(19)
(11)EP 3 275 866 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
04.12.2019 Bulletin 2019/49

(21)Application number: 16771228.0

(22)Date of filing:  08.03.2016
(51)Int. Cl.: 
C07D 213/82  (2006.01)
A61K 31/4412  (2006.01)
A61P 29/00  (2006.01)
C07D 405/12  (2006.01)
A61P 35/00  (2006.01)
(86)International application number:
PCT/CN2016/075853
(87)International publication number:
WO 2016/155473 (06.10.2016 Gazette  2016/40)

(54)

P-TOLUENESULFONATE FOR MEK KINASE INHIBITOR, AND CRYSTAL FORM THEREOF AND PREPARATION METHOD THEREFOR

P-TOLUENSULFONAT FÜR MEK-KINASEHEMMER UND KRISTALLINE FORM SOWIE HERSTELLUNGSVERFAHREN DAFÜR

P-TOLUÈNESULFONATE POUR INHIBITEUR DE KINASE MEK, FORME CRISTALLINE DE CELUI-CI ET PROCÉDÉ DE PRÉPARATION DE CELUI-CI


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 27.03.2015 CN 201510141303

(43)Date of publication of application:
31.01.2018 Bulletin 2018/05

(73)Proprietor: Jiangsu Hengrui Medicine Co., Ltd.
Jiangsu 222047 (CN)

(72)Inventors:
  • WU, Guaili
    Lianyungang Jiangsu 222047 (CN)
  • GAO, Xiaohui
    Lianyungang Jiangsu 222047 (CN)
  • BIAN, Lin
    Lianyungang Jiangsu 222047 (CN)
  • JIA, Junlei
    Lianyungang Jiangsu 222047 (CN)

(74)Representative: Pistolesi, Roberto et al
Dragotti & Associati Srl Via Nino Bixio, 7
20129 Milano
20129 Milano (IT)


(56)References cited: : 
WO-A1-2009/129938
WO-A1-2015/058589
US-A1- 2010 063 053
US-A1- 2012 238 599
WO-A1-2014/204263
CN-A- 102 459 188
US-A1- 2010 063 053
  
     
    Remarks:
    The file contains technical information submitted after the application was filed and not included in this specification
     
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description

    FIELD OF THE INVENTION



    [0001] The present invention relates to a p-toluenesulfonate of a MEK kinase inhibitor and crystal form I thereof, in particular to a 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide p-toluenesulfonate and crystal form I thereof.

    BACKGROUND OF THE INVENTION



    [0002] Melanoma is one of the common malignant tumors in clinical practice, and it is also one of the malignant tumors with fastest growing incidence, the annual growth rate of which is 3-5%. The annual number of new case of melanoma around the world is 199627, and the number of dead case is 46327. Although the incidence of melanoma is low in China, it has multiplied in recent years. In China, the incidence on 2000 is merely 0.2/100,000, the incidence on 2005-2007 is 1/100,000, the annual number of new case is about 20,000. Therefore, melanoma has become one of the diseases that seriously threaten the health of Chinese people.

    [0003] At present in China, the study of drugs for the treatment of this disease is still in initial stage. The drugs Vemurafenib tablet and Ipilimumab (a monoclonal antibody) are useful for the treatment of melanoma, but these two drugs may cause other skin diseases such as squamous cell carcinoma and the like while exert their activity. Therefore, it is of great significance to find effective drugs for the treatment of melanoma.

    [0004] According to results of clinical feedback, MEK kinase inhibitor has an excellent efficacy on the "king of cancers", i.e. advanced melanoma. Therefore, MEK kinase inhibitor has become a hot anti-cancer target, for which many major companies compete to develop.

    [0005] The patent application US2010063053 discloses 6-oxo-1,6-dihydropyridine compounds useful as inhibitors of MEK. The patent application PCT/CN2014/085976 of the present applicant provides a MEK kinase inhibitor of following formula, the chemical name of which is 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide. It has been found that this compound has strong inhibition activity on MEK kinase. It has the prospect to be developed as a new drug for the treatment of melanoma, and provides a new therapeutic selection for melanoma patients.



    [0006] It is known by those skilled in the art that a compound in the form of free base is usually pharmaceutically unacceptable due to its defects of property. For most of the drugs, it need to provide active compounds in other forms in order to improve these defects, and it is a common solution to transform compounds in the form of free base into pharmaceutically acceptable salts thereof. In addition, the crystal structure of the pharmaceutically active ingredient often affects the chemical stability of the drug. Different crystallization conditions and storage conditions can lead to changes in the crystal structure of the compound, and sometimes the accompanying production of other forms of crystal form. In general, an amorphous drug product does not have a regular crystal structure, and often has other defects such as poor product stability, smaller particle size, difficult filtration, easy agglomeration, and poor liquidity. Therefore, it is necessary to improve the various properties of the above product. There is a need to search a new crystal form with high purity and good chemical stability.

    SUMMARY OF THE INVENTION



    [0007] The present invention provides a 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide p-toluenesulfonate (as shown in formula (I)).



