Solid form of anlotinib dihydrochloride and preparation method thereof

Abstract

The invention relates to a crystal form of anlotinib dihydrochloride as well as a preparation method and a pharmaceutical composition of the crystal form. The invention provides seven crystal forms (crystal form 1, crystal form 2, crystal form 3, crystal form 4, crystal form 5, crystal form 6 and crystal form 7) of anlotinib dihydrochloride as well as a method and a pharmaceutical composition thereof. The present application relates to processes for the preparation of anlotinib and salts thereof, such as dihydrochloride salts. The present application also relates to intermediates useful in the preparation of anlotinib and salts thereof. The present application also relates to purification of anlotinib and salts thereof.

Description

Technical Field

[0001] The present application provides a crystalline form of Anlotinib dihydrochloride and a preparation method and a pharmaceutical composition thereof. The present application provides a new method for preparing Anlotinib. The present application also relates to a new intermediate that can be used to prepare Anlotinib and its salts. The present application also relates to the purification of Anlotinib and its salts. Background Art

[0002] Anlotinib dihydrochloride is the adopted name of a drug chemically described as 1-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-quinolin-7-yloxy)methyl)cyclopropylamine dihydrochloride, and is represented by structural formula (I).

[0003]

[0004] Anlotinib dihydrochloride is a novel oral tyrosine kinase inhibitor and is marketed in China under the trade name Fukewei capsules (8mg, 10mg and 12mg strengths) for the treatment of patients with locally advanced or metastatic non-small cell lung cancer who have progressed or relapsed after at least two prior systemic chemotherapy regimens.

[0005] U.S. Patent No. 8,148,532 B2 discloses a method for preparing anlotinib and / or its analogs.

[0006] CN102344438B discloses crystalline form A, crystalline form B and crystalline form C of anlotinib dihydrochloride characterized by PXRD spectra, and methods thereof.

[0007] CN107771078B, CN108864050B, CN109748902B, CN110357856B, CN110386892B, CN110376296A1 and CN110845406B describe methods for preparing anlotinib dihydrochloride and its intermediates.

[0008] However, there is still a need for alternative solid forms of anlotinib dihydrochloride that exhibit desirable properties, such as bioavailability and stability, and methods for preparing the same. Therefore, it is desirable to provide a feasible solid form of anlotinib dihydrochloride.

[0009] The prior art methods for preparing anlotinib and its pharmaceutically acceptable salts have the following major disadvantages: difficulty in removing process-related impurities; poor commercial feasibility due to the use of hazardous reactants; use of column chromatography, and / or low yield and purity of intermediates and final products. Therefore, there is still a need to develop such a method: it overcomes one or more of the above disadvantages associated with the prior art methods for preparing anlotinib dihydrochloride.

[0010] The present application further relates to a method for preparing anlotinib and a pharmaceutically acceptable salt thereof. The method of the present application is more economical, feasible and environmentally friendly than the prior art method. Summary of the invention

[0011] In a first aspect, the present invention provides anlotinib dihydrochloride crystalline form 1, characterized in that PXRD comprises peaks at about 5.8, 6.7, 9.0, 11.7, 17.6 ± 0.2° 2θ. In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 1, characterized in that PXRD has additional peaks at about 13.7, 15.0, 15.7, 17.1, 22.63, 25.1, 25.9 ± 0.2° 2θ.

[0012] In a second aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystal form 1, the method comprising:

[0013] a) providing a mixture of anlotinib dihydrochloride and an alcohol solvent;

[0014] b) optionally, heating the solution of step a);

[0015] c) adding an anti-solvent to the solution of anlotinib dihydrochloride; or adding the solution of anlotinib dihydrochloride to the anti-solvent;

[0016] d) Isolating anlotinib dihydrochloride form 1.

[0017] In a third aspect, the present invention provides anlotinib dihydrochloride crystal form 2, characterized in that PXRD contains peaks at about 7.8, 9.4, 15.7, 16.0, 16.9 ± 0.2° 2θ. In one embodiment, the present application provides anlotinib dihydrochloride crystal form 2, characterized in that PXRD has additional peaks at about 6.2, 8.4, 12.2, 12.5, 20.5, 24.0 ± 0.2° 2θ.

[0018] In a fourth aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystal form 2, the method comprising:

[0019] a) providing an aqueous solution of anlotinib dihydrochloride;

[0020] b) optionally, heating the solution of step a);

[0021] c) Isolating Anlotinib dihydrochloride Form 2.

[0022] In a fifth aspect, the present invention provides anlotinib dihydrochloride crystalline form 3, characterized in that PXRD comprises peaks at about 4.3, 8.3, 12.9, 15.1, 22.3, 26.0, 26.8 ± 0.2° 2θ. In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 3, characterized in that PXRD has additional peaks at about 10.8, 12.0, 19.6, 22.2, 28.2 ± 0.2° 2θ.

[0023] In a sixth aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystalline form 3, the method comprising drying anlotinib dihydrochloride crystalline form 2.

[0024] In a seventh aspect, the present invention provides anlotinib dihydrochloride crystalline form 4, characterized in that PXRD comprises peaks at about 5.8, 7.8, 8.7, 20.7, 21.3, 22.0, 22.4, 23.4, 26.5, 27.7 ± 0.2 ° 2θ. In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 4, characterized in that PXRD has additional peaks at about 9.5, 15.9, 16.5, 18.0, 19.3 ± 0.2 ° 2θ.

[0025] In an eighth aspect, the present invention provides a method for preparing anlotinib dihydrochloride form 4, the method comprising:

[0026] a) providing a mixture of anlotinib dihydrochloride and a polar aprotic solvent;

[0027] b) optionally, heating the solution of step a);

[0028] c) Isolating anlotinib dihydrochloride form 4.

[0029] In the ninth aspect, the present invention provides anlotinib dihydrochloride crystalline form 5, characterized in that PXRD comprises peaks at about 3.9, 4.7, 5.6, 11.4, 17.3 ± 0.2° 2θ. In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 5, characterized in that PXRD has additional peaks at about 12.4, 13.5, 14.7, 15.3, 15.7, 23.8 ± 0.2° 2θ.

[0030] In a tenth aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystal form 5, the method comprising:

[0031] a) providing a solution of anlotinib dihydrochloride and formamide;

[0032] b) optionally, heating the solution of step a);

[0033] c) Isolating anlotinib dihydrochloride form 5.

[0034] In the eleventh aspect, the present invention provides anlotinib dihydrochloride crystalline form 6, characterized in that PXRD contains peaks at about 5.2, 5.9, 12.8, 15.4, 15.7, 17.6, 20.3 ± 0.2 ° 2θ. In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 6, characterized in that PXRD has additional peaks at about 9.7, 10.11, 14.3, 16.8, 19.6, 24.1 ± 0.2 ° 2θ.

[0035] In a twelfth aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystal form 6, the method comprising:

[0036] a) providing a mixture of anlotinib dihydrochloride, formamide and water;

[0037] b) optionally, heating the solution of step a);

[0038] c) Isolating anlotinib dihydrochloride form 6.

[0039] In a thirteenth aspect, the present invention provides anlotinib dihydrochloride form 7, characterized in that PXRD comprises peaks at about 5.5, 6.2, 10.4, 11.2, 12.5, 14.17, 15.4, 16.3, 18.4, 19.3, 21.1 23.3, 25.1, 26.2, 26.7, 27.16, 27.8, 28.3, 30.7, 31.8, 34.1, 37.5, and 38.2 ± 0.2° 2θ.

[0040] In a fourteenth aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystal form 7, the method comprising:

[0041] a) providing a solution of anlotinib dihydrochloride and 2,2,2-trifluoroethanol;

[0042] b) optionally, heating the solution of step a);

[0043] c) Isolating anlotinib dihydrochloride form 7.

[0044] In a fifteenth aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystal form 7, the method comprising:

[0045] a) providing a solution of anlotinib free base and 2,2,2-trifluoroethanol;

[0046] b) optionally, heating the solution of step a);

[0047] c) treating the solution with an alcoholic hydrochloride;

[0048] d) Isolating anlotinib dihydrochloride form 7.

[0049] In the sixteenth aspect, the present application provides a pharmaceutical composition comprising anlotinib dihydrochloride crystalline form selected from Form 1, Form 2, Form 3, Form 4, Form 5, Form 6 and Form 7 or a mixture thereof, and at least one pharmaceutically acceptable excipient.

[0050] In the seventeenth aspect, the present application provides a method for preparing anlotinib dihydrochloride of formula (I), the method comprising:

[0051]

[0052] a) debenzylating a compound of formula (II) to a compound of formula (III),

[0053]

[0054] b) reacting a compound of formula (III) with a haloacetonitrile to produce a compound of formula (IV),

[0055]

[0056] c) converting the compound of formula (IV) into the compound of formula (V),

[0057]

[0058] d) reacting a compound of formula (V) with an amine protecting group to produce a compound of formula (VI),

[0059]

[0060] e) coupling a compound of formula (VI) with a compound of formula (VII) to produce a compound of formula (VIII),

[0061]

[0062] f) reducing the compound of formula (VIII) with a reducing agent to produce a compound of formula (IX);

[0063]

[0064] g) converting the compound of formula (IX) into a compound of formula (I),

[0065]

[0066] Wherein P is an amine protecting group.

