CN112679473A

CN112679473A - Lenalitinib intermediate crystal, preparation method and application thereof

Info

Publication number: CN112679473A
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: 2021-04-20
Anticipated expiration: 2039-10-18
Also published as: CN112679473B

Abstract

The application relates to a lenatinib intermediate crystal, a preparation method and application thereof. In particular, it relates to crystalline form II of the intermediate a compound 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile, which comprises diffraction peaks at diffraction angles 2 Θ 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 method for preparing the neratinib by using the intermediate crystal form II can obviously reduce the using amount of a solvent, shorten the reaction time, improve the yield and simultaneously obviously reduce the residual amount of the intermediate A in a final product.

Description

Lenalitinib intermediate crystal, preparation method and application thereof

Technical Field

The invention relates to the field of drug synthesis, and particularly relates to a crystal of a neratinib intermediate 6-amino-3-cyano quinoline derivative, a preparation method and application of the crystal in preparation of neratinib.

Background

Neratinib Maleate, originally developed by hui corporation, is an orally effective, irreversible pan-human Epidermal Growth Factor Receptor (EGFR) inhibitor capable of inhibiting HER1, HER2 and HER4 receptors and their associated tyrosine kinases. The composition is used for adjuvant treatment of early-stage HER2 overexpression and amplification breast cancer adult patients, prevents the signaling pathways of epidermal growth factor receptors HER1, HER2 and HER4 from being transferred, and achieves the aim of resisting cancers.

In the reported synthetic methods of neratinib maleate, an intermediate 6-amino-3-cyanoquinoline derivative (intermediate a) having the chemical name: the 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxy) aniline) -7-ethoxy quinoline-carbonitrile (CAS number 848139-78-6) undergoes a chemical reaction to obtain the neratinib, and then further reacts with maleic acid to obtain the neratinib maleate. The structural formula of the intermediate A is shown as follows:

chinese patent application CN 1761644 a discloses a method for synthesizing neratinib using intermediate a. Adding the solution of the intermediate A into the 4-N, N-dimethylaminocrotonyl chloride hydrochloride solution, and controlling the end point of the reaction to be that the residual quantity of the intermediate A is less than or equal to 0.5 percent. The reaction for preparing the neratinib needs to use a large amount of organic solvent, and more anti-solvent needs to be added after the reaction is finished to precipitate the product out of the system. And because the intermediate A has a genotoxicity warning structure, 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 higher, an additional purification process needs to be added, so that the yield loss is reduced, and the requirement of environmental protection is not met.

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

the patent reports that the 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 firstly under the condition of methane sulfonic acid/ethanol; the ethanol solution of the compound B is not separated, then hydrochloric acid aqueous solution is added into the reaction system, acetyl is removed in 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 was then desalted in sodium carbonate/water/methanol solution and dried by centrifugation to yield the free intermediate a.

The route for synthesizing neratinib from intermediate a in this patent application is similar to CN 1761644 a and suffers from the same problems.

The synthetic process for preparing neratinib from the intermediate A reported in the prior art generally has the following defects: (1) a large amount of solvent is needed, more anti-solvent is needed in the post-treatment process, the cost is high, and the pollution is easy to cause; (2) the residue of the intermediate A in the final product is large, an additional refining step is needed for removing, the yield is low, and the operation steps are increased; (3) long reaction time and increased energy consumption.

Therefore, it is very important to develop an improved synthetic method for preparing neratinib, which can reduce the usage amount of organic solvents and the residual amount of impurities.

Disclosure of Invention

In view of the above, the present application aims to solve the above technical problems. To this end, the invention provides crystals of 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile (intermediate a), a process for their preparation and their use.

A first aspect of the invention provides a crystalline form II of 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile (intermediate a) which comprises characteristic peaks at diffraction angles (2 Θ) 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 for the 2 Θ values is ± 0.2 degrees.

Specifically, the XRPD pattern of form II of intermediate a includes diffraction peaks at diffraction angles (2 θ) 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, with a 2 θ value error range of ± 0.2 degrees.

More specifically, the XRPD pattern of form II of intermediate a includes diffraction peaks at diffraction angles (2 θ) 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, with a 2 θ value error range of ± 0.2 degrees.