    [0008] The compound of formula (I) can be obtained by reacting p-toluenesulfonic acid with 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3 -carboxamide.

    [0009] Compared to 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide, the solubility and bioavailability of the compound of formula (I) has been greatly improved, and the compound of formula (I) is more pharmaceutically acceptable.

    [0010] A series of crystal products of the compound of formula (I) have been obtained under various crystallization conditions, and X-ray diffraction and differential scanning calorimetry (DSC) measurement have been conducted on the crystal products obtained. It was found that a stable crystal form of the compound of formula (I), which is referred to as crystal form I, can be obtained under specific crystallization condition of the present invention. The DSC spectrum of crystal form I of the present application shows a melting endothermic peak at about 237 °C. The X-ray powder diffraction spectrum, which is obtained by using Cu-Ka radiation and represented by 2θ angle and interplanar distance (d value), is shown in Figure 1, in which there are characteristic peaks at about 10.18 (8.68), 11.51 (7.68), 12.34 (7.17), 12.97 (6.82), 13.72 (6.45), 14.83 (5.97), 15.76 (5.62), 17.13 (5.17), 17.59 (5.04), 17.92 (4.95), 18.50 (4.79), 19.72 (4.50), 20.03 (4.43), 20.42 (4.35), 21.04 (4.22), 21.51 (4.13), 21.88 (4.06), 23.15 (3.84), 24.14 (3.68), 24.53 (3.63), 24.77 (3.59), 25.88 (3.44) and 26.37 (3.38).

    [0011] The present invention also provides a method of preparing crystal form I of 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide p-toluenesulfonate. The method comprises the following steps of:
    1. (1) dissolving p-toluenesulfonic acid and 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide, or any crystal form or amorphous form of the compound of formula (I) into an organic solvent or a mixed solvent of an organic solvent and water to precipitate a crystal, wherein the organic solvent is selected from one or more of alcohols, ketones, nitriles and ethers having 3 or less carbon atoms;
    2. (2) filtering the crystal, then washing and drying it.


    [0012] In a preferable embodiment of the present invention, in step (1), the organic solvent is preferably methanol, ethanol or isopropanol; the mixed solvent of organic solvent and water is preferably methanol/water, ethanol/water, isopropanol/water, acetonitrile/water, acetone/water or tetrahydrofuran/water.

    [0013] Further, the most preferable single solvent is isopropanol.

    [0014] In an embodiment of the present invention, the preferable mixed solvent is acetone/water, and the ratio of the two is not particularly limited. In a preferable embodiment of the present invention, the volume ratio of the two is 9:1.

    [0015] The recrystallization method is not particularly limited, and can be carried out by a conventional recrystallization process. For example, the material, i.e., the compound of formula (I), can be dissolved in a solvent under heating, and then the solution is cooled slowly to precipitate a crystal. After the completion of crystallization, the desired crystal can be obtained via filtering and drying. In particular, the crystal obtained by filtration is usually dried in vacuum under reduced pressure at a heating temperature of about 30∼100°C, preferably 40∼60°C, to remove the recrystallization solvent.

    [0016] The resulting crystal form of the compound of formula (I) is determined by DSC and X-ray diffraction spectra. Meanwhile, the residual solvent in the obtained crystal is also determined.

    [0017] Crystal form I of the compound of formula (I) prepared according to the method of the present invention does not contain or contains only a relatively low content of residual solvent, which meets the requirement of the National Pharmacopoeia concerning the limitation of the residual solvent of drug products. Therefore, the crystal of the present invention is suitable for use as pharmaceutical active ingredient.

    [0018] The research results show that crystal form I of the compound of formula (I) prepared according to present invention is stable under conditions of high temperature and high humidity, crystal form I is also stable under conditions of grinding, pressure and heating, which meets the production, transportation and storage requirements of drug products. The preparation process thereof is stable, repeatable and controllable, which is suitable for industrial production.

    DESCRIPTION OF THE DRAWINGS



    [0019] 

    Figure 1 is the X-ray powder diffraction spectrum of crystal form I of the compound of formula (I).

    Figure 2 is the DSC spectrum of crystal form I of the compound of formula (I).


    DETAILED DESCRIPTION OF THE INVENTION



    [0020] The present invention is illustrated by the following examples in detail. The examples of the present invention are merely intended to describe the technical solution of the present invention, and should not be considered as limiting the scope of the present invention.

    Test instruments used in the experiments


    1. DSC spectrum



    [0021] 

    Instrument type: Mettler Toledo DSC 1 Staree System

    Purging gas: Nitrogen

    Heating rate: 10.0 °C/min

    Temperature range: 40-300 °C


    2. X-ray diffraction spectrum



    [0022] 

    Instrument type: Bruker D8 Focus X-ray powder diffractometer

    Ray: monochromatic Cu-Kα ray (λ=1.5406)

    Scanning mode: θ/2θ, Scanning range: 2-40°

    Voltage: 40 KV, Electric current: 40 mA



    [0023] Example 1: Preparation of 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3 -carboxamide


