 36.0, 37.4, and 38.0 degrees, wherein the error range of 2θ values is ± 0.2 degrees.

More specifically, the diffraction peaks and corresponding relative intensities of form I of intermediate a in the XRPD pattern are as follows:

wherein the error range of the 2 theta value is + -0.2 degrees.

More specifically, the XRPD pattern of form I of intermediate a is shown in figure 2.

In a fifth aspect the invention provides the use of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile in crystalline form for the preparation of lenatinib.

Wherein the crystalline form is selected from form I and form II.

Preferably, the present invention provides the use of crystalline form II of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile for the preparation of lenatinib.

The invention has the beneficial effects that the crystal form, especially the crystal form II, of the lenatinib intermediate A compound (6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile) is provided, the solvent consumption can be obviously reduced, the reaction time can be shortened, the yield can be improved, the residual quantity of the intermediate A in the final product can be obviously reduced, and the high-purity target product can be obtained, thereby being very beneficial to commercial production in the process of preparing the lenatinib.

Drawings

FIG. 1 is a powder X-ray diffraction pattern of form II of intermediate A prepared in example 1;

FIG. 2 is a powder X-ray diffraction pattern of form I of intermediate A prepared in example 2;

FIG. 3 is a powder X-ray diffraction pattern of intermediate A prepared in comparative example 1.

Detailed Description

The following description of the embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some, but not all embodiments of the invention. All other embodiments, based on the embodiments of the invention, which are apparent to those of ordinary skill in the art without inventive faculty, are intended to be within the scope of the invention.

Definition of the definition

Throughout the specification, unless specifically indicated otherwise, the terms used herein should be understood as meaning as commonly used in the art. Accordingly, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification will control.

The term "crystalline form" or "crystal" as used herein refers to any solid material that exhibits a three-dimensional ordering, as opposed to an amorphous solid material, that produces a characteristic XRPD pattern with well-defined peaks.

The term "X-ray powder diffraction pattern (XRPD pattern)" as used herein refers to experimentally observed diffraction patterns or parameters, data or values derived therefrom. XRPD patterns are typically characterized by peak position (abscissa) and/or peak intensity (ordinate).

The term "2θ" as used herein refers to the peak position in degrees (degrees) set based on X-ray diffraction experiments and is typically the unit of abscissa in the diffraction pattern. If the incident beam is diffracted by reflection when it makes an angle θ with a certain lattice plane, the experimental setup requires recording the reflected beam at an angle 2θ. Unless otherwise specified, the error range of the 2θ value is ±0.2 degrees.

As used herein, the term "substantially the same" means taking into account representative peak positions and/or intensity variations. For example, for an X-ray diffraction peak, one skilled in the art will appreciate that the peak position (2θ) will show some variation, typically up to 0.1-0.2 degrees, and that the instrument used to measure diffraction will also cause some variation. In addition, one skilled in the art will appreciate that the relative peak intensities will vary due to differences between instruments as well as the degree of crystallinity, preferred orientation, surface of the sample prepared, and other factors known to those skilled in the art.

The term "room temperature" as used herein refers to 10 to 30 ℃.

The reagents used in the examples below are all commercially available.

All the following test methods are general methods, and the test parameters are as follows:

xrpd pattern testing method:

test equipment: x' Pert3 Power X-ray diffraction analyzer

Test conditions: cu kα1=1.5406A, monochromatic radiation, voltage: 40kV and current: excitation of 40mA, start angle 3.5 degrees, end angle 40 degrees, step size: 0.013 degrees, residence time: 50s.

Hplc detection method:

test equipment: agilent 1260 high performance liquid chromatography

Chromatographic column: c18 column

Mobile phase a: phosphate buffer-methanol

Mobile phase B: aqueous methanol solution

Gradient elution, flow rate: 1.0mL/min, wavelength: 266nm; sample injection volume: 20 _μ L, column temperature: 45 DEG C

Preparation of intermediate a:

example 1 preparation of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino]-7-ethoxy-3-quinoline Form II of formonitrile (intermediate A)

