Crystal of 7H-pyrrolo[2,3-d]pyrimidine-4-amine derivative

Abstract

Provided is a crystal of a compound having FGFR inhibition ability or a salt thereof, said crystal being excellent in one or more characteristics of stability, hygroscopicity and oral absorbability. One aspect of the present invention provides a crystal form of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide the diffraction angle (2θ±0.2°) of which has a peak at a preset angle in the X-ray powder diffraction spectrum.

Description

Crystal of 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivative

[0001] The present invention relates to a compound having an epidermal growth factor receptor (EGFR) inhibitory activity, a crystal of a 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivative, a method for crystallizing the same, and the like.

[0002] EGFR is a receptor tyrosine kinase that exerts physiological functions in normal tissues by binding to its ligand, epidermal growth factor (EGF), and contributes to proliferation and apoptosis inhibition in epithelial tissues (Non-Patent Document 1).

[0003] EGFR is also an oncogene, and amplification of the EGFR gene and high protein expression and mutation are known to occur in various types of cancer, such as head and neck cancer, breast cancer, colon cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, skin cancer, and brain tumors (Non-Patent Document 2). In particular, the number of deaths from lung cancer reaches approximately 1.4 million per year worldwide, and non-small cell lung cancer accounts for more than 80% of lung cancer cases, so the development of an effective treatment is desired (Non-Patent Document 3).

[0004] Currently, several EGFR inhibitors have been reported as antitumor agents. Patent Document 1 describes a compound represented by the following formula (I) as a compound having excellent EGFR inhibitory activity.

[0005]

[0006] The document discloses a pyrimidine compound represented by the formula (chemical name: N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (hereinafter also referred to as "compound (1)")).

[0007] Patent Document 1 describes a method for producing compound (1) by adding DMF, DIPEA, 5-methylpyrazine-2-carboxylic acid, and HATU to a THF solution of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2.3-d]pyrimidin-4-amine, stirring the mixture at room temperature, and then concentrating and purifying the mixture to obtain the compound. However, Patent Document 1 does not specifically disclose what kind of crystalline form compound (1) or a salt thereof may form.

[0008] International Publication No. WO2020 / 166680 Pamphlet

[0009] Nature Rev. Cancer, vol. 6, pp803-811 (2006) Current Opinion in Oncology, vol. 13, pp506-513 (2001) Lung Cancer, vol. 69, pp1-12 (2010)

[0010] When a compound is used as an active ingredient of a pharmaceutical, it is desirable for the compound to have a stable crystalline form in order to maintain stable quality and / or facilitate storage and management. Furthermore, it is preferable for the crystalline form of the compound to have low hygroscopicity or good oral absorbability, etc. However, it is difficult to predict whether a specific compound or its salt will form crystals and which crystalline form will have excellent physical properties such as stability.

[0011] In view of the above circumstances, there is a demand for crystals of a compound having EGFR inhibitory activity or a salt thereof, which are excellent in one or more of the properties of stability, hygroscopicity, and oral absorbability.

[0012] As a result of extensive research, the present inventors have obtained several crystalline forms of the free form of Compound (1). Furthermore, they have obtained crystalline forms of salts or co-crystals of Compound (1) with succinic acid, sorbic acid, citric acid, or phosphoric acid.

[0013] That is, the present invention provides, for example, the following items [1] to