    Step 1


    1-(2-fluoro-4-iodophenyl)urea



    [0024] 2-fluoro-4-iodoaniline 1a (50.80 g, 214 mmol) was dissolved in 254 mL of trichloromethane, followed by addition of triethylamine (60 mL, 429 mmol). The reaction solution was cooled down to 0°C, and added with N,N'-carbonyldiimidazole (69.50 g, 429 mmol). After stirring for 15 minutes, the reaction solution was warmed up to room temperature and stirred for 4 hours. The reaction solution was cooled down to 0°C, then added with 254 mL of ammonia water and filtered. The filter cake was washed with water (50 mL×2), trichloromethane (20 mL×2) and ethyl acetate (50 mL×2) successively, and dried to obtain the crude title compound 1-(2-fluoro-4-iodophenyl)urea 1b (53 g, white solid), which was used directly in the next step without further purification.
    MS m/z (ESI): 281.0 [M+1]

    Step 2


    2-cyano-N-((2-fluoro-4-iodophenyl)carbamoyl)acetamide



    [0025] The crude 1-(2-fluoro-4-iodophenyl)urea 1b (113 g, 404 mmol) was dissolved in 450 mL of N,N-dimethylformamide, followed by addition of 2-cyanoacetic acid (41 g, 488 mmol). After cooling down to 0°C, the reaction solution was added with methanesulfonyl chloride (55.44 g, 484 mmol), then warmed up to room temperature and stirred for 2 hours. The reaction solution was added with 780 mL of a mixed solution of water and isopropanol (V: V = 1: 2), stirred for 1 hour, and filtered. The filter cake was washed with water (200 mL×2) and ethyl acetate (50 mL) successively, and dried to obtain the crude title compound 2-cyano-N-((2-fluoro-4-iodophenyl)carbamoyl)acetamide 1c (143 g, white solid), which was used directly in the next step without further purification.
    MS m/z (ESI): 345.9 [M-1]

    Step 3


    6-amino-1-(2-fluoro-4-iodophenyl)pyrimidine-2,4(1H,3H)-dione



    [0026] The crude 2-cyano-N-((2-fluoro-4-iodophenyl)carbamoyl)acetamide 1c (156 g, 430 mmol) was dissolved in 628 mL of water, followed by addition of 2 M sodium hydroxide solution (22.6 mL, 42 mmol). The reaction solution was warmed up to 85°C and stirred for 1 hour. After cooling down to 0°C, the reaction solution was added dropwise with 2 M hydrochloric acid to adjust the pH to 3, followed by addition of 300 mL of isopropanol, and filtered. The filter cake was washed with water (200 mL×2) and isopropanol (100 mL×3) successively, and dried to obtain the crude title compound 6-amino-1-(2-fluoro-4-iodophenyl)pyrimidine-2,4(1H,3H)-dione 1d (128 g, white solid), which was used directly in the next step without further purification.
    MS m/z (ESI): 348.0 [M+1]

    Step 4


    (E)-N'-(3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N -dimethylformamidine



    [0027] The crude 6-amino-1-(2-fluoro-4-iodophenyl)pyrimidine-2,4(1H,3H)-dione 1d (128 g, 368.80 mmol) was dissolved in 250 mL of N,N-dimethylformamide, followed by addition of N,N-dimethylfirmanmide dimethyl acetal (124 mL, 935 mmol), and stirred for 4.5 hours. The reaction solution was added with 720 mL of a mixed solution of water and isopropanol (V: V = 5: 1), stirred for 1 hour, and filtered. The filter cake was washed with water (200 mL×2) and isopropanol (50 mL×2) successively, and dried to obtain the crude title compound (E)-N'-(3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dim ethylformamidine 1e (132 g, white solid), which was used directly in the next step without further purification.
    MS m/z (ESI): 403.0 [M+1]

    Step 5


    (E)-N'-(3-(2-fluoro-4-iodophenyl)-1-(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahyd ropyrimidin-4-yl)-N,N-dimethylformamidine



    [0028] The crude (E)-N'-(3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-N,N-dim ethylformamidine 1e (20 g, 50 mmol) was dissolved in 150 mL of N,N-dimethylformamide, followed by addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (22.4 mL, 150 mmol) and 4-methoxybenzyl chloride (14.1 mL, 104.30 mmol). The reaction solution was warmed up to 75°C and stirred for 3 hours. After cooling down to room temperature, the reaction solution was added with 675 mL of a mixed solution of water and isopropanol (V: V = 2: 1), stirred for 1 hour and filtered. The filter cake was washed with water (200 mL×2) and isopropanol (50 mL×2) successively, and dried to obtain the crude title compound (E)-N'-(3-(2-fluoro-4-iodophenyl)-1-(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropy rimidin-4-yl)-N,N-dimethylformamidine 1f (35 g, white solid), which was used directly in the next step without further purification.
    MS m/z (ESI): 523.0 [M+1]

    Step 6


    1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6-(methylamino)pyrimidine-2,4(1 H,3H)-dione