[0067] In the eighteenth aspect, the present application provides a method for preparing a compound of formula (IV), which comprises reacting a compound of formula (III) with a halogenated acetonitrile.

[0068]

[0069] In a nineteenth aspect, the present application provides a method for preparing a compound of formula (V), the method comprising converting a compound of formula (IV) into a compound of formula (V).

[0070]

[0071] In the twentieth aspect, the present application provides a method for preparing formula (VI), the method comprising reacting a compound of formula (V) with an amine protecting group,

[0072]

[0073] Wherein P is an amine protecting group.

[0074] In a twenty-first aspect, the present application provides a method for preparing a compound of formula (VIII), the method comprising reacting a compound of formula (VI) with a compound of formula (VII),

[0075]

[0076] Wherein P is an amine protecting group.

[0077] In a sixth embodiment of the twenty-second aspect, the present application provides a method for preparing formula (IX), the method comprising reducing a compound of formula (VIII) with a reducing agent:

[0078]

[0079] Wherein P is an amine protecting group.

[0080] In the twenty-third aspect, the present application provides a compound of the following formula:

[0081]

[0082] Wherein P is an amine protecting group.

[0083] In the twenty-fourth aspect, the present application provides a compound of the following formula:

[0084]

[0085] In the twenty-fifth aspect, the present application provides a purification method for preparing anlotinib or a salt thereof of formula (Xa), the purification method comprising:

[0086] a) dissolving anlotinib of formula (X) with an organic acid to form anlotinib acid addition salt of formula (Xa);

[0087] b) precipitating the anlotinib acid addition salt of formula (Xa).

[0088] In the twenty-sixth aspect, the present application provides a method for preparing anlotinib of formula (X), the method comprising:

[0089] a) reacting a compound of formula (XI) with a haloacetonitrile to form a compound of formula (XII);

[0090]

[0091] b) converting the compound of formula (XII) into anlotinib of formula (X).

[0092] In the twenty-seventh aspect, the present application provides an amorphous form of anlotinib tartrate of formula (Xb). BRIEF DESCRIPTION OF THE DRAWINGS

[0093] Figure 1 is an exemplary X-ray powder diffraction of anlotinib dihydrochloride form 1 prepared by the method of Example 1.

[0094] Figure 2 is an exemplary X-ray powder diffraction of anlotinib dihydrochloride form 2 prepared by the method of Example 2.

[0095] Figure 3 is an exemplary X-ray powder diffraction of anlotinib dihydrochloride form 3 prepared by the method of Example 3.

[0096] Figure 4 is an exemplary X-ray powder diffraction of anlotinib dihydrochloride form 4 prepared by the method of Example 4.

[0097] Figure 5 is an exemplary X-ray powder diffraction of anlotinib dihydrochloride form 5 prepared by the method of Example 5.

[0098] Figure 6 is an exemplary X-ray powder diffraction of anlotinib dihydrochloride form 6 prepared by the method of Example 6.

[0099] Figure 7 is an exemplary X-ray powder diffraction of anlotinib dihydrochloride form 7 prepared by the method of Example 7.

[0100] Figure 8 is an exemplary X-ray powder diffraction of anlotinib dihydrochloride form 7 prepared by the method of Example 8.

[0101] Fig. 9 is an exemplary thermogravimetric analysis (TGA) of anlotinib dihydrochloride form 7 prepared by the method of Example 23.

[0102] Fig.10 is an exemplary differential scanning calorimetry (DSC) analysis of anlotinib dihydrochloride form 7 prepared by the method of Example 23.

[0103] Fig.11 is an exemplary X-ray powder diffraction of the amorphous form of anlotinib tartrate of formula (Xb) prepared by the method of Example 16. DETAILED DESCRIPTION

[0104] As used herein, "comprising" means the listed elements, or their equivalent in structure or function, plus any other one or more elements not listed. The terms "having" and "including" should also be interpreted as open ended unless the context implies otherwise.

[0105] All ranges recited herein are inclusive of the endpoints, including those reciting a range "between" two values.

[0106] Terms such as "about," "generally," "substantially," and the like should be interpreted as modifying a term or value so that it is not absolute, but is not interpreted on the basis of the prior art. Such terms will be defined by the context and the terms they modify as those terms are understood by those skilled in the art. This includes at least the degree of expected experimental error, technical error, and instrument error for a given technique used to measure a value.

[0107] In a first aspect, the present invention provides anlotinib dihydrochloride crystalline form 1, characterized in that PXRD comprises peaks at about 5.8, 6.7, 9.0, 11.7, 17.6 ± 0.2° 2θ. In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 1, characterized in that PXRD has additional peaks at about 13.7, 15.0, 15.7, 17.1, 22.63, 25.1, 25.9 ± 0.2° 2θ.

[0108] In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 1, characterized in that it is substantially as follows Figure 1 PXRD shown.

[0109] In a second aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystal form 1, the method comprising:

[0110] a) providing a mixture of anlotinib dihydrochloride and an alcohol solvent;

[0111] b) optionally, heating the solution of step a);

[0112] c) adding an anti-solvent to the solution of anlotinib dihydrochloride; or adding the solution of anlotinib dihydrochloride to the anti-solvent;

[0113] d) Isolating anlotinib dihydrochloride form 1.

[0114] Suitable alcohol solvents used in step a) include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, tert-butanol, 1-propanol, and the like.

[0115] In the embodiment involving step a), the solution may be optionally treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and / or clarify the solution. In step a), anlotinib dihydrochloride is dissolved in an alcohol solvent.

[0116] Optionally, the above solution obtained can be filtered to remove any insoluble particles. Insoluble particles can be suitably removed by filtering, centrifuging, decanting or any other suitable technique. The solution can be filtered through a bed of paper, glass fiber or other membrane material, or a clarifying agent such as diatomaceous earth or hyflow. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration equipment to avoid premature crystallization.

[0117] The above steps may be performed at a temperature between about 10°C and about 100°C, depending on the solvent or mixture of solvents used in a particular step.

[0118] In the embodiment involving step c), an anti-solvent is added to the solution obtained in step b), or the solution obtained in step b) is added to an anti-solvent. After adding the anti-solvent, the reaction mass may be maintained for 15 minutes to 24 hours.

[0119] Suitable anti-solvents used in step c) include, but are not limited to, alkanes, such as n-pentane, n-heptane, n-hexane, n-heptane, etc., ethers, such as tetrahydrofuran (THF), diethyl ether, methyl tert-butyl ether, diisopropyl ether, petroleum ether, etc., cyclohexane or mixtures thereof.

[0120] As required, the separation in step d) can be achieved by any suitable separation method, such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container, conventional separation and purification means such as concentration, concentration under reduced pressure, or by a combination of these procedures.

[0121] Suitable temperatures for separation may be less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, less than about 5°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperature.

[0122] In a third aspect, the present invention provides anlotinib dihydrochloride crystal form 2, characterized in that PXRD contains peaks at about 7.8, 9.4, 15.7, 16.0, 16.9 ± 0.2° 2θ. In one embodiment, the present application provides anlotinib dihydrochloride crystal form 2, characterized in that PXRD has additional peaks at about 6.2, 8.4, 12.2, 12.5, 20.5, 24.0 ± 0.2° 2θ.

[0123] In one embodiment, the present application provides anlotinib dihydrochloride crystal form 2, characterized in that it is substantially as follows Figure 2 PXRD shown.

[0124] In a fourth aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystal form 2, the method comprising:

[0125] a) providing an aqueous solution of anlotinib dihydrochloride;

[0126] b) optionally, heating the solution of step a);

[0127] c) Isolating Anlotinib dihydrochloride Form 2.

[0128] In embodiments involving step a), the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and / or clarify the solution. In step a), anlotinib dihydrochloride is dissolved in water.

[0129] Optionally, the above solution obtained can be filtered to remove any insoluble particles. Insoluble particles can be suitably removed by filtering, centrifuging, decanting or any other suitable technique. The solution can be filtered through a bed of paper, glass fiber or other membrane material, or a clarifying agent such as diatomaceous earth or hyflow. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration equipment to avoid premature crystallization.

[0130] The above steps may be performed at a temperature between about 10°C and about 100°C, depending on the solvent or mixture of solvents used in a particular step.

[0131] As required, the separation in step c) can be achieved by any suitable separation method, such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container, conventional separation and purification means such as concentration, concentration under reduced pressure, or by a combination of these procedures.

[0132] In a fifth aspect, the present invention provides anlotinib dihydrochloride crystalline form 3, characterized in that PXRD comprises peaks at about 4.3, 8.3, 12.9, 15.1, 22.3, 26.0, 26.8 ± 0.2° 2θ. In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 3, characterized in that PXRD has additional peaks at about 10.8, 12.0, 19.6, 22.2, 28.2 ± 0.2° 2θ.

[0133] In one embodiment, the present application provides anlotinib dihydrochloride crystal form 3, which is characterized in that it is substantially as follows Figure 3 PXRD shown.

[0134] In a sixth aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystalline form 3, the method comprising drying anlotinib dihydrochloride crystalline form 2.