N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide (20.0 g,0.069 mol), 3-chloro-4- (pyridin-2-methoxy) aniline (24.3 g,0.103 mol), methanesulfonic acid (0.66 g) were heated to 70 to 75℃in N, N-dimethylformamide (200 mL) at room temperature (20 to 30 ℃) and reacted with stirring. After the reaction is completed, the temperature is reduced to 20-30 ℃, potassium carbonate aqueous solution (20 g in 60mL of water) is added to adjust the pH to be alkaline, suction filtration is carried out, the filter cake is washed three times by purified water (100 mL), and a wet product is obtained after suction drying. The wet product was suspended in purified water (450 mL) to form a suspension, concentrated hydrochloric acid (76.5 mL) was added with stirring, and the temperature was raised to 80-85℃for reaction. Cooling to 20-30 ℃ after the reaction is completed, filtering, washing a filter cake by using a mixed solvent of water and ethanol (1:2, 45 mL), and drying to obtain a wet product. The wet product was resuspended in aqueous potassium carbonate (8 g in 90 mL) and methanol (120 mL), and kept at 20-30deg.C for 2h with stirring, suction filtered, the filter cake was washed 2 times with water (200 mL), then with a mixed solvent of water and methanol (3:4, 200 mL), and the wet product was dried by suction to give the title compound after vacuum drying at 50deg.C. The title compound was subjected to XRPD detection, the powder X-ray diffraction data are shown in table 1, and the powder X-ray diffraction pattern is shown in fig. 1, which is form II.

Table 1 powder X-ray diffraction data for form II of intermediate a

EXAMPLE 2 preparation of intermediate A, form I

6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile (form II) (5 g) (prepared as described in example 1) is suspended in N, N-dimethylacetamide (10 mL), heated to 80-85℃for 2h with stirring, subsequently cooled to 20-30℃filtered with suction and washed with purified water (10 mL) and the resulting filter cake dried in vacuo at 40-50℃for at least 20h to give the title compound. The title compound was subjected to XRPD detection, the powder X-ray diffraction data are shown in table 2, and the powder X-ray diffraction pattern is shown in fig. 2, which is form I.

TABLE 2 powder X-ray diffraction data for form I of intermediate A

EXAMPLE 3 preparation of intermediate A, form I

6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile (form II) (5 g) (prepared as described in example 1) is suspended in N-methylpyrrolidone (10 mL), heated to 80-85℃for 2h with stirring, subsequently cooled to 20-30℃filtered with suction and washed with purified water (10 mL) and the resulting filter cake is dried in vacuo at 40-50℃for at least 20h to give the title compound. The title compound was subjected to XRPD detection with a pattern consistent with figure 2, form I.

Comparative example 1 preparation of intermediate A using the prior art method

Intermediate A was prepared by the method disclosed in example 1, 3a/4a/5 of patent CN 101203494A.

N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide (33.3 g,0.142 mol), 3-chloro-4- (pyridin-2-methoxy) aniline (35.0 g,0.11 mol) and methanesulfonic acid (0.2 mL) were heated to 70 to 75℃in ethanol (480 mL) and stirred for 2h before detection. After the reaction was completed, ethanol (160 mL) and concentrated hydrochloric acid (138 mL) were added to the reaction solution to adjust the pH to a range of 1 to 3, and the reaction was stirred at 70 to 75 ℃, ethanol (80 mL) was added to the reaction solution after 1 hour to facilitate the stirring, purified water (680 mL) was added after 2 hours, and the mixture was stirred for 1 hour, cooled to 35 to 45 ℃ and stirred overnight. Filtering at 35-45 deg.c, rinsing the filter cake with mixed ethanol and water solvent (1:1, 84 mL) for 2 times, and draining. Transferring the filter cake to a flask, adding methanol (720 mL) and 10% potassium carbonate solution (22 g of potassium carbonate dissolved in 227mL of water), adjusting the pH of the system to be alkaline, filtering, washing with a mixed solvent of methanol and water (1:1, 84 mL), and drying to obtain a wet product, and drying the wet product in vacuum at 50 ℃ to obtain the title compound. The title compound was subjected to XRPD detection and its powder X-ray diffraction pattern is shown in fig. 3.

The powder X-ray diffraction spectrogram of the intermediate A prepared by the method is different from that of the crystal forms I and II. It can be seen that the conventional preparation method cannot obtain neither form I nor form II.

The properties of the different crystalline forms of intermediate a are further illustrated by the following test examples.