    [0029] Sodium borohydride (3.80 g, 100 mmol) was dissolved in 210 mL of a mixed solution of ethanol and tert-butanol (V: V = 1: 2), followed by addition of the crude (E)-N'-(3-(2-fluoro-4-iodophenyl)-1-(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropy rimidin-4-yl)-N,N-dimethylformamidine 1f (35 g, 67 mmol). The reaction solution was warmed up to 65°C and stirred for 1 hour. After cooling down to 0°C, the reaction solution was added with 175 mL of water and 140 mL of 10% citric acid successively, and filtered. The filter cake was washed with water (200 mL×2) and isopropanol (50 mL×2) successively, and dried to obtain the crude title compound 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6-(methylamino)pyrimidine-2,4(1H,3H )-dione 1g (33 g, white solid), which was used directly in the next step without further purification.
    MS m/z (ESI): 482.0 [M+1]

    Step 7


    1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-8-methylpyrido[2,3-d] pyrimidine-2,4,7(1H,3H,8H)-trione



    [0030] The crude 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6-(methylamino)pyrimidine-2,4(1H,3H )-dione 1g (10.80 g, 22.44 mmol) and diethyl malonate (21.20 g, 157.09 mmol) were dissolved in 100 mL of phenyl ether. The reaction solution was warmed up to 230°C and stirred for 1 hour. After cooling down to room temperature, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with elution system B to obtain the title compound 1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-8-methylpyrido[2,3-d]pyri midine-2,4,7(1H,3H,8H)-trione 1h (8.97 g, orange solid), yield: 72.9%.
    MS m/z (ESI): 550.0 [M+1]

    Step 8


    1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-8-methyl-2,4,7-trioxo-pyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate



    [0031] 1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-8-methylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione 1h (8.97 g, 16.33 mmol) was dissolved in 100 mL of dichloromethane, followed by addition of triethylamine (7.00 g, 65.32 mmol). After cooling down to 0°C, the reaction solution was added with trifluoromethanesulfonic anhydride (9.21 g, 32.66 mmol), then warmed up to room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with elution system B to obtain the title compound 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-8-methyl-2,4,7-trioxo-pyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate 1j (4.13 g, yellow solid), yield: 37.1%.
    MS m/z (ESI): 682.0 [M+1]

    Step 9


    5-(6-methylpyridin-3-yloxy)-1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-8-m ethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione



    [0032] 6-methyl-3-hydroxy-pyridine (26 mg, 0.24 mmol) was dissolved in 5 mL of tetrahydrofuran, followed by addition of sodium hydride (12 mg, 0.30 mmol). After stirring for 2 hours, the reaction solution was added with 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-8-methyl-2,4,7-trioxo-pyrido[2,3-d]pyr imidin-5-yl trifluoromethanesulfonate 1j (136 mg, 0.20 mmol), and warmed up to 60°C and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 5-(6-methylpyridin-3-yloxy)-1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-8-methylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-t rione 31a (128 mg, pale yellow liquid), which was used directly in the next step without further purification.
    MS m/z (ESI): 641.1 [M+1]

    Step 10


    4-(6-methylpyridin-3-yloxy)-2-(2-fluoro-4-iodophenylamino)-N-(4-methoxybenzyl )-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide



    [0033] The crude 5-(6-methylpyridin-3-yloxy)-1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-8-methylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione 1k (128 mg, 0.20 mmol) was dissolved in 6 mL of a mixed solution of tetrahydrofuran and water (V: V = 4: 1), followed by addition of lithium hydroxide (168 mg, 4 mmol). The reaction solution was warmed up to 40°C and stirred for 1 hour, followed by addition of 50 mL of ethyl acetate. The organic phase was washed with 1 M sodium hydroxide solution (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 4-(6-methylpyridin-3-yloxy)-2-(2-fluoro-4-iodophenylamino)-N-(4-methoxybenzyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide 1l (123 mg, brown oil), which was used directly in the next step without further purification.
    MS m/z (ESI): 615.0 [M+1]

    Step 11


    4-(6-methylpyridin-3-yloxy)-2-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3 -carboxamide



    [0034] The crude 4-(6-methylpyridin-3-yloxy)-2-(2-fluoro-4-iodophenylamino)-N-(4-methoxybenzyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide 1l (123 mg, 0.20 mmol) was dissolved in 5 mL of anisole, followed by addition of aluminum chloride (133 mg, 1 mmol). The reaction solution was warmed up to 120°C and stirred for 4 hours, followed by addition of 50 mL of ethyl acetate and 15 mL of water. The organic phase was washed with water (25 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative separation method to obtain the title compound 2-(2-fluoro-4-iodophenylamino)-1-methyl-4-(6-methylpyridin-3-yloxy)-6-oxo-1,6-dihy dropyridine-3-carboxamide 1 (30 mg, light brown solid), yield: 30.3%.
    MS m/z (ESI): 495.0 [M+1]
    1H NMR (400 MHz, DMSO-d6): δ 9.78 (s, 1H), 8.38-8.44 (m, 1H), 7.57-7.75 (m, 4H), 7.35-7.49 (m, 2H), 6.65 (t, 1H), 5.09 (s, 1H), 3.15 (s, 3H), 2.51 (s, 3H).