[0135] Drying can be carried out in a tray dryer, a vacuum tray dryer, a vacuum oven, an air oven, a conical vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a rotary flash dryer, a flash dryer, and the like. Drying can be carried out at less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperature, at atmospheric pressure or under reduced pressure, as long as the quality of anlotinib dihydrochloride does not decrease. Drying can be carried out for any desired time until the desired product quality is achieved. The dried product can be optionally subjected to a comminution procedure to produce the desired particle size. Grinding or micronization can be performed before or after the product is dried. Techniques that can be used for particle size crushing include, but are not limited to, ball milling, roller milling and hammer milling, and jet milling.

[0136] It was found that Anlotinib dihydrochloride Form 3 was stable within three months. The data presented below demonstrate that Anlotinib dihydrochloride Form 3 has high storage stability.

[0137]

[0138] In a seventh aspect, the present invention provides anlotinib dihydrochloride crystalline form 4, characterized in that PXRD comprises peaks at about 5.8, 7.8, 8.7, 20.7, 21.3, 22.0, 22.4, 23.4, 26.5, 27.7 ± 0.2 ° 2θ. In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 4, characterized in that PXRD has additional peaks at about 9.5, 15.9, 16.5, 18.0, 19.3 ± 0.2 ° 2θ.

[0139] In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 4, characterized in that it is substantially as follows Figure 4 PXRD shown.

[0140] In an eighth aspect, the present invention provides a method for preparing anlotinib dihydrochloride form 4, the method comprising:

[0141] a) providing a mixture of anlotinib dihydrochloride and a polar aprotic solvent;

[0142] b) optionally, heating the solution of step a);

[0143] c) Isolating anlotinib dihydrochloride form 4.

[0144] Suitable polar aprotic solvents used in step a) include, but are not limited to, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), formamide, acetamide, propionamide, hexamethylphosphoramide (HMPA), and the like.

[0145] In the embodiment involving step a), the solution may be optionally treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and / or clarify the solution. In step a), anlotinib dihydrochloride is dissolved in a polar aprotic solvent.

[0146] Optionally, the above solution obtained can be filtered to remove any insoluble particles. Insoluble particles can be suitably removed by filtering, centrifuging, decanting or any other suitable technique. The solution can be filtered through a bed of paper, glass fiber or other membrane material, or a clarifying agent such as diatomaceous earth or hyflow. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration equipment to avoid premature crystallization.

[0147] The above steps may be performed at a temperature between about 10°C and about 100°C, depending on the solvent or mixture of solvents used in a particular step.

[0148] As required, the separation in step c) can be achieved by any suitable separation method, such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container, conventional separation and purification means such as concentration, concentration under reduced pressure, or by a combination of these procedures.

[0149] Suitable temperatures for separation may be less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, less than about 5°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperature.

[0150] In the ninth aspect, the present invention provides anlotinib dihydrochloride crystalline form 5, characterized in that PXRD comprises peaks at about 3.9, 4.7, 5.6, 11.4, 17.3 ± 0.2° 2θ. In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 5, characterized in that PXRD has additional peaks at about 12.4, 13.5, 14.7, 15.3, 15.7, 23.8 ± 0.2° 2θ.

[0151] In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 5, characterized in that it is substantially as follows Figure 5 PXRD shown.

[0152] In a tenth aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystal form 5, the method comprising:

[0153] a) providing a solution of anlotinib dihydrochloride and formamide;

[0154] b) optionally, heating the solution of step a);

[0155] c) Isolating anlotinib dihydrochloride form 5.

[0156] In the embodiment involving step a), the solution may be optionally treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and / or clarify the solution. In step a), anlotinib dihydrochloride is dissolved in formamide solvent.

[0157] Optionally, the above solution obtained can be filtered to remove any insoluble particles. Insoluble particles can be suitably removed by filtering, centrifuging, decanting or any other suitable technique. The solution can be filtered through a bed of paper, glass fiber or other membrane material, or a clarifying agent such as diatomaceous earth or hyflow. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration equipment to avoid premature crystallization.

[0158] The temperature at which the above steps can be carried out ranges from about 10° C. to about 100° C., depending on the solvent or mixture of solvents used in a particular step. The reaction mass can be maintained for 15 minutes to 240 hours.

[0159] As required, the separation in step c) can be achieved by any suitable separation method, such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container, conventional separation and purification means such as concentration, concentration under reduced pressure, or by a combination of these procedures.

[0160] Suitable temperatures for separation may be less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, less than about 5°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperature.

[0161] In the eleventh aspect, the present invention provides anlotinib dihydrochloride crystalline form 6, characterized in that PXRD contains peaks at about 5.2, 5.9, 12.8, 15.4, 15.7, 17.6, 20.3 ± 0.2 ° 2θ. In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 6, characterized in that PXRD has additional peaks at about 9.7, 10.11, 14.3, 16.8, 19.6, 24.1 ± 0.2 ° 2θ.

[0162] In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 6, characterized in that it is substantially as follows Figure 6 PXRD shown.

[0163] In a twelfth aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystal form 6, the method comprising:

[0164] a) providing a mixture of anlotinib dihydrochloride, formamide and water;

[0165] b) optionally, heating the solution of step a);

[0166] c) Isolating anlotinib dihydrochloride form 6.

[0167] In embodiments involving step a), the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and / or clarify the solution. In step a), anlotinib dihydrochloride is dissolved in formamide and water.

[0168] Optionally, the above solution obtained can be filtered to remove any insoluble particles. Insoluble particles can be suitably removed by filtering, centrifuging, decanting or any other suitable technique. The solution can be filtered through a bed of paper, glass fiber or other membrane material, or a clarifying agent such as diatomaceous earth or hyflow. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration equipment to avoid premature crystallization.

[0169] The above steps may be performed at a temperature between about 10°C and about 100°C, depending on the solvent or mixture of solvents used in a particular step.

[0170] As required, the separation in step c) can be achieved by any suitable separation method, such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container, conventional separation and purification means such as concentration, concentration under reduced pressure, or by a combination of these procedures.

[0171] Suitable temperatures for separation may be less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, less than about 5°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperature.

[0172] In a thirteenth aspect, the present invention provides anlotinib dihydrochloride form 7, characterized in that PXRD comprises peaks at about 5.5, 6.2, 10.4, 11.2, 12.5, 14.17, 15.4, 16.3, 18.4, 19.3, 21.1 23.3, 25.1, 26.2, 26.7, 27.16, 27.8, 28.3, 30.7, 31.8, 34.1, 37.5, and 38.2 ± 0.2° 2θ.

[0173] In one embodiment, the present application provides anlotinib dihydrochloride crystalline form 7, characterized in that it is substantially as follows Figure 7 or Figure 8 PXRD shown.

[0174] In another embodiment, the present application provides anlotinib dihydrochloride crystal form 7, characterized in that differential scanning calorimetry (DSC) begins to absorb heat at about 196±5°C. In yet another embodiment, the present application provides anlotinib dihydrochloride crystal form 7, characterized in that it is substantially as follows Fig.10 DSC shown.

[0175] In yet another embodiment, the present application provides anlotinib dihydrochloride crystalline form 7, characterized in that it is substantially as follows Fig. 9 TGA shown.

[0176] In a fourteenth aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystal form 7, the method comprising:

[0177] a) providing a solution of anlotinib dihydrochloride and 2,2,2-trifluoroethanol;

[0178] b) optionally, heating the solution of step a);

[0179] c) Isolating anlotinib dihydrochloride form 7.

[0180] In embodiments involving step a), the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and / or clarify the solution. In step a), anlotinib dihydrochloride is dissolved in 2,2,2-trifluoroethanol.

[0181] Optionally, the above solution obtained can be filtered to remove any insoluble particles. Insoluble particles can be suitably removed by filtering, centrifuging, decanting or any other suitable technique. The solution can be filtered through a bed of paper, glass fiber or other membrane material, or a clarifying agent such as diatomaceous earth or hyflow. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration equipment to avoid premature crystallization.

[0182] The above steps may be performed at a temperature between about 10°C and about 100°C, depending on the solvent or mixture of solvents used in a particular step.

[0183] As required, the separation in step c) can be achieved by any suitable separation method, such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container, conventional separation and purification means such as concentration, concentration under reduced pressure, or by a combination of these procedures.

[0184] Suitable temperatures for separation may be less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, less than about 5°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperature.

[0185] In a fifteenth aspect, the present invention provides a method for preparing anlotinib dihydrochloride crystal form 7, the method comprising:

[0186] a) providing a solution of anlotinib free base and 2,2,2-trifluoroethanol;

[0187] b) optionally, heating the solution of step a);

[0188] c) treating the solution with an alcohol hydrochloride;

[0189] d) Isolating anlotinib dihydrochloride form 7.

[0190] In embodiments involving step a), the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and / or clarify the solution. In step a), anlotinib dihydrochloride is dissolved in 2,2,2-trifluoroethanol.

[0191] Optionally, the above solution obtained can be filtered to remove any insoluble particles. Insoluble particles can be suitably removed by filtering, centrifuging, decanting or any other suitable technique. The solution can be filtered through a bed of paper, glass fiber or other membrane material, or a clarifying agent such as diatomaceous earth or hyflow. Depending on the equipment used and the concentration and temperature of the solution, it may be necessary to preheat the filtration equipment to avoid premature crystallization.