[53] : [1] A type II crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide, having peaks in a powder X-ray diffraction spectrum at diffraction angles (2θ±0.2°) of (i) one or more selected from the group consisting of 15.6°, 20.1°, 24.7°, and 28.9°, and (ii) two or more selected from the group consisting of 7.8°, 10.6°, 14.0°, 14.8°, 17.2°, 21.6°, 22.2°, and 25.8°. [2] The crystal according to [1], wherein the powder X-ray diffraction spectrum has a diffraction angle (2θ±0.2°) of at least five peaks selected from group (i) and group (ii). [3] The crystal according to [1] or [2], wherein the powder X-ray diffraction spectrum has a diffraction angle (2θ±0.2°) of at least seven peaks selected from group (i) and group (ii). [4] The crystal according to any of [1] to [3], wherein the crystal has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 3. [5] The crystal according to any of [1] to [4], wherein the exothermic peak determined by simultaneous differential thermal and thermogravimetry analysis is around 236°C. [6] The crystal according to any of [1] to [5], wherein the crystal has a crystal purity of at least 50% by weight (preferably at least 75% by weight, more preferably at least 80% by weight, and even more preferably at least 95% by weight). [7] The crystal according to any one of [1] to [6], having a chemical purity of 90% or more (preferably 95% or more, more preferably 98% or more, and even more preferably 99% or more).[8] N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide according to any one of [1] to [7], characterized in that N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide is stirred in a single solvent of a lower alcohol having 3 or more carbon atoms, tetrahydrofuran, acetone, and ethyl acetate, or a mixed solvent containing two or more of these. A method for producing type II crystals of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide. [9] A type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with succinic acid, having peaks at three or more diffraction angles (2θ±0.2°) selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5° in a powder X-ray diffraction spectrum.

[10] The crystal according to [9], having peaks at five or more diffraction angles (2θ±0.2°) selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5° in its powder X-ray diffraction spectrum.

[11] The crystal according to

[10] or

[11] , having peaks at seven or more diffraction angles (2θ±0.2°) selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5° in its powder X-ray diffraction spectrum.

[12] The crystal according to any of [9] to

[11] , which is a crystal having a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 13.

[13] The crystal according to any one of [9] to

[12] , which has an endothermic peak at around 202°C as determined by simultaneous differential thermal and thermogravimetric measurements.

[14] The crystal according to any one of [9] to

[13] , having a crystal purity of 50% by weight or more (preferably 75% by weight or more, more preferably 80% by weight or more, and even more preferably 95% by weight or more).

[15] The crystal according to any one of [9] to

[14] , having a chemical purity of 90% or more (preferably 95% by weight or more, more preferably 98% by weight or more, and even more preferably 99% by weight or more).

[16] A method for producing a crystalline product by dissolving N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and succinic acid in an equivalent ratio of 1:1 to 10 in a solvent containing acetonitrile, a lower alcohol having 2 or more carbon atoms, methyl ethyl ketone, tetrahydrofuran, and 2-methyltetrahydrofuran. A method for producing a Type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with succinic acid according to any one of [9] to

[15] , characterized in that the mixture is stirred in a single solvent selected from the group consisting of:

[17] A type I crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with sorbic acid, having peaks at three or more diffraction angles (2θ±0.2°) selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4° in a powder X-ray diffraction spectrum.

[18] The crystal according to

[17] , which has peaks at five or more diffraction angles (2θ±0.2°) selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4° in a powder X-ray diffraction spectrum.

[19] The crystal according to

[17] or

[18] , which has peaks at seven or more diffraction angles (2θ±0.2°) selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4° in its powder X-ray diffraction spectrum.

[20] The crystal according to any of

[17] to

[19] , which has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 15.

[21] The crystal according to any of

[17] to

[20] , which has an endothermic peak determined by simultaneous differential thermal analysis-thermogravimetry at around 173°C.

[22] The crystal according to any of

[17] to

[21] , which has a crystal purity of 50% by weight or more (preferably 75% by weight or more, more preferably 80% by weight or more, and even more preferably 95% by weight or more).

[23] The crystal according to any one of

[17] to

[22] , having a chemical purity of 90% or more (preferably 95% or more, more preferably 98% or more, and even more preferably 99% or more).

[24] N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and sorbic acid in an equivalent ratio of 1:1 to 10, and stirred in a single solvent selected from acetonitrile, lower alcohols, tetrahydrofuran, acetone, methyl ethyl ketone, water, and ethyl acetate, or a mixed solvent containing two or more of these.

[17] -

[23] N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and sorbic acid. A method for producing type I crystals of sorbic acid according to any one of

[17] to

[23] .