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

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

Preferably, said crystalline form II of intermediate a has an XPRD pattern substantially the same as shown in figure 1.

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

A second aspect of the invention provides a process for the preparation of crystalline form II of 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile, which comprises the steps of: reacting N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide with 3-chloro-4- (pyridine-2-methoxy) aniline at 70-90 ℃ in a reaction solvent under the condition of methanesulfonic acid, adding an aqueous solution of an alkaline salt into a reaction system to make the pH value of a reaction liquid alkaline, and filtering to obtain wet N- [4- [ 3-chloro-4- (2-pyridylmethoxy) aniline ] -3-cyano-7-ethoxy-6-quinolyl ] acetyl; suspending the wet product in water, adding hydrochloric acid to react at 80-85 ℃, and filtering after complete reaction to obtain hydrochloride of 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxyl) aniline) -7-ethoxyquinoline-carbonitrile; and the hydrochloride is resuspended in a mixed solution of a potassium carbonate water solution and alcohol, stirred at room temperature for 0.5-12 h, filtered and dried 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 alkalinity means that the pH value is 7-12, and the preferred pH value is 8.

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

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

preferably, the drying temperature is 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 for washing is a mixed solvent of water and alcohol, and the alcohol includes methanol, ethanol, and isopropanol, but is not limited thereto, wherein the content of the alcohol is greater than 40 vol%, for example, 50 vol%.

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

A fourth aspect of the invention provides a crystalline form I of 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile (intermediate a) having a powder X-ray diffraction (XRPD) pattern predominantly comprising characteristic peaks at diffraction angles (2 Θ) 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, wherein the 2 Θ values have an error range of ± 0.2 degrees.

Specifically, the XRPD pattern of form I of intermediate a includes diffraction peaks at diffraction angles (2 θ) 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 for the 2 θ value is ± 0.2 degrees.

More specifically, the diffraction peaks and corresponding relative intensities of the crystalline 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 the crystal form I of the intermediate A is shown as attached figure 2.

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

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 in the preparation of neratinib.

The invention has the beneficial effects that the crystal form, especially the crystal form II, of the neratinib intermediate A compound (6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxyl) aniline) -7-ethoxyquinoline-carbonitrile) is provided, and the intermediate A in the crystal form can obviously reduce the solvent consumption, shorten the reaction time, improve the yield, obviously reduce the residual quantity of the intermediate A in the final product, obtain a high-purity target product and is very favorable for commercial production.

Drawings

Figure 1 is a powder X-ray diffraction pattern of crystalline form II of intermediate a prepared in example 1;

figure 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 technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention and the accompanying drawings, and it is apparent that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.

Definition of

Throughout the specification, unless otherwise specifically noted, terms used herein should be understood as having meanings 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. If there is a conflict, the present specification will control.

The term "crystalline form" or "crystalline" as used herein refers to any solid substance exhibiting a three-dimensional ordering, as opposed to an amorphous solid substance, which results in a characteristic XRPD pattern having well-defined peaks.

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

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

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

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

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

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

XRPD pattern test method:

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

The test conditions are as follows: cu K α 1 ═ 1.5406a, monochromatic radiation, voltage: 40kV, current: 40mA excitation, start angle 3.5 degrees, end angle 40 degrees, step size: 0.013 degree, residence time: for 50 s.

HPLC detection method:

test equipment: agilent 1260 high performance liquid chromatography

A chromatographic column: c18 column

Mobile phase A: phosphate buffer-methanol

Mobile phase B: aqueous methanol solution

Gradient elution, flow rate: 1.0mL/min, wavelength: 266 nm; sample introduction volume: 20_μL, 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-quinolines Crystalline form II of carbonitrile (intermediate A)