[0192] The alcohol hydrochloride used in step c) includes but is not limited to methanol hydrochloride, ethanol hydrochloride, isopropanol hydrochloride and the like.

[0193] The above steps may be performed at a temperature between about 10°C and about 100°C, depending on the solvent or mixture of solvents used in a particular step.

[0194] As required, the separation in step d) can be achieved by any suitable separation method, such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container, conventional separation and purification means such as concentration, concentration under reduced pressure, or by a combination of these procedures.

[0195] Suitable temperatures for separation may be less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, less than about 5°C, less than about 0°C, less than about -10°C, less than about -20°C, or any other suitable temperature.

[0196] The raw material of anlotinib dihydrochloride of the present invention may be crystalline form A, crystalline form B, crystalline form C, or an amorphous form or any other form known in the literature.

[0197] Anlotinib dihydrochloride form 7 may be in the form of a dihydrate having a water content of about 6-9 weight / weight%.

[0198] It was found that Anlotinib dihydrochloride Form 7 was stable within three months. The data presented below demonstrate that Anlotinib dihydrochloride Form 7 has high storage stability.

[0199]

[0200] In the sixteenth aspect, the present application provides a pharmaceutical composition comprising anlotinib dihydrochloride crystalline form selected from Form 1, Form 2, Form 3, Form 4, Form 5, Form 6 and Form 7 or a mixture thereof, and at least one pharmaceutically acceptable excipient.

[0201] In the seventeenth aspect, the present application provides a novel method for preparing anlotinib dihydrochloride of formula (I), the novel method comprising:

[0202]

[0203] a) debenzylating a compound of formula (II) to a compound of formula (III),

[0204]

[0205] b) reacting a compound of formula (III) with a haloacetonitrile to produce a compound of formula (IV),

[0206]

[0207] c) converting the compound of formula (IV) into the compound of formula (V),

[0208]

[0209] d) reacting a compound of formula (V) with an amine protecting group to produce a compound of formula (VI),

[0210]

[0211] e) coupling a compound of formula (VI) with a compound of formula (VII) to produce a compound of formula (VIII),

[0212] f) reducing the compound of formula (VIII) with a reducing agent to produce a compound of formula (IX);

[0213]

[0214] g) converting the compound of formula (IX) into a compound of formula (I),

[0215]

[0216] Wherein P is an amine protecting group.

[0217] The above step a) reaction can be carried out in the presence of a suitable reagent and an organic solvent.

[0218] Suitable reagents that may be used in step a) include, but are not limited to, methanesulfonic acid, trifluoroacetic acid or mixtures thereof. Alternatively, conventional hydrogenation conditions may be employed using a combination of palladium / carbon and hydrogen under pressure in an organic solvent.

[0219] Suitable organic solvents used in step a) include, but are not limited to, trifluoroacetic acid, ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1,4-dioxane, etc.; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C 3 -C6 Ketones, etc.; aromatic hydrocarbon solvents, such as toluene, xylene, chlorobenzene, tetralin, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, etc.; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, etc.; nitrile solvents, such as acetonitrile, propionitrile, C 2 -C 6 Nitrile, etc.; ester solvents such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, methyl butyrate, ethyl butyrate, etc.; or mixtures thereof.

[0220] The above step b) reaction can be carried out in the presence of a base and an organic solvent.

[0221] The halogenated acetonitrile used in step b) includes, but is not limited to, 2-bromoacetonitrile, 2-chloroacetonitrile and 2-iodoacetonitrile.

[0222] Suitable bases used in step b) include, but are not limited to, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium bicarbonate, potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, hexyllithium or hydride-based bases such as sodium hydride and potassium hydride.

[0223] Suitable organic solvents used in step b) include, but are not limited to, polar aprotic solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidine, formamide, acetamide, etc.; ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1,4-dioxane, etc.; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C 3 -C 6 Ketones, etc.; aromatic hydrocarbon solvents, such as toluene, xylene, chlorobenzene, tetralin, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, etc.; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, etc.; nitrile solvents, such as acetonitrile, propionitrile, C 2 -C 6 Nitrile, etc.; ester solvents such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, methyl butyrate, ethyl butyrate, etc.; or mixtures thereof.

[0224] The above step c) reaction can be carried out in the presence of a suitable reagent and an organic solvent.

[0225] Suitable reagents used in step c) include, but are not limited to, ethylmagnesium bromide, ethylmagnesium chloride, titanium isopropoxide, BF 3 OE 2 And mixtures thereof. Methyl titanium triisopropoxide or chlorotitanium triisopropoxide and Cp 2 Zr(ethylene) can be used as a substitute for titanium tetraisopropoxide. Titanium tetrachloride can be used as BF3 OE 2 alternatives.

[0226] Suitable organic solvents used in step c) include, but are not limited to, polar aprotic solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidine, formamide, acetamide, etc.; ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1,4-dioxane, etc.; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C 3 -C 6 Ketones, etc.; aromatic hydrocarbon solvents, such as toluene, xylene, chlorobenzene, tetralin, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, etc.; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, etc.; nitrile solvents, such as acetonitrile, propionitrile, C 2 -C 6 Nitrile, etc.; ester solvents such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, methyl butyrate, ethyl butyrate, etc.; or mixtures thereof.

[0227] The above step d) reaction can be carried out in the presence of a base and an organic solvent.

[0228] The amine protecting group used in step d) can be any amine protecting group known in the art. Specifically, the amine protecting group is an acid-labile amine protecting group, such as a carbamate group. More specifically, the amine protecting group is tert-butyloxycarbonyl (BOC).

[0229] Suitable bases used in step d) include, but are not limited to, triethylamine, 1,4-diazabicyclo[2.2.2]octane ("DABCO"), 1,8-diazabicyclo[5.4.0]undec-7-ene ("DBU"), tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, etc., or any other suitable reagent. Inorganic bases such as cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide and potassium hydroxide may be used.

[0230] Suitable organic solvents used in step d) include, but are not limited to, polar aprotic solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidine, formamide, acetamide, etc.; ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1,4-dioxane, etc.; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C 3 -C 6Ketones, etc.; aromatic hydrocarbon solvents, such as toluene, xylene, chlorobenzene, tetralin, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, etc.; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, etc.; nitrile solvents, such as acetonitrile, propionitrile, C 2 -C 6 Nitrile, etc.; ester solvents such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, methyl butyrate, ethyl butyrate, etc.; or mixtures thereof.

[0231] The above step e) reaction can be carried out in the presence of a base and an organic solvent.

[0232] Suitable bases used in step e) include, but are not limited to, N,N-diisopropylethylamine, triethylamine, 1,4-diazabicyclo[2.2.2]octane ("DABCO"), 1,8-diazabicyclo[5.4.0]undec-7-ene ("DBU"), tributylamine, N-methylmorpholine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, etc., or any other suitable reagent. Inorganic bases such as cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide and potassium hydroxide can be used.

[0233] Suitable organic solvents used in step e) include, but are not limited to, aromatic hydrocarbon solvents such as toluene, xylene, chlorobenzene, tetralin, etc.; polar aprotic solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidine, formamide, acetamide, etc.; ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1,4-dioxane, etc.; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C 3 -C 6 Ketones, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, etc.; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, etc.; nitrile solvents, such as acetonitrile, propionitrile, C 2 -C 6 Nitrile, etc.; ester solvents such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, methyl butyrate, ethyl butyrate, etc.; or mixtures thereof.

[0234] The above step f) reaction can be carried out in the presence of a reducing agent and an organic solvent.

[0235] Suitable reducing agents used in step f) include, but are not limited to, iron powder, diisobutylaluminum hydride, Raney nickel, sodium hypophosphite, palladium, ammonium chloride, etc.; or any other suitable reducing agent. Palladium / carbon and hydrogen, palladium / carbon and ammonium formate can be used as substitutes. A combination of iron powder and acetic acid can also be used.

[0236] Suitable organic solvents used in step f) include, but are not limited to, water, alcohol solvents such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropanol, ethylene glycol, 1-propanol, 2-propanol (isopropanol), 2-methoxyethanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, 2-ethoxyethanol, etc.; alcohol aromatic hydrocarbon solvents such as toluene, xylene, chlorobenzene, tetralin, etc.; polar aprotic solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidine, formamide, acetamide, etc.; ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1,4-dioxane, etc.; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C 3 -C 6 Ketones, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, etc.; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, etc.; nitrile solvents, such as acetonitrile, propionitrile, C 2 -C 6 Nitrile, etc.; ester solvents such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, methyl butyrate, ethyl butyrate, etc.; or mixtures thereof.

[0237] The above step g) reaction can be carried out in the presence of HCl and an organic solvent.

[0238] Suitable sources of HCl used in step g) include, but are not limited to, hydrochloric acid, methanolic HCl, ethanolic HCl, isopropanol HCl, dioxane-HCl, and the like.