Test example: solubility experiment of intermediate A

In the synthesis of lenatinib, N-Dimethylacetamide (DMA) and N-methylpyrrolidone (NMP) are generally used as reaction solvents. Thus, the present invention examined the solubility of the three crystal forms of intermediate a prepared in example 1, example 2 and comparative example 1 in N, N-Dimethylacetamide (DMA) and N-methylpyrrolidone (NMP), respectively, at room temperature, and the results are shown in table 3.

TABLE 3 solubility of intermediate A

From the above table, it can be seen that the form II has better solubility than the form I and the intermediate a prepared in comparative example 1, and can be well dissolved in DMA and NMP, which is beneficial to the conversion of the reaction process.

The following examples used intermediate a to prepare lenatinib, the synthetic route is shown in the following figure:

example 4-1 preparation of (E) -N- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) benzene from Crystal form II of intermediate A Group) amino) -3-cyano-7-ethoxyquinolin-6-yl) -4- (dimethylamino) but-2-enamide (lenatinib)

A solution of 4-N, N-dimethylaminocrotonic acid hydrochloride (108 g,0.65 mol) in tetrahydrofuran (1.13L) and a catalytic amount of N, N-dimethylformamide (1.2 mL) was cooled to 0-5 ℃. Oxalyl chloride (55 mL,0.62mol,0.95 eq) was added dropwise over 50 min. The mixture is then heated to 25-30 ℃ and stirred for 2h, after which it is cooled to 0-5 ℃. N-methylpyrrolidone (0.225L) was added thereto over 25min while maintaining the temperature at 0 to 5℃and then a solution of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile (form II) (150 g,0.32 mol) prepared in example 1 in N-methylpyrrolidone (0.75L) was added dropwise over 2h. The mixture is stirred for at least about 3 hours, heated to 10-15 ℃ and stirred for a further 12 hours. The mixture was cooled to 0-10 ℃, the reaction was stopped by adding purified water (1.8L) over 2h, and stirred for 30min. The mixture was heated to 40℃and aqueous sodium hydroxide (101 g in 0.75L of water) was added over 1h to bring the pH to 10-11. The mixture was stirred for 1h, filtered off while hot (40 ℃) and washed 2 times with water until the final wash had a pH of around 7, the filter cake was further washed with ethanol and water mixed solvent and then dried under vacuum at 50-60℃for at least 16h to give 0.175Kg of the title compound. Yield 98%, HPLC purity 99.6%, HPLC detection intermediate a residual amount 0.12%.

Example 4-2 preparation of lenatinib from Crystal form I of intermediate A

A solution of 4-N, N-dimethylaminocrotonic acid hydrochloride (108 g,0.65 mol) in tetrahydrofuran (1.13L) and a catalytic amount of N, N-dimethylformamide (1.2 mL) was cooled to 0-5 ℃. Oxalyl chloride (55 mL,0.62mol,0.95 eq) was added dropwise over 50 min. The mixture was then warmed to 25-30 ℃ and stirred for 2h, after which it was cooled to 0-5 ℃. N-methylpyrrolidone (0.225L) was added over 25min while maintaining the temperature at 0 to 5℃and then a suspension of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile (form I) (150 g,0.32 mol) prepared in example 2 in N-methylpyrrolidone (0.75L) was added dropwise over 2h. The mixture is stirred for at least about 3 hours, heated to 10-15 ℃ and stirred for a further 12 hours. The mixture was cooled to 0-10 ℃, the reaction was stopped by adding purified water (1.8L) over 2h, and stirred for 30min. The mixture was heated to 40℃and aqueous sodium hydroxide (101 g in 0.75L of water) was added over 1h to bring the pH to 10-11. The mixture was stirred for 1h, filtered off while hot (40 ℃) and washed 2 times with water until the final wash had a pH of around 7, the filter cake was further washed with ethanol and water mixed solvent, followed by vacuum drying at 50-60℃for at least 16h to give 0.151Kg of the title compound. Yield 72%, HPLC purity 74.6%, HPLC detection intermediate a residual amount 23.7%.