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

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

Example 2 preparation of crystalline form I of intermediate a

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

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

Comparative example 1 preparation of intermediate a using a prior art procedure

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 (33.3g, 0.142mol), 3-chloro-4- (pyridine-2-methoxy) aniline (35.0g, 0.11mol) and methanesulfonic acid (0.2mL) were heated to 70-75 ℃ in ethanol (480mL) and stirred for 2h before detection was complete. After the reaction is completed, adding ethanol (160mL) and concentrated hydrochloric acid (138mL) into the reaction solution to adjust the pH value to be within the range of 1-3, stirring and reacting at 70-75 ℃, adding ethanol (80mL) into the reaction solution after 1h to enable the reaction solution to be easily stirred, adding purified water (680mL) after 2h, stirring and reacting the mixture for 1h, cooling to 35-45 ℃, and stirring overnight. And (3) carrying out suction filtration at 35-45 ℃, rinsing the filter cake for 2 times by using a mixed solvent (1: 1, 84mL) of ethanol and water, and carrying out suction drying. The filter cake was transferred to a flask, methanol (720mL) and 10% potassium carbonate solution (22g potassium carbonate in 227mL water) were added, the pH of the system was adjusted to basic, suction filtered and washed with a mixed solvent of methanol and water (1: 1, 84mL), and dried to give a wet product, which was dried under vacuum at 50 ℃ to give the title compound. The title compound was detected by XRPD and its X-ray diffraction pattern shown in figure 3.

The powder X-ray diffraction spectrogram of the intermediate A prepared by the method is different from the spectrograms of the crystal forms I and II. It can be seen that conventional preparation methods do not allow either form I or form II to be obtained.

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

Test example: solubility test of intermediate A

In the synthesis of neratinib, N-Dimethylacetamide (DMA), N-methylpyrrolidone (NMP) is generally used as a reaction solvent. Therefore, the present inventors examined the solubility of the three crystalline forms of intermediate a prepared in example 1, example 2 and comparative example 1, respectively, in N, N-Dimethylacetamide (DMA) and N-methylpyrrolidone (NMP) at room temperature, and the results are shown in table 3.

TABLE 3 solubility of intermediate A

As can be seen from the above table, the crystal form II has more excellent solubility than the crystal 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 during the reaction process.

The following examples use intermediate a to prepare neratinib, 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 crystalline form II of intermediate A Yl) amino) -3-cyano-7-ethoxyquinolin-6-yl) -4- (dimethylamino) but-2-enamide (lenatinib)

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

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

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

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

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

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

4-N, N-dimethylaminocrotonate (67g, 0.40mol) is put into N, N-dimethylacetamide (640g), cooled to-14 to-19 ℃, phosphorus oxychloride (61g, 0.40mol) is added dropwise, the temperature is kept within the range during the dropwise adding process, and the reaction is carried out for 2-3 h at-15 ℃ after the dropwise adding is finished. Controlling the temperature to be between 14 ℃ below zero and 19 ℃ below zero, adding 1Kg of N, N-dimethylacetamide (N, N-dimethylacetamide) solution of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile (crystal form II) (126g, 0.28mol), then reacting at 15 ℃ below zero for 5h, monitoring the residue of the intermediate A by a liquid phase to be less than 0.5%, keeping the temperature to be between 7 ℃ below zero and 16 ℃ below zero after the reaction is finished, adding 870g of water for quenching, heating to 37-42 ℃, adjusting the pH to 10-11 by using 25% KOH solution, adding 950g of water for further dilution, performing suction filtration, washing, drying at 45-50 ℃, collecting 160g of the title compound, obtaining the yield of 95%, the purity of 99.6% by HPLC, and detecting the residue of the intermediate A to be 0.11.

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

4-N, N-dimethylaminocrotonate (67g, 0.40mol) is put into N, N-dimethylacetamide (640g), cooled to-14 to-19 ℃, phosphorus oxychloride (61g, 0.40mol) is added dropwise, the temperature is kept within the range during the dropwise adding process, and the reaction is carried out for 2-3 h at-15 ℃ after the dropwise adding is finished. 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile (form I) (126g, 0.28mol) N was added at a controlled temperature of-14 to-19 ℃, n-dimethylacetamide (1.3Kg) suspension is reacted for 5h at-15 ℃, the liquid phase monitors that the intermediate A has more residues and is not further converted, 870g of water is added to keep the temperature between-7 and-16 ℃ for quenching, the temperature is increased to 37 to 42 ℃, 25% KOH solution is used for adjusting the pH value to 10 to 11, 950g of water is added for further dilution, the filtration and the washing are carried out, the drying is carried out at 45 to 50 ℃, 143g of the title compound is collected, the yield is 85%, the HPLC purity is 93.5%, and the residue of the intermediate A is 6.1% by HPLC detection.