    Example 2



    [0035] 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide (1 g, 2.02 mmol), p-toluenesulfonic acid (0.39 g, 2.27 mmol) and isopropanol (20.41 g) were added to a flask, and refluxed for 2-2.5 h. The heating was stopped, and the reaction mixture was stirred continuously for 12-14 h. The reaction was terminated and filtered, and the filter cake was washed with isopropanol (100 g), dried at 40-45°C under reduced pressure for 6-7 hours to obtain a solid (1.10 g) in an yield of 81.6%. The X-ray powder diffraction spectrum of crystal sample is shown in Figure 1, in which there are characteristic peaks at about 10.18 (8.68), 11.51 (7.68), 12.34 (7.17), 12.97 (6.82), 13.72 (6.45), 14.83 (5.97), 15.76 (5.62), 17.13 (5.17), 17.59 (5.04), 17.92 (4.95), 18.50 (4.79), 19.72 (4.50), 20.03 (4.43), 20.42 (4.35), 21.04 (4.22), 21.51 (4.13), 21.88 (4.06), 23.15 (3.84), 24.14 (3.68), 24.53 (3.63), 24.77 (3.59), 25.88 (3.44) and 26.37 (3.38). The DSC spectrum is shown in Figure 2, having a sharp melting endothermic peak at about 237 °C. The crystal form was defined as crystal form I.

    Example 3



    [0036] The compound of formula (I) (1.0 g, 1.50 mmol) (prepared according to Example 2) was added to a 50 ml one-necked flask, and dissolved in 28 mL of methanol under heating. The mixture was cooled to room temperature to precipitate a crystal under stirring. The mixture was filtered and dried in vacuum to obtain a solid (0.30 g, yield: 30.0%). The product was identified as crystal form I after studying and comparing the X-ray diffraction and DSC spectra.

    Example 4



    [0037] The compound of formula (I) (1.0 g, 1.50 mmol) (prepared according to Example 2) was added to a 250 ml one-necked flask, and dissolved in 100 mL of ethanol under heating. The mixture was cooled to room temperature to precipitate a crystal under stirring. The mixture was filtered and dried in vacuum to obtain a solid (0.40 g, yield: 40.0%). The product was identified as crystal form I after studying and comparing the X-ray diffraction and DSC spectra.

    Example 5



    [0038] The compound of formula (I) (1.0 g, 1.50 mmol) (prepared according to Example 2) was added to a 25 ml one-necked flask, and dissolved in 6 mL of 95% methanol under heating. The mixture was cooled to room temperature to precipitate a crystal under stirring. The mixture was filtered and dried in vacuum to obtain a solid (0.48 g, yield: 48.0%). The product was identified as crystal form I after studying and comparing the X-ray diffraction and DSC spectra.

    Example 6



    [0039] The compound of formula (I) (1.0 g, 1.50 mmol) (prepared according to Example 2) was added to a 50 ml one-necked flask, and dissolved in 24 mL of 95% ethanol under heating. The mixture was cooled to room temperature to precipitate a crystal under stirring. The mixture was filtered and dried in vacuum to obtain a solid (0.50 g, yield: 50.0%). The product was identified as crystal form I after studying and comparing the X-ray diffraction and DSC spectra.

    Example 7



    [0040] The compound of formula (I) (1.0 g, 1.50 mmol) (prepared according to Example 2) was added to a 50 ml one-necked flask, and dissolved in 18 mL of 90% isopropanol under heating. The mixture was cooled to room temperature to precipitate a crystal under stirring. The mixture was filtered and dried in vacuum to obtain a solid (0.48 g, yield: 48.0%). The product was identified as crystal form I after studying and comparing the X-ray diffraction and DSC spectra.

    Example 8



    [0041] The compound of formula (I) (1.0 g, 1.50 mmol) (prepared according to Example 2) was added to a 50 ml one-necked flask, and dissolved in 12 mL of 90% acetonitrile under heating. The mixture was cooled to room temperature to precipitate a crystal under stirring. The mixture was filtered and dried in vacuum to obtain a solid (0.46 g, yield: 46.0%). The product was identified as crystal form I after studying and comparing the X-ray diffraction and DSC spectra.

    Example 9



    [0042] The compound of formula (I) (1.0 g, 1.50 mmol) (prepared according to Example 2) was added to a 50 ml one-necked flask, and dissolved in 28 mL of 95% tetrahydrofuran under heating. The mixture was cooled to room temperature to precipitate a crystal under stirring. The mixture was filtered and dried in vacuum to obtain a solid (0.70 g, yield: 70.0%). The product was identified as crystal form I after studying and comparing the X-ray diffraction and DSC spectra.

    Example 10



    [0043] The compound of formula (I) (1.0 g, 1.50 mmol) (prepared according to Example 2) was added to a 50 ml one-necked flask, and dissolved in 20 mL of 90% acetone under heating. The mixture was cooled to room temperature to precipitate a crystal under stirring. The mixture was filtered and dried in vacuum to obtain a solid (0.54 g, yield: 54.0%). The product was identified as crystal form I after studying and comparing the X-ray diffraction and DSC spectra.