Examples 4-3 preparation of lenatinib from form I of intermediate a

A solution of 4-N, N-dimethylaminocrotonic acid hydrochloride (108 g,0.65 mol) in tetrahydrofuran (1.13L) and a catalytic amount of N, N-dimethylformamide (1.2 mL) was cooled to 0-5 ℃. Oxalyl chloride (55 mL,0.62mol,0.95 eq) was added dropwise over 50 min. The mixture was then warmed to 25-30 ℃ and stirred for 2h, after which it was cooled to 0-5 ℃. N-methylpyrrolidone (0.225L) was added over 25min while maintaining the temperature at 0 to 5℃and then a suspension of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile (form I) (150 g,0.32 mol) prepared in example 2 in N-methylpyrrolidone (1.8L) was added dropwise over 2h. The mixture is stirred for at least about 3 hours, heated to 10-15 ℃ and stirred for a further 12 hours. The mixture was cooled to 0-10 ℃, the reaction was stopped by adding purified water (1.8L) over 2h, and stirred for 30min. The mixture was heated to 40℃and aqueous sodium hydroxide (101 g in 0.75L of water) was added over 1h to bring the pH to 10-11. The mixture was stirred for 1h, filtered off while hot (40 ℃) and washed 2 times with water until the final wash had a pH of around 7, the filter cake was further washed with ethanol and water mixed solvent and then dried in vacuo at 50-60℃for at least 16h to give 0.146Kg of the title compound. Yield 91%, HPLC purity 95.7%, HPLC detection intermediate a residual amount 3.2%.

Example 5-1 preparation of lenatinib from form II of intermediate A

4-N, N-dimethyl amino crotonic acid hydrochloride (67 g,0.40 mol) is added into N, N-dimethyl acetamide (640 g), cooled to-14 to-19 ℃, phosphorus oxychloride (61 g,0.40 mol) is added dropwise, the temperature is kept in the range during the dripping process, and the mixture is reacted for 2-3 hours at-15 ℃. A solution of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile (form II) (126 g,0.28 mol) in N, N-dimethylacetamide (1 Kg) was added at-14 to-19℃and then reacted at-15℃for 5h, the remaining intermediate A was monitored as < 0.5%, after the reaction was completed 870g of water was added to quench it, the temperature was raised to 37-42℃and the pH was adjusted to 10-11 using 25% KOH solution, 950g of water was added for further dilution, suction filtration, washing, drying at 45-50℃and 160g of the title compound was recovered in 95% yield, 99.6% HPLC purity, and the residual amount of intermediate A was 0.11% by HPLC detection.

Example 5-2 preparation of lenatinib from Crystal form I of intermediate A

4-N, N-dimethyl amino crotonic acid hydrochloride (67 g,0.40 mol) is added into N, N-dimethyl acetamide (640 g), cooled to-14 to-19 ℃, phosphorus oxychloride (61 g,0.40 mol) is added dropwise, the temperature is kept in the range during the dripping process, and the mixture is reacted for 2-3 hours at-15 ℃. A suspension of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile (form I) (126 g,0.28 mol) in N, N-dimethylacetamide (1.3 Kg) was added at-14 to-19℃and then reacted at-15℃for 5h, the liquid phase was monitored for more intermediate A remaining unconverted, 870g of water was then added at-7 to-16℃to quench it, the temperature was raised to 37-42℃and the pH was adjusted to 10-11 using 25% KOH solution, 950g of water was added for further dilution, suction filtration, washing and drying at 45-50℃to yield 143g of the title compound in 85% yield, 93.5% HPLC purity, the residual amount of intermediate A was 6.1% HPLC detection.

Example 6 preparation of lenatinib from form II of intermediate a

A solution of 4-N, N-dimethylaminocrotonic acid hydrochloride (2.16 Kg,13.0 mol) in tetrahydrofuran (22.6L) and a catalytic amount of N, N-dimethylformamide (24 mL) was cooled to 0-5 ℃. Oxalyl chloride (1100 mL,13.0mol,0.95 eq) was added dropwise over 50 min. The mixture was then warmed to 25-30 ℃ and stirred for 2h, after which it was cooled to 0-5 ℃. N-methylpyrrolidone (4.5L) was added thereto over 25min while maintaining the temperature at 0 to 5℃and then a solution of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile (form II) (3.0 Kg,6.4 mol) prepared in example 1 in N-methylpyrrolidone (15.0L) was added dropwise over 2h. The mixture is stirred for at least about 3 hours, heated to 10-15 ℃ and stirred for a further 12 hours. The mixture was cooled to 0-10 ℃, quenched by the addition of purified water (36.0L) over 2h, and stirred for 30min. The mixture was heated to 40℃and aqueous sodium hydroxide (2.02 Kg in 15.0L of water) was added over 1h to bring the pH to 10-11. The mixture was stirred for 1h, filtered off while hot (40 ℃) and washed 2 times with water until the final wash had a pH of around 7, the filter cake was further washed with ethanol and water mixed solvent and then dried in vacuo at 50-60℃for at least 16h to give 3.48Kg of the title compound. Yield 98%, HPLC purity 99.6%, HPLC detection intermediate a residual amount 0.13%.