[0239] Suitable organic solvents used in step g) include, but are not limited to, ester solvents such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, methyl butyrate, ethyl butyrate, etc.; ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1,4-dioxane, etc.; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, 1-propanol, etc.; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C 3 -C 6 Ketones, etc.; aromatic hydrocarbon solvents, such as toluene, xylene, chlorobenzene, tetralin, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, etc.; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, etc.; water or a mixture thereof.

[0240] The above steps can be carried out at a temperature between about -20°C and about 200°C, preferably about 0°C and about 150°C, and most preferably about 0°C and about 100°C, depending on the solvent or mixture of solvents used in a particular step.

[0241] The intermediate obtained in the present invention can be directly used in the next step with or without isolation, or if isolated, it can be further purified to improve the purity of the product.

[0242] The present invention has the following advantages:

[0243] Using inexpensive chemicals (such as titanium tetraisopropoxide, ethylmagnesium bromide, and BF 3 OE 2 ) The cyclopropylamine part is provided to make the preparation of anlotinib cost-effective.

[0244] Reduction of the nitro group to the amine in the presence of the ketal prevents the hydroxylamine (i.e., the intermediate in the reduction of the nitro group to the amine) from cyclizing in situ on the ketone to the corresponding N-hydroxyindole.

[0245] In the eighteenth aspect, the present application provides a method for preparing a compound of formula (IV), which comprises reacting a compound of formula (III) with a halogenated acetonitrile.

[0246]

[0247] The present invention further includes the use of the compound of formula (IV) for preparing anlotinib or its salts and intermediates thereof.

[0248] The present invention further includes converting the compound of formula (IV) into anlotinib or a salt thereof (I).

[0249] In a nineteenth aspect, the present application provides a method for preparing a compound of formula (V), which comprises converting a compound of formula (IV) into a compound of formula (V).

[0250]

[0251] The present invention further includes the use of the compound of formula (V) for preparing anlotinib or its salts and intermediates thereof.

[0252] The present invention further includes converting the compound of formula (V) into anlotinib or a salt thereof (I).

[0253] In the twentieth aspect, the present application provides a method for preparing a compound of formula (VI), the method comprising reacting a compound of formula (V) with an amine protecting group,

[0254]

[0255] Wherein P is an amine protecting group.

[0256] The amine protecting group used in step d) can be any amine protecting group known in the art. Specifically, the amine protecting group is an acid-labile amine protecting group, such as a carbamate group. More specifically, the amine protecting group is tert-butyloxycarbonyl (BOC).

[0257] The present invention further includes the use of the compound of formula (VI) for preparing anlotinib or its salts and intermediates thereof.

[0258] The present invention further includes converting the compound of formula (VI) into anlotinib or a salt thereof (I).

[0259] In a twenty-first aspect, the present application provides a method for preparing a compound of formula (VIII), the method comprising reacting a compound of formula (VI) with a compound of formula (VII),

[0260]

[0261] Wherein P is an amine protecting group.

[0262] The present invention further includes the use of the compound of formula (VIII) for preparing anlotinib or its salts and intermediates thereof.

[0263] The present invention further includes converting the compound of formula (VIII) into anlotinib dihydrochloride (I).

[0264] In a twenty-second aspect, the present application provides a method for preparing a compound of formula (IX), the method comprising reducing a compound of formula (VIII) with a reducing agent:

[0265]

[0266] Wherein P is an amine protecting group.

[0267] The present invention further includes the use of the compound of formula (IX) for preparing anlotinib and its salts.

[0268] The present invention further includes converting the compound of formula (IX) into anlotinib dihydrochloride (I).

[0269] In the twenty-third aspect, the present application provides a compound of the following formula:

[0270]

[0271] The present invention further includes the use of the compounds of formula (VI), (VIII) and (IX) for preparing anlotinib and its salts.

[0272] In the twenty-fourth aspect, the present application provides a compound of the following formula:

[0273]

[0274] The present invention further includes the use of compounds of formula (IV), (V), (VIa), (VIIIa) and (IXa) for preparing anlotinib and salts thereof.

[0275] In the twenty-fifth aspect, the present application provides a purification method for preparing anlotinib or a salt thereof of formula (Xa), the purification method comprising:

[0276] a) dissolving anlotinib of formula (X) with an organic acid to form anlotinib acid addition salt of formula (Xa);

[0277] b) precipitating the anlotinib acid addition salt of formula (Xa).

[0278]

[0279] Suitable solvents used in step a) and step b) include, but are not limited to, ester solvents such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, methyl butyrate, ethyl butyrate, etc.; ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1,4-dioxane, etc.; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, 1-propanol, etc.; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C 3 -C 6 Ketones, etc.; aromatic hydrocarbon solvents, such as toluene, xylene, chlorobenzene, tetralin, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, etc.; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, etc.; nitrile solvents, such as acetonitrile, propionitrile, C 2 -C 6 Nitrile, etc.; water, or a mixture thereof. Preferably, the solvent may be ethyl acetate for step a) and acetone for step b).

[0280] Suitable organic acids used in step b) include, but are not limited to, acetic acid, formic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, citric acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, etc. Specifically, the organic acid addition salt is tartaric acid.

[0281] The above steps may be performed at a temperature between about 0°C and about 200°C, preferably about 0°C and about 150°C, and most preferably about 0°C and about 100°C, depending on the solvent or mixture of solvents used in a particular step.

[0282] The salt of Anlotinib of formula (Xa) as obtained in step b) can be crystallized from a suitable solvent.

[0283] The prior art method describes crude anlotinib dihydrochloride containing undesirable impurities and having a purity of only 95-97%. The prior art method describes purification by column chromatography, which may not be suitable for industrial scale preparation. The inventors of the present invention surprisingly found that using an organic acid addition salt of anlotinib as an intermediate led to excellent results, such as purer anlotinib dihydrochloride.

[0284] In the twenty-sixth aspect, the present application provides a method for preparing anlotinib of formula (X), the method comprising:

[0285] a) reacting a compound of formula (XI) with a haloacetonitrile to form a compound of formula (XII);

[0286]

[0287] b) converting the compound of formula (XII) into anlotinib of formula (X).

[0288] The halogenated acetonitrile used in step a) includes, but is not limited to, 2-bromoacetonitrile, 2-chloroacetonitrile and 2-iodoacetonitrile.

[0289] Suitable bases used in step a) include, but are not limited to, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium bicarbonate, potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, hexyllithium or hydride-based bases such as sodium hydride and potassium hydride.

[0290] Suitable organic solvents used in step a) and step b) include, but are not limited to, polar aprotic solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidine, formamide, acetamide, etc.; ether solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1,4-dioxane, etc.; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C 3 -C 6 Ketones, etc.; aromatic hydrocarbon solvents, such as toluene, xylene, chlorobenzene, tetralin, etc.; halogenated hydrocarbons, such as dichloromethane, chloroform, etc.; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, etc.; nitrile solvents, such as acetonitrile, propionitrile, C 2 -C 6 Nitrile, etc.; ester solvents such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, methyl butyrate, ethyl butyrate, etc.; or mixtures thereof.

[0291] Suitable reagents used in step b) include, but are not limited to, ethylmagnesium bromide, ethylmagnesium chloride, titanium isopropoxide, BF 3 OE 2And mixtures thereof. Methyl titanium triisopropoxide or chlorotitanium triisopropoxide and Cp 2 Zr(ethylene) can be used as a substitute for titanium tetraisopropoxide. Titanium tetrachloride can be used as BF 3 OE 2 alternatives.

[0292] In the twenty-seventh aspect, the present application provides an amorphous form of anlotinib tartrate of formula (Xb).

[0293]

[0294] In other embodiments, the present application provides an amorphous form of anlotinib tartrate of formula (Xb), characterized in that it is substantially as follows Fig.11 PXRD shown.

[0295] In another embodiment, the present application relates to the use of anlotinib tartrate of formula (Xb) for preparing pure anlotinib and pharmaceutically acceptable salts thereof.

[0296] Removal of solvent at any stage of the method of the present application can be carried out by methods known in the art or any procedures disclosed in the present application. In a preferred embodiment, removal of solvent can include but is not limited to: evaporation or sublimation of solvent under atmospheric pressure or reduced pressure / vacuum, such as using Rotary distillation, spray drying, freeze drying (lyophilization), stirred thin film drying, etc.

[0297] The compounds at any stage of the present application method can be separated using conventional techniques known in the art. For example, available techniques include, but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentration, cooling, stirring, shaking, combining with anti-solvent, adding crystal seeds, evaporation, flash evaporation, simple evaporation, rotary drying, spray drying, film drying, freeze drying, etc. Separation can be optionally carried out under atmospheric pressure or reduced pressure. The obtained solid may carry a small proportion of the occlusion mother liquor containing a higher percentage of impurities, and the solid can be washed with a solvent as required to wash out the mother liquor.

[0298] The solid obtained can be optionally further dried. Drying can be suitably carried out using equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, etc. at atmospheric pressure or reduced pressure. Drying can be less than about 100 ° C, less than about 60 ° C, less than about 40 ° C or any other suitable temperature, at atmospheric pressure or reduced pressure, and in the presence or absence of an inert atmosphere (such as nitrogen, argon, neon or helium) to carry out. Drying can be carried out for any desired time period, to achieve desired product purity, for example, from about 1 to about 15 hours or longer.