    Example 11



    [0044] The compound of formula (I) (1.0 g, 1.50 mmol) (prepared according to Example 2) was added to a 50 ml one-necked flask, followed by addition of 20 mL of 90% acetone. The mixture was heated to reflux until the solution was clear. The solution was cooled to room temperature, and 40 mL of acetone was added during the cooling process to precipitate a crystal under stirring. On the next day, the mixture was filtered and dried to obtain a white solid (710 mg, yield: 71.0%).

    Example 12



    [0045] The product sample of crystal form I prepared in Example 2 was spread flat in the air, to test its stability under conditions of lighting, heating (40 °C, 60 °C), and high humidity (RH 75%, RH 90%). Samplings were carried out on Day 5 and Day 10. The purity as detected by HPLC is shown in Table 1.
    Table 1. Stability of crystal form I of the compound of formula (I)
    Batch numberTime (day)4500 Lux40 °C60 °CRH75%RH90%
    S011312140508 0 98.86% 98.86% 98.86% 98.86% 98.86%
    5 99.08% 98.85% 98.89% 98.88% 98.86%
    10 99.17% 98.88% 98.88% 98.88% 98.88%


    [0046] After crystal form I of the compound of formula (I) was spread flat in the air under conditions of lighting, heating, and high humidity, the results of the stability study showed that lighting, high humidity and high temperature do not have much effect on the quality of product, and demonstrated that the crystal form I has good stability.

    Example 13



    [0047] Crystal form I of the compound of formula (I) prepared according to the method of Example 2 was ground, heated and pressed. The results showed that the crystal form is stable. The detailed experimental data are shown in Table 2 below.
    Table 2. Special stability study of crystal form I of the compound of formula (I)
    Batch numberTreatment ProcessExperimental procedureCrystal formDSC peak
    S011312140508G Grinding treatment for 10 min 1 g sample of crystal form I of the compound of formula (I) was ground for 10 min in a mortar under nitrogen atmosphere. Crystal form I DSC peak 237.66 °C
    S011312140508H Heating treatment for 3 h at 80°C 1 g sample of crystal form I of the compound of formula (I) was spread flat and heated at 80°C for 3 h. Crystal form I DSC peak 237.45 °C
    S011312140508P Pressing treatment Sample of crystal form I of the compound of formula (I) was pressed to a slice. Crystal form I DSC peak 237.75 °C



    Claims

    1. 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide p-toluenesulfonate of formula (I),


     
    2. Crystal form I of the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 1, characterized in that the crystal has an X-ray powder diffraction spectrum, which is obtained by using Cu-Ka radiation and represented by 2θ angle, as shown in Figure 1, in which there are characteristic peaks at about 10.18, 11.51, 12.34, 12.97, 13.72, 14.83, 15.76, 17.13, 17.59, 17.92, 18.50, 19.72, 20.03, 20.42, 21.04, 21.51, 21.88, 23.15, 24.14, 24.53, 24.77, 25.88 and 26.37.
     
    3. The crystal form I according to claim 2, characterized in that the crystal has an X-ray powder diffraction spectrum, which is obtained by using Cu-Ka radiation and represented by 2θ angle and interplanar distance, as shown in Figure 1, in which there are characteristic peaks at about 10.18 (8.68), 11.51 (7.68), 12.34 (7.17), 12.97 (6.82), 13.72 (6.45), 14.83 (5.97), 15.76 (5.62), 17.13 (5.17), 17.59 (5.04), 17.92 (4.95), 18.50 (4.79), 19.72 (4.50), 20.03 (4.43), 20.42 (4.35), 21.04 (4.22), 21.51 (4.13), 21.88 (4.06), 23.15 (3.84), 24.14 (3.68), 24.53 (3.63), 24.77 (3.59), 25.88 (3.44) and 26.37 (3.38).
     
    4. A method of preparing the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 1, comprising the step of reacting p-toluenesulfonic acid with 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide.
     
    5. A method of preparing the crystal form I of the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 2 or claim 3, comprising the following steps of:

    1) dissolving p-toluenesulfonic acid and 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide, or any crystal form or amorphous form of the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide p-toluenesulfonate of formula (I) into an organic solvent or a mixed solvent of an organic solvent and water to precipitate a crystal, wherein the organic solvent is selected from one or more of alcohols, ketones, nitriles and ethers having 3 or less carbon atoms;

    2) filtering the crystal, then washing and drying it.


     
    6. The method according to claim 5, characterized in that the organic solvent in step 1) is selected from one or more of methanol, ethanol and isopropanol; the mixed solvent of organic solvent and water is selected from methanol/water, ethanol/water, isopropanol/water, acetonitrile/water, acetone/water and tetrahydrofuran/water; preferably, the single solvent is isopropanol, or the mixed solvent is acetone/water.
     
    7. A pharmaceutical composition, comprising the 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 1 or the crystal form I according to claim 2 or claim 3, and a pharmaceutically acceptable carrier.
     
    8. The 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide p-toluenesulfonate of formula (I) according to claim 1, the crystal form I according to claim 2 or claim 3 or the pharmaceutical composition according to claim 7 for use in the treatment of tumor.
     