From examples 4 to 6, it can be seen that when the crystal form I of the intermediate A is used for preparing lenatinib, the final product has low yield and purity and large residual amount of the intermediate A under the condition of the same solvent consumption, and the requirements of production and quality cannot be met. If the solvent consumption is increased, the reaction yield and purity can be improved to a certain extent, the residual quantity of the intermediate A is reduced, but a larger quantity of anti-solvent is needed to be added after the reaction is finished to obtain the target product.

When the intermediate A crystal form II is adopted to prepare the lenatinib, the reaction solvent consumption is greatly reduced, the reaction yield is over 95 percent, the purity of the final product is up to 99.6 percent, no additional refining or pulping treatment is needed, the residual quantity of the intermediate A is not higher than 0.13 percent, and the high-quality medicinal requirement is met.

The foregoing description is only of the preferred embodiments of the present invention, and is not intended to limit the scope of the invention, but rather, the equivalent structural changes made by the description of the present invention and the accompanying drawings or the direct/indirect application in other related technical fields are included in the scope of the invention.

Claims

Form II of 6-amino-4- (3-chloro-4- (pyridin-2-substituted-methoxy) aniline) -7-ethoxyquinoline-carbonitrile, characterized in that the form II comprises diffraction peaks at diffraction angles 2Θ of 6.3, 7.8, 8.2, 11.2, 12.7, 13.6, 14.0, 15.1, 15.8, 16.3, 17.1, 18.8, 19.3, 20.1, 21.5, 22.2, 22.6, 22.8, 23.4, 23.7, 24.2, 25.1, 27.0, 27.5, 28.6, 29.3 and 32.1 degrees, wherein the error range of 2Θ values is ± 0.2 degrees.
2. Form II of claim 1, wherein the XRPD pattern of form II is as shown in figure 1.
3. A process for the preparation of crystalline form II of 6-amino-4- (3-chloro-4- (pyridin-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile according to claim 1 or 2, characterized in that the process comprises the steps of: under the condition of methanesulfonic acid, N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide and 3-chloro-4- (pyridine-2-methoxy) aniline react at 70-90 ℃ in a reaction solvent, then an aqueous solution of an alkaline salt is added into the reaction system to enable the pH value of the reaction solution to be alkaline, and the reaction solution is filtered to obtain an N- [4- [ 3-chloro-4- (2-pyridylmethoxy) aniline ] -3-cyano-7-ethoxy-6-quinolyl ] acetamide wet product; suspending the wet product in water, adding hydrochloric acid to react at 80-85 ℃, and filtering after the reaction is completed to obtain hydrochloride of 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile; and (3) re-suspending the hydrochloride in a mixed solution of potassium carbonate aqueous solution and alcohol, stirring for 0.5-12 h at room temperature, filtering, and drying to obtain the crystal form II.
4. A process for the preparation of form II according to claim 3, wherein the reaction solvent is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
5. The process for preparing form II according to claim 3, wherein the pH to alkaline means pH 7 to 12.
6. The process for preparing form II according to claim 5, wherein the pH to alkaline means pH 8.
7. A process for the preparation of form II according to claim 3, wherein the basic salt in aqueous solution of the basic salt is selected from the group consisting of alkali metal carbonates and bicarbonates.
8. The process for the preparation of form II according to claim 7, wherein the alkaline salt in the aqueous solution of the alkaline salt is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.
9. A process for the preparation of form II according to claim 3, wherein the alcohol is selected from the group consisting of methanol, ethanol and isopropanol in a mixed solution of the aqueous potassium carbonate solution and the alcohol; wherein, the volume ratio of the aqueous solution of potassium carbonate to the alcohol is 3:4.
10. a process for the preparation of lenatinib or a pharmaceutically acceptable salt thereof, comprising the step of preparing lenatinib from crystalline form II of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile according to claim 1 or 2.
11. Use of crystalline form II of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile according to claim 1 or 2 for the preparation of lenatinib.