[0299] Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for illustrative purposes only and should not be construed as limiting the scope of the present application in any way.

[0300] Example

[0301] Example 1: Preparation of Anlotinib Dihydrochloride Form 1

[0302] Anlotinib dihydrochloride (200 mg) was placed in an amber 5 ml vial, then methanol (2 mL) was added and stirred at 50°C for 30-60 minutes, the solution was filtered after dissolution, THF (10 mL) was added to the solution at 25°C, precipitation was observed, and the slurry was filtered and sucked dry. The material was kept dry in a vacuum tray dryer at 50°C for 4-5 hours to obtain the title compound.

[0303] PXRD: Anlotinib dihydrochloride form 1 ( Figure 1 ).

[0304] Example 2: Preparation of Anlotinib Dihydrochloride Form 2

[0305] Anlotinib dihydrochloride (300 mg) was placed in an amber 5 ml vial, then DM-water (0.5 mL) was added and kept stirring at 25°C for 3-4 hours, dissolution was initially observed, then precipitation of the material was performed, and PXRD was performed on the precipitate.

[0306] PXRD: Anlotinib dihydrochloride form 2 ( Figure 2 ).

[0307] Example 3: Preparation of Anlotinib Dihydrochloride Form 3

[0308] The anlotinib dihydrochloride form 2 was kept dry in a VTD at 50° C. for 3-4 hours to obtain the title compound.

[0309] PXRD: Anlotinib dihydrochloride form 3 ( Figure 3 ).

[0310] Example 4: Preparation of Anlotinib Dihydrochloride Form 4

[0311] Anlotinib dihydrochloride (200 mg) was placed in an amber 5 ml vial, then N,N-dimethylacetamide (1 mL) was added and kept stirring at 25°C for 30-60 minutes to obtain the title compound.

[0312] PXRD: Anlotinib dihydrochloride form 4 ( Figure 4 ).

[0313] Example 5: Preparation of Anlotinib Dihydrochloride Form 5

[0314] Anlotinib dihydrochloride (50 mg) was placed in an amber 5 ml vial, then formamide (0.2 mL) was added and kept slowly evaporating at 25°C for 50 days, after which precipitation was observed. The material was kept dry in a vacuum tray dryer at 40°C for 48 hours to obtain the title compound.

[0315] PXRD: Anlotinib dihydrochloride form 5 ( Figure 5 ).

[0316] Example 6: Preparation of Anlotinib Dihydrochloride Form 6

[0317] Anlotinib dihydrochloride (300 mg) was placed in an amber 5 ml vial, then formamide (1 mL) and DM-water (0.1 mL) were added and kept stirring at 25°C for 10 hours, initially dissolution was observed, then precipitation of the material was performed, the precipitate was subjected to PXRD.

[0318] PXRD: Anlotinib dihydrochloride form 6 ( Figure 6 ).

[0319] Example 7: Preparation of Anlotinib Dihydrochloride Form 7

[0320] Anlotinib dihydrochloride (1.5 g) was placed in a 25 ml vial, then 2,2,2-trifluoroethanol (15 mL) was added and kept stirring at 25°C for 10 hours. The obtained slurry was filtered and sucked dry. The material was kept dry in a vacuum tray dryer at 40°C for 24 hours to obtain the title compound.

[0321] PXRD: Anlotinib dihydrochloride form 7 ( Figure 7 ).

[0322] Example 8: Preparation of Anlotinib Dihydrochloride Form 7

[0323] Anlotinib dihydrochloride obtained from Example 7 (10 mg) was placed in a TGA pan and heated up to 120°C, the material was kept at 120°C for 30 minutes, then the temperature was lowered to 25°C and PXRD was collected.

[0324] PXRD: Anlotinib dihydrochloride form 7 ( Figure 8 ).

[0325] Example 9: Preparation of 4-chloro-6-methoxyquinoline-7-ol (III)

[0326] At 25-30℃ and N 2Under atmosphere, 7-(benzyloxy)-4-chloro-6-methoxyquinoline (5.0 g; (II)) and TFA (30 mL) were charged into a RB flask. At 25-30° C., methanesulfonic acid (3.21 g) was slowly added to the reaction mixture, which was then heated to 75-80° C. and maintained at the same temperature for 3 hours. The reaction mass was cooled to 25-35° C., and the reaction mass was distilled off. The pH of the resulting reaction mass was adjusted to 7-8 by gradually adding 10% sodium hydroxide solution. The resulting solid thus obtained was filtered, washed with water and dried to obtain the title compound (3.8 g) for the next reaction.

[0327] Mass spectrum: 209.96 (m / z).

[0328] NMR Details: 1 H NMR(DMSO-d6,500MHz): δ8.922(d,1H,J=6.0Hz),7.971(d,1H,J

[0329] =6.0Hz),7.555(s,1H),7.523(s,1H),4.026(s,3H).

[0330] Example 10: Preparation of 2-((4-chloro-6-methoxyquinolin-7-yl)oxy)acetonitrile (IV)

[0331] At 25-30℃ and N 2 Under atmosphere, 4-chloro-6-methoxyquinoline-7-ol (1.0 g; (III)) and DMF (40.0 mL) were loaded into a RB flask. At 25-30 ° C, cesium carbonate (3.11 g, 2.0 equivalents) was loaded into the resulting reaction mass. Subsequently, chloroacetonitrile (0.396 g, 1.1 equivalents) was added to the reaction mixture. The reaction mass thus obtained was stirred overnight at 25-30 ° C. At 25-30 ° C, water was slowly added to the reaction mass and stirred for 10 minutes. The obtained solid was precipitated and filtered to obtain the title compound.

[0332] Yield: 0.7 g, 59.32%; mass spectrum: 248.94 (m / z).

[0333] NMR Details: 1 H NMR (DMSO-d6, 500MHz): δ8.656 (d, 1H, J = 4.5Hz), 7.666 (s, 1H),

[0334] 7.618(d,1H,J=4.5Hz),7.425(s,1H),5.423(s,2H),3.994(s,3H).

[0335] Example 11: Preparation of 1-(((4-chloro-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropane-1-amine (V)

[0336] At 25-30℃ and N 2 Under atmosphere, 2-((4-chloro-6-methoxyquinolin-7-yl)oxy)acetonitrile (0.5 g; (IV)) and THF (15.0 mL) were charged into a RB flask. Subsequently, titanium isopropoxide (0.629 g, 1.1 eq) was charged into the reaction mixture at 25-30° C. Ethylmagnesium bromide (4.42 mL, 1.0 M, 2.2 eq) was slowly charged into the resulting reaction mass over 1 hour at 25-30° C. and maintained at 25-30° C. for 60 minutes. Boron trifluoride etherate (0.57 g, 2.0 eq) was charged into the reaction mass thus obtained at 25-30° C. and maintained for 1.5 hours. The reaction mass was quenched with 10% sodium hydroxide solution. The two layers were separated and the organic layer was concentrated to obtain a crude compound (0.5 g), which was purified by column chromatography to obtain 0.1 g of the title compound.

[0337] Yield: 0.1 g, 17.8%; mass spectrum: 279.19 (M+H).

[0338] NMR Details: 1 H NMR (DMSO-d6, 500MHz): δ8.594 (d, 1H, J = 5.0Hz), 7.542 (d, 1H, J

[0339] =5.0Hz),7.413(s,1H),7.379(s,1H),4.067(s,2H),3.992(s,3H),1.904(s,2H),1.217(s,2H),0.64(d,1H,J=6.0Hz).

[0340] Example 12: Preparation of tert-butyl (1-(((4-chloro-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate (VIa)

[0341] At 25-30℃ and N 2Under atmosphere, 1-(((4-chloro-6-methoxyquinoline-7-yl)oxy)methyl)cyclopropane-1-amine (3.0 g; (V)) and THF (30 mL) were charged into a RB flask. At 25-30° C., triethylamine (2.17 g, 2.0 eq.) was slowly added to the reaction mass. The reaction mass was then cooled to 0° C. At 0° C., di-tert-butyl dicarbonate (3.05 g, 1.3 eq.) was slowly added to the reaction mass, and the reaction mass temperature was slowly raised to 25-30° C., and the reaction mass was stirred overnight. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate, and the organic layer was concentrated to obtain a solid compound. The crude solid thus obtained was recrystallized in acetonitrile (10 V) to obtain the title compound (1.6 g).

[0342] Yield: 39.24%; Mass spectrum: 379.27 (M+H + )

[0343] NMR Details: 1 H NMR (DMSO-d6, 500MHz): δ8.591 (d, 1H, J = 4.0Hz), 7.537 (d, 1H, J

[0344] =4.0Hz),7.422(s,1H),7.680(s,1H),7.351(s,1H),4.189(s,2H),3.973(s,3H),1.341(s,9H),0.855(s,2H),0.773(d,2H).