[25] A type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide, having, in its powder X-ray diffraction spectrum, peaks at diffraction angles (2θ±0.2°) selected from the group consisting of: (i) one or more peaks selected from the group consisting of 8.8°, 11.6°, and 17.9°, and (ii) two or more peaks selected from the group consisting of 6.6°, 12.3°, 13.8°, 18.6°, 21.3°, and 22.3°.

[26] The crystal according to

[25] , having, in its powder X-ray diffraction spectrum, peaks at diffraction angles (2θ±0.2°) selected from the group (i) and the group (ii) in total.

[27] The crystal according to

[25] or

[26] , which has, in its powder X-ray diffraction spectrum, diffraction angle (2θ±0.2°) peaks at a total of seven or more peaks selected from group (i) and group (ii).

[28] The crystal according to any of

[25] to

[27] , which has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in FIG. 1.

[29] The crystal according to any of

[25] to

[28] , which has an exothermic peak determined by simultaneous differential thermal analysis-thermogravimetry at around 228°C.

[30] The crystal according to any of

[25] to

[29] , which has a crystal purity of 50% by weight or more (preferably 75% by weight or more, more preferably 80% by weight or more, even more preferably 95% by weight or more).

[31] The crystal according to any of

[25] to

[30] , which has a chemical purity of 90% or more (preferably 95% by weight or more, more preferably 98% by weight or more, even more preferably 99% by weight or more).

[32] N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide according to any one of

[25] to

[31] , characterized by stirring N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide in a methanol-containing solvent. A method for producing type III crystals of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide.

[33] A pharmaceutical composition comprising the crystal according to any one of [1] to [7], [9] to

[15] ,

[17] to

[23] and

[25] to

[31] .

[34] A pharmaceutical composition comprising the crystal according to any one of [1] to [7], [9] to

[15] ,

[17] to

[23] and

[25] to

[31] and a pharmaceutically acceptable carrier.

[35] An antitumor agent comprising the crystal according to any one of [1] to [7], [9] to

[15] ,

[17] to

[23] and

[25] to

[31] .

[36] A method for treating a tumor, comprising orally administering to a subject in need thereof an effective amount of the crystal according to any one of [1] to [7], [9] to

[15] ,

[17] to

[23] and

[25] to

[31] .

[37] Use of the crystal according to any one of [1] to [7], [9] to

[15] ,

[17] to

[23] , and

[25] to

[31] for the production of an antitumor agent for oral administration.

[38] A type III co-crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with succinic acid, having peaks at three or more diffraction angles (2θ±0.2°) selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5° in a powder X-ray diffraction spectrum.

[39] The cocrystal according to

[38] , having peaks at five or more diffraction angles (2θ±0.2°) selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5° in a powder X-ray diffraction spectrum.

[40] The cocrystal according to

[38] or

[39] , having peaks at seven or more diffraction angles (2θ±0.2°) selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5° in a powder X-ray diffraction spectrum.

[41] The cocrystal according to any one of

[38] to

[40] , which is a crystal having a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in FIG. 13.

[42] The cocrystal according to any one of

[38] to

[41] , which has an endothermic peak determined by simultaneous differential thermal and thermogravimetric analysis at around 202°C.

[43] The cocrystal according to any one of

[38] to

[42] , which has a crystal purity of 50% by weight or more (preferably 75% by weight or more, more preferably 80% by weight or more, and even more preferably 95% by weight or more).

[44] The cocrystal according to any one of

[38] to

[43] , which has a chemical purity of 90% or more (preferably 95% by weight or more, more preferably 98% or more, and even more preferably 99% or more).

[45] N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and succinic acid in an equivalent ratio of 1:1 to 10, in a solvent containing acetonitrile, a lower alcohol having two or more carbon atoms, methyl ethyl ketone, tetrahydrofuran, and 2-methyltetrahydrofuran. The method for producing a type III cocrystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with succinic acid according to any one of [9] to

[15] , characterized in that the cocrystal is stirred in a single solvent selected from the group consisting of:

[46] A type I co-crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with sorbic acid, having peaks at three or more diffraction angles (2θ±0.2°) selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4° in a powder X-ray diffraction spectrum.