    9. The 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridine-3-carboxamide p-toluenesulfonate of formula (I), the crystal form I, or the pharmaceutical composition for use according to claim 8, wherein the tumor is melanoma.
     


    Ansprüche

    1. 2-((2-Dluor-4-iodphenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridin-3-carboxamid-p-toluolsulfonat der Formel (I),


     
    2. Kristalline Form I des 2-((2-Fluor-4-iodphenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridin-3-carboxamid-p-toluolsulfonat der Formel (I) nach Anspruch 1, dadurch gekennzeichnet, dass der Kristall ein Pulver-Röntgenbeugungsspektrum aufweist, das unter Verwendung von Cu-Ka-Strahlung erhalten wurden und durch einen Winkel von 20 dargestellt ist, wie in Figur 1 gezeigt, in dem charakteristische Peaks bei etwa 10,18, 11,51, 12,34, 12,97, 13,72, 14,83, 15,76, 17,13, 17,59, 17,92, 18,50, 19,72, 20,03, 20,42, 21,04, 21,51, 21,88, 23,15, 24,14, 24,53, 24,77, 25,88 und 26,37 liegen.
     
    3. Kristalline Form I nach Anspruch 2, dadurch gekennzeichnet, dass der Kristall ein Pulver-Röntgenbeugungsspektrum aufweist, das unter Verwendung von Cu-Ka-Strahlung erhalten wird und durch einen Winkel von 20 und eine interplanare Entfernung, wie in Figur 1 gezeigt, dargestellt ist, in dem charakteristische Peaks bei etwa 10,18 (8,68), 11,51 (7,68), 12,34 (7,17), 12,97 (6,82), 13,72 (6,45), 14,83 (5,97), 15,76 (5,62), 17,13 (5,17), 17,59 (5,04), 17,92 (4,95), 18,50 (4,79), 19,72 (4,50), 20,03 (4,43), 20,42 (4,35), 21,04 (4,22), 21,51 (4,13), 21,88 (4,06), 23,15 (3,84), 24,14 (3,68), 24,53 (3,63), 24,77 (3,59), 25,88 (3,44) und 26,37 (3,38) sind.
     
    4. Verfahren zur Herstellung des 2-((2-Fluor-4-iodphenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridin-3-carboxamid-p-toluolsulfonat der Formel (I) nach Anspruch 1, welches den Schritt umfasst, Umsetzen von p-Toluolsulfonsäure mit 2-((2-Fluor-4-iodphenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihy-dropyridin-3-carboxamid.
     
    5. Verfahren zur Herstellung der kristallinen Form von 2-((2-Fluor-4-iodphenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamid-p-toluolsulfonat der Formel (I) nach Anspruch 2 oder Anspruch 3, welches die folgenden Schritte umfasst:

    1) Lösen von p-Toluolsulfonsäure und 2-((2-Fluor-4-iodphenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridin-3-carboxamid, oder jede kristalline Form oder amorphe Form des 2-((2-Fluor-4-iodphenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridin-3-carboxamid-p-toluolsulfonats der Formel (I) in einem organischen Lösungsmittel oder einem gemischten Lösungsmittel eines organischen Lösungsmittels mit Wasser, um einen Kristall auszufällen, worin das organische Lösungsmittel ausgewählt ist unter einem oder mehreren von Alkoholen, Ketonen, Nitrilen und Ethern mit drei oder weniger Kohlenstoffatomen;

    2) Filtern des Kristalls, dann Waschen und Trocknen.


     
    6. Verfahren nach Anspruch 5, dadurch gekennzeichnet, dass das organische Lösungsmittel in Schritt 1) ausgewählt ist unter einem oder mehreren von Methanol, Ethanol und Isopropanol; worin das gemischte Lösungsmittel des organischen Lösungsmittels mit Wasser ausgewählt ist unter Methanol/Wasser, Ethanol/Wasser, Isopropanol/Wasser, Acetonitril/Wasser, Aceton/Wasser und Tetrahydrofuran/Wasser; vorzugsweise worin das einzige Lösungsmittel Isopropanol ist, oder worin das gemischte Lösungsmittel Aceton/Wasser ist.
     
    7. Pharmazeutische Zusammensetzung umfassend das 2-((2-Fluor-4-iodphenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamid-p-toluolsulfonat der Formel (I) nach Anspruch 1 oder die kristalline Form I nach Anspruch 2 oder Anspruch 3, und einen pharmazeutisch annehmbaren Träger.
     
    8. 2-((2-Fluor-4-iodphenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridin-3-carboxamid-p-toluolsulfonat der Formel (I) nach Anspruch 1, die kristalline Form I nach Anspruch 2 oder Anspruch 3 oder die pharmazeutische Zusammensetzung nach Anspruch 7 zur Verwendung bei der Behandlung eines Tumors.
     
    9. 2-((2-Fluor-4-iodphenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-oxo-1,6-di hydropyridin-3-carboxamid-p-toluolsulfonat der Formel (I), die kristalline Form I, oder die pharmazeutische Zusammensetzung zur Verwendung nach Anspruch 8, worin der Tumor ein Melanom ist.
     