[0345] Example 13: Preparation of tert-butyl (1-(((4-(2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate (VIIIa)

[0346] At 25-30℃ and N 2 Under atmosphere, tert-butyl (1-(((4-chloro-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate (1.6 g; (VIa)) and 2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)-4-nitrophenol (1.086 g, 1.0 eq.; (VII)), xylene (18.75 mL) were charged in a RB flask. DIPEA (1.637 g, 3.0 eq.) was added to the reaction mass at 25-30°C, and the reaction mass was heated to 135-145°C and maintained at the same temperature for 48 hours. After completion of the reaction, the reaction mass was cooled to 25-30°C, and n-hexane (15 V) was added to the reaction mass at the same temperature. The obtained reaction mass was stirred for 20 minutes and the obtained solid was filtered.

[0347] To the obtained wet compound, tert-butanol (7.5 mL) was charged and stirred for 30 minutes at 25-30° C. The obtained solid was filtered and washed with hexane (7.5 mL) to obtain the title compound (1.7 g).

[0348] Yield: 67.19%; Mass spectrum: 600.45 (M+H + )

[0349] NMR Details: 1 H NMR(DMSO-d6,500MHz): δ8.534(d,1H,J=5.0Hz),7.88(dd,1H,J

[0350] =8.5,1.0Hz),7.560(t,1H,J=8.5Hz),7.494(s,1H),7.419(s,1H),7.36(bs,1H),6.60(d,1H,J=5.5Hz),4.19(s,2H),3. 949(s,3H),3.802-3.774(m,2H),3.482-3.399(m,4H),1.389(s,9H),1.352-1.235(m,5H),0.864(s,2H),0.779(s,2H).

[0351] Example 14: Preparation of tert-butyl (1-(((4-(4-amino-2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)phenoxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate (IXa)

[0352] At 25-30°C, tert-butyl (1-(((4-(2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate (1.7 g; (VIIIa)), isopropanol (17 mL) and water (8.5 mL) were charged into a RB flask. At 25-30°C, Fe powder (2.064 g, 13.0 eq.) and NH 4 Cl (0.455g, 3.0 equivalents) is loaded into the reaction mixture. The resulting reaction mixture is heated to 65 ° C and maintained for 8 hours. After the reaction is completed (monitored by TLC), the reaction mass is cooled to 25-30 ° C, the cooled reaction mass is filtered by hyflo and washed with ethyl acetate. The obtained filtered solution is concentrated under reduced pressure to obtain a brown crude compound. By using 90% ethyl acetate / hexane as eluent, the obtained crude compound is purified by flash column chromatography to obtain the title compound (0.5g) as a brown solid.

[0353] Yield: 30.95%; Mass spectrum: 570.17 (M+H + ).

[0354] Example 15: Preparation of Anlotinib dihydrochloride (I)

[0355] IPA·HCl (5 mL) was added dropwise to a solution of tert-butyl (1-(((4-(4-amino-2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)phenoxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate (0.5 g) in isopropyl acetate (10 mL) maintained at 0-5° C. The obtained reaction mixture was warmed to 55-60° C. and maintained at the same temperature for 5 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was distilled to obtain a brown solid. The obtained solid was washed with isopropyl acetate (4 mL) and finally dried under reduced pressure at 45° C. to obtain the title compound (0.20 g).

[0356] Yield = 47.61%; Mass spectrum: 408.35 (free base - M + H + ); HPLC purity: 88.069%.

[0357] NMR Details: 1 H NMR (DMSO-d6, 500MHz): δ11.703 (s, 1H), 8.921 (bs, 3H), 8.77 (d, 1H, J = 5.5Hz), 7.844-7.834 (m, 2H), 7.30 (d, 1H, J = 7.2Hz), 7.11 (t, 1H,J=6.65Hz),6.83(d,1H,J=5.4Hz),6.321(s,1H),4.448(s,2H),4.091(s,3H),2.433(s,3H),1.243(s,2H),1.096-1.076(m,2H).

[0358] Example 16: Preparation of Anlotinib Tartrate of Formula (Xb) from Anlotinib Dihydrochloride (I)

[0359] Anlotinib dihydrochloride (0.50 g; HPLC purity: 97.42%) was added to EtOAC (5 mL) and stirred. 10% sodium carbonate solution was charged into the resulting reaction mass, and the reaction mass was stirred at room temperature for 45 minutes. The reaction mass was allowed to settle, and the organic layer was separated. The separated organic layer was washed with DM water (5 mL). The separated organic layer was dried over sodium sulfate and distilled to obtain 0.3 g of anlotinib free base, which was used to form tartrate without any characterization.

[0360] Anlotinib tartrate of formula (Xb):

[0361] The thus obtained Anlotinib free base (0.3 g) was dissolved in acetone and the reaction mass was allowed to reach a temperature of 50-55° C. Subsequently, a solution of tartaric acid (1.0 equivalent) dissolved in acetone was added to the reaction mass at 50-55° C. and the resulting reaction mass was maintained at the same temperature for 30 minutes and cooled to room temperature. The resulting solid was filtered and submitted to HPLC purity.

[0362] HPLC purity: 99.06%.

[0363] Example 17: Preparation of Anlotinib Free Base via Cyclopropanation

[0364] Step (a):

[0365] 4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-ol (2.0 gm) was charged into a clean, dry round bottom flask and dissolved in DMF (60.0 mL). Cesium carbonate (3.9 gm) was added to the reaction mixture. 2-bromoacetonitrile (0.5 mL) was dissolved in DMF and slowly added to the reaction mixture through an addition funnel. Stirring was continued for 1 hour. Subsequently, water was charged into the reaction mass and extracted with ethyl acetate. The organic layer was separated and washed with saline solution and dried over sodium sulfate. The crude product thus obtained was purified by column chromatography to obtain the desired solid, which was further used in the next step.

[0366] Step (b):

[0367] Under inert atmosphere, 2-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)acetonitrile (1.0 g) was charged into a clean, dry round-bottom flask. Anhydrous THF (13.0 mL) was charged and stirred for 10 minutes to dissolve the substrate. Subsequently, titanium (IV) isopropoxide (0.86 mL) was added to the reaction mass. Ethyl magnesium bromide (8.5 mL) was slowly added to the reaction mixture over 20 minutes and the reaction was maintained at room temperature for 1 hour. BF was charged into the resulting reaction mass. 3 ·(OEt) 2 (0.65 mL) and maintained for 1 hour. 10% NaOH aqueous solution was added to the reaction mixture and washed with EtOAc / H 2 The reaction mixture was submitted for mass analysis.

[0368] Observed [M+2] + =409.37

[0369] Example 18: Preparation of 2-((4-chloro-6-methoxyquinolin-7-yl)oxy)acetonitrile (IV)

[0370] At 25-30℃ and N 2 At 40 ℃, 4-chloro-6-methoxyquinoline-7-ol (500 g; (III)) and DMF (5.5 L) were loaded into a RB flask. At 25-30 ℃, potassium carbonate (824 g) was loaded into the resulting reaction mass and stirred for 30 minutes. Subsequently, 2-chloroacetonitrile (225 g) in DMF (500 mL) was slowly added to the reaction mixture. The reaction mass was heated to 35-40 ℃ and maintained for 12 hours. The reaction mass was cooled to 30 ℃. At 30 ℃, water (10 L) was slowly added to the reaction mass and stirred for 2 hours. The obtained solid was precipitated and filtered, and washed with water (5 L) to obtain the title compound, which was then dried in vacuo at 45-50 ℃.

[0371] Yield: 92%; purity (by HPLC): 99.65%; mass spectrum: 248.94 (m / z).

[0372] NMR Details: 1 H NMR (DMSO-d6, 500MHz): δ8.656 (d, 1H, J = 4.5Hz), 7.666 (s, 1H),

[0373] 7.618(d,1H,J=4.5Hz),7.425(s,1H),5.423(s,2H),3.994(s,3H).

[0374] Example 19: Preparation of 1-(((4-chloro-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropane-1-amine (V)

[0375] At 25-30℃ and N 2At 40 ℃, 2-((4-chloro-6-methoxyquinolin-7-yl)oxy)acetonitrile (50 g; (IV)) and THF (1380 mL) were charged into a RB flask. The reaction mixture was cooled to 20° C. Subsequently, titanium isopropoxide (74.3 g) was charged into the reaction mixture at 20° C. and maintained for 10 minutes. At 20° C., ethylmagnesium bromide (72.4 g) was slowly added to the reaction mass over 2 hours and maintained at 20° C. for 120 minutes. At 20° C., boron trifluoride etherate (57.1 g) was slowly charged into the reaction mass and maintained for 30 minutes. The reaction mass was quenched with 10% sodium hydroxide solution (200 mL) and ethyl acetate (100 mL). The reaction mass was filtered and washed with ethyl acetate (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (500 mL). The two organic layers were combined and the organic layer was completely concentrated to obtain a crude compound. Ethyl acetate (250mL) is loaded into the crude obtained above and stirred for 2 hours. Filter salt, and the organic layer is loaded into a new RBF. Citric acid solution (25g in 250mL) is added to the organic layer, and stirred for 60 minutes. Separate two layers, and the water layer is adjusted to pH 7-8 with 10% sodium hydroxide solution. Ethyl acetate (500mL) is added to the reaction mass and stirred for 60 minutes. Separate two layers, and extract the water layer with ethyl acetate (500mL). Merge two organic layers. 20% sodium chloride solution is added to the organic layer, and stirred for 60 minutes. Separate two layers, and the solvent from the organic layer is concentrated in vacuo at 48 ° C to obtain the title compound.