[47] The cocrystal according to

[46] , having peaks at five or more diffraction angles (2θ±0.2°) selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4° in a powder X-ray diffraction spectrum.

[48] ​​The cocrystal according to

[46] or

[47] , which has peaks at seven or more diffraction angles (2θ±0.2°) selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4° in its powder X-ray diffraction spectrum.

[49] The cocrystal according to any of

[46] to

[48] , which is a crystal having a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 15.

[50] The cocrystal according to any of

[46] to

[49] , which has an endothermic peak determined by simultaneous differential thermal analysis-thermogravimetry at around 173°C.

[51] The cocrystal according to any of

[46] to

[50] , which has a crystal purity of 50% by weight or more (preferably 75% by weight or more, more preferably 80% by weight or more, and even more preferably 95% by weight or more).

[52] The cocrystal according to any one of

[46] to

[51] , having a chemical purity of 90% or more (preferably 95% or more, more preferably 98% or more, and even more preferably 99% or more).

[53] A method for producing a type I cocrystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with sorbic acid according to any one of

[17] to

[23] , characterized in that an equivalent ratio of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide to sorbic acid is set to 1:1 to 10, and the mixture is stirred in a single solvent selected from acetonitrile, a lower alcohol, tetrahydrofuran, acetone, methyl ethyl ketone, water, and ethyl acetate, or a mixed solvent containing two or more of these solvents.

[0014] According to one aspect of the present invention, there is provided a crystal of a compound having EGFR inhibitory activity or a salt thereof, which is excellent in one or more properties of stability, hygroscopicity, and oral absorbability.

[0015] 1 shows the powder X-ray diffraction spectrum of the free-form III crystal of compound (1) obtained in Example 1 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). The results of simultaneous differential thermal analysis and thermogravimetry (TG-DTA) of the free-form III crystal of compound (1) obtained in Example 1 are shown (the left vertical axis represents weight (%) in the TG curve, the right vertical axis represents heat flux (μV) in the DTA curve, and the horizontal axis represents temperature (°C)). The results of simultaneous differential thermal analysis and thermogravimetry (TG-DTA) of the free-form II crystal of compound (1) obtained in Example 2 are shown (the left vertical axis represents weight (%) in the TG curve, the right vertical axis represents heat flux (μV) in the DTA curve, and the horizontal axis represents temperature (°C)). 1 shows the powder X-ray diffraction spectrum of the free form VII crystal of compound (1) obtained in Reference Example 1 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). The results of simultaneous differential thermal analysis and thermogravimetry (TG-DTA) of the free form VII crystal of compound (1) obtained in Reference Example 1 are shown (the left vertical axis represents weight (%) in the TG curve, the right vertical axis represents heat flux (μV) in the DTA curve, and the horizontal axis represents temperature (°C)). The results of simultaneous differential thermal analysis and thermogravimetry (TG-DTA) of the free form VIII crystal of compound (1) obtained in Comparative Example 1 are shown (the left vertical axis represents weight (%) in the TG curve, the right vertical axis represents heat flux (μV) in the DTA curve, and the horizontal axis represents temperature (°C)). 1 shows the results of a dynamic moisture adsorption / desorption (DVS) test of the free form type II crystal of compound (1) in Test Example 2. 2 shows the results of a dynamic moisture adsorption / desorption (DVS) test of the free form type III crystal of compound (1) in Test Example 2. 3 shows the results of a dynamic moisture adsorption / desorption (DVS) test of the free form type VII crystal of compound (1) in Test Example 2. 4 shows the results of a dynamic moisture adsorption / desorption (DVS) test of the free form type VIII crystal of compound (1) in Test Example 2. 5 shows the powder X-ray diffraction spectrum of the type III crystal of compound (1) with succinic acid obtained in Example 3 (the vertical axis represents intensity (counts), and the horizontal axis represents the diffraction angle (2θ)).1 shows the results of simultaneous differential thermal analysis-thermogravimetry (TG-DTA) of type III crystals of compound (1) with succinic acid obtained in Example 3 (the left vertical axis represents weight (%) in the TG curve, the right vertical axis represents heat flux (μV) in the DTA curve, and the horizontal axis represents temperature (°C)). 1 shows the powder X-ray diffraction spectrum of type I crystals of compound (1) with sorbic acid obtained in Example 4 (the vertical axis represents intensity (counts) and the horizontal axis represents diffraction angle (2θ)). 1 shows the results of simultaneous differential thermal analysis-thermogravimetry (TG-DTA) of type I crystals of compound (1) with sorbic acid obtained in Example 4 (the left vertical axis represents weight (%) in the TG curve, the right vertical axis represents heat flux (μV) in the DTA curve, and the horizontal axis represents temperature (°C)). 1 shows the powder X-ray diffraction spectrum of type I crystals of compound (1) with citric acid obtained in Comparative Example 2 (the vertical axis represents intensity (counts) and the horizontal axis represents diffraction angle (2θ)). 1 shows the results of simultaneous differential thermal analysis-thermogravimetry (TG-DTA) of type I crystals of compound (1) with citric acid obtained in Comparative Example 2 (the left vertical axis represents weight (%) in the TG curve, the right vertical axis represents heat flux (μV) in the DTA curve, and the horizontal axis represents temperature (°C)). 1 shows the powder X-ray diffraction spectrum of type IV crystals of compound (1) with citric acid obtained in Comparative Example 3 (the vertical axis represents intensity (counts) and the horizontal axis represents diffraction angle (2θ)). 1 shows the results of simultaneous differential thermal analysis-thermogravimetry (TG-DTA) of type IV crystals of compound (1) with citric acid obtained in Comparative Example 3 (the left vertical axis represents weight (%) in the TG curve, the right vertical axis represents heat flux (μV) in the DTA curve, and the horizontal axis represents temperature (°C)). 1 shows the powder X-ray diffraction spectrum of type I crystals of compound (1) with phosphoric acid obtained in Comparative Example 4 (the vertical axis represents intensity (counts) and the horizontal axis represents diffraction angle (2θ)).