    Revendications

    1. p-toluènesulfonate de 2-((2-fluoro-4-iodophényl)amino)-1-méthyl-4-((6-méthylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide de formule (I) :


     
    2. Forme cristalline I du p-toluènesulfonate de 2-((2-fluoro-4-iodophényl)amino)-1-méthyl-4-((6-méthylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide de formule (I) selon la revendication 1, caractérisée en ce que le cristal a un spectre de diffraction des rayons X par la technique des poudres, qui est obtenu par utilisation d'un rayonnement Cu-Ka et qui est représenté par l'angle 2θ, comme le montre la Figure 1, dans lequel il y a des pics caractéristiques à environ 10,18, 11,51, 12,34, 12,97, 13,72, 14,83, 15,76, 17,13, 17,59, 17,92, 18,50, 19,72, 20,03, 20,42, 21,04, 21,51, 21,88, 23,15, 24,14, 24,53, 24,77, 25,88 et 26,37.
     
    3. Forme cristalline I selon la revendication 2, caractérisée en ce que le cristal a un spectre de diffraction des rayons X par la technique des poudres, qui est obtenu par utilisation d'un rayonnement Cu-Ka et qui est représenté par l'angle 2θ et la distance interplanaire, comme le montre la Figure 1, dans lequel il y a des pics caractéristiques à environ 10,18 (8,68), 11,51 (7,68), 12,34 (7,17), 12,97 (6,82), 13,72 (6,45), 14,83 (5,97), 15,76 (5,62), 17,13 (5,17), 17,59 (5,04), 17,92 (4,95), 18,50 (4,79), 19,72 (4,50), 20,03 (4,43), 20,42 (4,35), 21,04 (4,22), 21,51 (4,13), 21,88 (4,06), 23,15 (3,84), 24,14 (3,68), 24,53 (3,63), 24,77 (3,59), 25,88 (3,44) et 26,37 (3,38).
     
    4. Procédé de préparation du p-toluènesulfonate de 2-((2-fluoro-4-iodophényl)amino)-1-méthyl-4-((6-méthylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide de formule (I) selon la revendication 1, comprenant l'étape de réaction d'acide p-toluènesulfonique avec du 2-((2-fluoro-4-iodophényl)amino)-1-méthyl-4-((6-méthylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide.
     
    5. Procédé de préparation de la forme cristalline I du p-toluènesulfonate de 2-((2-fluoro-4-iodophényl)amino)-1-méthyl-4-((6-méthylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide de formule (I) selon la revendication 2 ou 3, comprenant les étapes suivantes :

    1) dissolution d'acide p-toluènesulfonique et de 2-((2-fluoro-4-iodophényl)amino)-1-méthyl-4-((6-méthylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide, ou de n'importe quelle forme cristalline ou forme amorphe du p-toluènesulfonate de 2-((2-fluoro-4-iodophényl)amino)-1-méthyl-4-((6-méthylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide de formule (I), dans un solvant organique ou un mélange solvant d'un solvant organique et d'eau pour qu'un cristal précipite, dans laquelle le solvant organique est un ou plusieurs choisis parmi les alcools, les cétones, les nitriles et les éthers ayant 3 atomes de carbone ou moins ;

    2) filtration du cristal, puis lavage et séchage de celui-ci.


     
    6. Procédé selon la revendication 5, caractérisé en ce que le solvant organique dans l'étape 1) est un ou plusieurs choisis parmi le méthanol, l'éthanol et l'isopropanol ; le mélange solvant de solvant organique et d'eau est choisi parmi le méthanol/eau, l'éthanol/eau, l'isopropanol/eau, l'acétonitrile/eau, l'acétone/eau et le tétrahydrofurane/eau ; de préférence le seul solvant est l'isopropanol, ou le mélange solvant est l'acétone/eau.
     
    7. Composition pharmaceutique comprenant le p-toluènesulfonate de 2-((2-fluoro-4-iodophényl)amino)-1-méthyl-4-((6-méthylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide de formule (I) selon la revendication 1 ou la forme cristalline I selon la revendication 2 ou la revendication 3, et un véhicule pharmaceutiquement acceptable.
     
    8. p-toluènesulfonate de 2-((2-fluoro-4-iodophényl)amino)-1-méthyl-4-((6-méthylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide de formule (I) selon la revendication 1, forme cristalline I selon la revendication 2 ou 3, ou composition pharmaceutique selon la revendication 7, pour une utilisation dans le traitement d'une tumeur.
     
    9. p-toluènesulfonate de 2-((2-fluoro-4-iodophényl)amino)-1-méthyl-4-((6-méthylpyridin-3-yl)oxy)-6-oxo-1,6-dihydropyridine-3-carboxamide de formule (I), forme cristalline I, ou composition pharmaceutique pour une utilisation selon la revendication 8, dans lequel la tumeur est un mélanome.
     




    Drawing









    REFERENCES CITED IN THE DESCRIPTION



    This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

    Patent documents cited in the description