Example 6 preparation of lenatinib from crystalline form II of intermediate a

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

From examples 4 to 6, it can be seen that when the crystal form I of the intermediate a is used for preparing neratinib, under the condition of the same solvent dosage, the final product has low yield and low purity, and the residual amount of the intermediate a is large, so that the production and quality requirements cannot be met. If the dosage of the solvent is increased, the reaction yield and purity can be improved to a certain extent, and the residual quantity of the intermediate A is reduced, but a larger amount of anti-solvent needs 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 neratinib, the using amount of a reaction solvent is greatly reduced, the reaction yield is over 95 percent, the purity of a final product is 99.6 percent, additional refining or pulping treatment is not needed, the residual amount of the intermediate A is not higher than 0.13 percent, and the high-quality medicinal requirement is met.

The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and all modifications and equivalents made by the contents of the present specification and drawings, or directly/indirectly applied to other related technical fields, are included in the scope of the present invention.

Claims

Crystalline form II of 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile, characterized in that it comprises diffraction peaks in the XRPD pattern at diffraction angles 2 Θ of 6.3, 7.8, 14.0, 15.1, 17.1, 18.8, 21.5, 22.2, 23.4, and 27.5 degrees, with a range of error in the 2 Θ values of ± 0.2 degrees.
2. Form II according to claim 1, wherein the diffraction peaks of form II in the XRPD pattern comprise diffraction peaks at diffraction angles 2 Θ 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, with a range of error in 2 Θ values of ± 0.2 degrees.
3. Form II according to claim 1, wherein the diffraction peaks of form II in the XRPD pattern comprise diffraction peaks at diffraction angles 2 Θ 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, with a 2 Θ value having a range of error of ± 0.2 degrees.
4. The crystalline form II of claim 1, wherein the form II has an XRPD pattern as depicted in figure 1.
5. A process for the preparation of 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxy) aniline) -7-ethoxyquinoline-carbonitrile in crystalline form II according to any of claims 1 to 4, comprising the steps of: reacting N- (4-chloro-3-cyano-7-ethoxyquinolin-6-yl) acetamide with 3-chloro-4- (pyridine-2-methoxy) aniline at 70-90 ℃ in a reaction solvent under the condition of methanesulfonic acid, adding an aqueous solution of an alkaline salt into a reaction system to make the pH value of a reaction liquid alkaline, and filtering to obtain wet N- [4- [ 3-chloro-4- (2-pyridylmethoxy) aniline ] -3-cyano-7-ethoxy-6-quinolyl ] acetyl; suspending the wet product in water, adding hydrochloric acid to react at 80-85 ℃, and filtering after complete reaction to obtain hydrochloride of 6-amino-4- (3-chloro-4- (pyridine-2-substituted methoxyl) aniline) -7-ethoxyquinoline-carbonitrile; and the hydrochloride is resuspended in a mixed solution of a potassium carbonate water solution and alcohol, stirred at room temperature for 0.5-12 h, filtered and dried to obtain the crystal form II.
6. The process for preparing form II according to claim 5, wherein the reaction solvent is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidinone.
7. The method for preparing the crystalline form II according to claim 5, wherein the pH value to alkaline is a pH value of 7 to 12, preferably a pH value of 8.
8. A process for the preparation of form II according to claim 5, wherein the basic salt in the aqueous solution of a basic salt is selected from the group consisting of alkali metal carbonates, bicarbonates and hydroxides; preferably selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide.
9. A process for preparing form II according to claim 5, wherein the solution of the mixture of aqueous potassium carbonate and an alcohol selected from the group consisting of methanol, ethanol and isopropanol; wherein the volume ratio of the potassium carbonate aqueous solution to the alcohol is 3: 4.
10. a process for the preparation of neratinib or a pharmaceutically acceptable salt thereof, comprising the step of preparing neratinib using crystalline form II of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile according to any one of claims 1 to 4.
11. Use of the crystalline form II of 6-amino-4- [ 3-chloro-4- (-2-pyridylmethoxy) anilino ] -7-ethoxy-3-quinolinecarbonitrile of any one of claims 1 to 4 in the preparation of neratinib.