[0376] Purity (by HPLC): 76.9%; Mass spectrum: 279.19 (M+H)

[0377] NMR Details: 1 H NMR (DMSO-d6, 500MHz): δ8.594 (d, 1H, J = 5.0Hz), 7.542 (d, 1H, J

[0378] =5.0Hz),7.413(s,1H),7.379(s,1H),4.067(s,2H),3.992(s,3H),1.904(s,2H),1.217(s,2H),0.64(d,1H,J=6.0Hz).

[0379] Example 20: Preparation of tert-butyl (1-(((4-(2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate (VIIIa)

[0380] At 25-30℃ and N 2Under atmosphere, tert-butyl (1-(((4-chloro-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate (100 g; (VIa)) and 2-fluoro-3-((2-methyl-1,3-dioxolane-2-yl)methyl)-4-nitrophenol (67.9 g (VII)), xylene (1000 mL) were charged into RB flask. At 25-30°C, DIPEA (138 mL) was slowly added to the reaction mass, and the reaction mass was heated to 130-140°C and maintained at the same temperature for 48 hours. After completion of the reaction, the reaction mass was cooled to 25-30°C, and n-hexane (1000 mL) was added to the reaction mass at the same temperature. The obtained reaction mass was stirred for 20 minutes and the obtained solid was filtered and washed with n-hexane (500 mL).

[0381] At 25-30 ℃, dichloromethane (1000mL) and water (500mL) are loaded into the wet compound obtained and stirred for 60 minutes at 25-30 ℃. The solid obtained is filtered and washed with dichloromethane (500mL). Two layers are separated, and the aqueous layer is extracted with dichloromethane (500mL). Two layers are separated, and the solvent from the organic layer is completely concentrated under vacuum to obtain a crude compound. Isopropyl alcohol (500mL) is added to obtain a crude compound. The reaction mixture is heated to 50 ℃ and maintained at the same temperature for 2 hours. The reaction mass is cooled to 5 ℃ and maintained for 4 hours. The compound obtained is filtered, and washed with cooling isopropyl alcohol to obtain the title compound.

[0382] Yield: 68.35%; Purity (by HPLC): 97.02%; Mass spectrum: 600.45 (M+H + )

[0383] NMR Details: 1 H NMR(DMSO-d6,500MHz): δ8.534(d,1H,J=5.0Hz),7.88(dd,1H,J

[0384] =8.5,1.0Hz),7.560(t,1H,J=8.5Hz),7.494(s,1H),7.419(s,1H),7.36(bs,1H),6.60(d,1H,J=5.5Hz),4.19(s,2H),3. 949(s,3H),3.802-3.774(m,2H),3.482-3.399(m,4H),1.389(s,9H),1.352-1.235(m,5H),0.864(s,2H),0.779(s,2H).

[0385] Example 21: Preparation of tert-butyl (1-(((4-(4-amino-2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)phenoxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate (IXa)

[0386] At 25-30°C, tert-butyl (1-(((4-(2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate (100 g; (VIIIa)), ethanol (2000 mL) and water (500 mL) were charged into a RB flask. At 25-30°C, Fe powder (46.7 g) and NH 4 Cl (26.8g) was loaded into the reaction mixture. The resulting reaction mixture was heated to 75 ° C and maintained for 4 hours. After the reaction was completed (monitored by TLC), the reaction mass was cooled to 50 ° C. The reaction mass was filtered through hyflow and washed with ethyl acetate (500mL). The obtained filtered solution was concentrated under reduced pressure to obtain a crude compound. Ethyl acetate (1000mL) and water (1000mL) were loaded into the crude compound and stirred for 15 minutes. Two layers were separated. The aqueous layer was extracted with ethyl acetate (500mL). Two organic layers were combined and washed with 20% NaCl solution. The solvent from the organic layer was concentrated under reduced pressure to obtain a crude compound. IPA (300mL) was added to obtain a crude compound. The reaction mass was heated to 60 ° C and maintained for 1 hour. The reaction mass was cooled to 25 ° C and maintained for 12 hours. Similarly, the reaction mass was cooled to 5 ° C and maintained for 4 hours. The reaction mass was filtered, washed with IPA (100mL), and vacuum dried at 50 ° C for 12 hours to obtain the title compound.

[0387] Yield: 88%; Purity (by HPLC): 99.2%

[0388] Example 22: Preparation of Anlotinib Free Base

[0389] Trifluoroethanol (500 mL), tert-butyl (1-(((4-(4-amino-2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)phenoxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropyl)carbamate (100 g) were charged into the reactor. The reaction mixture was heated to 40-45° C. A mixture of IPA·HCl (250 mL) and isopropanol (200 mL) was added to the reaction mass at 45° C. and maintained for 3 hours. The reaction mass was cooled to 25-30° C. DM-water (1200 mL) was added to the reaction mass at 25° C. and stirred for 10 minutes. Aqueous ammonia solution (180 mL) and water (300 mL) were added to the reaction mass at 25° C. and maintained for 12 hours. The obtained solid was filtered and washed with water (500 mL). The obtained wet compound was dried at 50°C under vacuum for 6 hours to obtain the title compound.

[0390] The above dried compound (57g), trifluoroethanol (69mL) are loaded into the reactor. The reaction mass is heated to 50 ℃ and maintained for 20 minutes. At 50 ℃, isopropanol (570mL) is slowly added to the reaction mass, and maintained for 2 hours. The reaction mass is cooled to 25 ℃ and maintained for 12 hours. Similarly, the reaction mass is cooled to 5 ℃ and maintained for 4 hours. The obtained compound is filtered, and washed with IPA (114mL) to obtain the title compound. The obtained compound is vacuum dried at 50 ℃ for 12 hours.

[0391] Yield: 87.7 g; purity (by HPLC): 99.73%

[0392] NMR details: 1H NMR (DMSO-d6, 500 MHz): δ 11.42 (s, 1H), 8.41-8.42 (bs, 1H), 7.61 (s, 1H) 7.37 (s, 1H), 7.23-7.21 (d, 1H), 7.01-6.98 (t, 1H), 6.33-6.32 (d, 1H) 6.27 (s, 1H), 4.04 (s, 2H) 3.99 (s, 3H), 2.50 (s, 3H), 2.03 (s, 2H), 0.65-0.59 (m, 4H).

[0393] Example 23: Preparation of Anlotinib dihydrochloride (I) Form 7

[0394] Anlotinib free base (3 g), trifluoroethanol (15 mL) were loaded and stirred at 25 ° C for 10 minutes. At 25 ° C, IPA·HCl (4.5 mL) was added dropwise to the reaction mass and maintained for 60 minutes. At 25 ° C, IPA (10.5 mL) was slowly added to the reaction mass and maintained for 12-15 hours. The reaction mass was filtered and washed with a mixture of trifluoroethanol (4.5 mL) and IPA (4.5 mL) to obtain the title compound. The obtained compound was vacuum dried at 25 ° C for 5 hours and then vacuum dried at 40 ° C for 24 hours.

[0395] Yield: 85%; purity (by HPLC): 99.70%.

Claims

1. Anlotinib dihydrochloride crystal form 7, characterized in that One or more of the following: (i) a PXRD comprising peaks at about 5.5, 6.2, 10.4, 11.2, 12.5, 14.17, 15.4, 16.3, 18.4, 19.3, 21.1, 23.3, 25.1, 26.2, 26.7, 27.16, 27.8, 28.3, 30.7, 31.8, 34.1, 37.5, 38.2 ± 0.2° 2θ; (ii) Differential Scanning Calorimetry (DSC) showed an onset of endothermic absorption at about 196±5°C.

2. The anlotinib dihydrochloride crystalline form 7 according to claim 1, wherein the crystalline form is characterized in that the PXRD spectrum has peaks positioned substantially as shown in the spectrum of Figure 7 or Figure 8.

3. A pharmaceutical composition comprising anlotinib dihydrochloride form 7 according to claim 1 and at least one pharmaceutically acceptable excipient.

4. A method for preparing anlotinib dihydrochloride of formula (I), comprising: a) reacting a compound of formula (III) with a haloacetonitrile to produce a compound of formula (IV), b) converting the compound of formula (IV) into a compound of formula (V), c) reacting a compound of formula (V) with an amine protecting group to produce a compound of formula (VI), d) coupling a compound of formula (VI) with a compound of formula (VII) to produce a compound of formula (VIII), e) reducing the compound of formula (VIII) with a reducing agent to produce a compound of formula (IX); f) converting the compound of formula (IX) into a compound of formula (I), Wherein P is an amine protecting group.

5. Compounds of formula (VI): Wherein P is an amine protecting group.

6. Compounds of formula (VIII): Wherein P is an amine protecting group.

7. Compounds of formula (IX): Wherein P is an amine protecting group.

8. Compounds of formula (IV):

9. Compounds of formula (V):

10. A method for preparing anlotinib of formula (X), comprising: a) reacting a compound of formula (XI) with a haloacetonitrile to form a compound of formula (XII); b) converting the compound of formula (XII) into anlotinib of formula (X).

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