[0033] Figure 1 shows the results of simultaneous differential thermal analysis-thermogravimetry (TG-DTA) of type I crystals of compound (1) with phosphoric acid obtained in Comparative Example 4 (the left vertical axis represents weight (%) in the TG curve, the right vertical axis represents heat flux (μV) in the DTA curve, and the horizontal axis represents temperature (°C)).

[0034] Figure 1 shows the results of a dynamic moisture sorption / desorption (DVS) test of type III crystals of compound (1) with succinic acid in Test Example 4.

[0035] Figure 1 shows the results of a dynamic moisture sorption / desorption (DVS) test of type I crystals of compound (1) with citric acid in Test Example 4.

[0036] Figure 1 shows the results of a dynamic moisture sorption / desorption (DVS) test of type IV crystals of compound (1) with citric acid in Test Example 4.

[0037] Figure 1 shows the results of a dynamic moisture sorption / desorption (DVS) test of type I crystals of compound (1) with sorbic acid in Test Example 4.1 shows the results of a dynamic moisture sorption / desorption (DVS) test of type I crystals of compound (1) with phosphoric acid in Test Example 4.

[0016] The present invention relates to a crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide represented by the following formula (I), and a crystal of the same with an acid (a crystal of a salt thereof or a co-crystal thereof). Specifically, the present invention relates to a free-form type II crystal, a free-form type III crystal, a type III crystal with succinic acid, and a type I crystal with sorbic acid of compound (1). Note that, in this specification, the terms type I, type II, type III, etc. are convenient names for distinguishing between crystalline forms, and the crystals according to the present invention are not limited to these names.

[0017] In this specification, a crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (compound (1)) with an acid refers to a crystal of a salt or a co-crystal with an acid. A salt crystal is a crystal in which compound (1) and an acid molecule are bound by an ionic bond, and a co-crystal is a crystal in which compound (1) and an acid molecule are bound by a non-ionic interaction. In the present invention, a crystal of compound (1) with an acid may be a crystal of a salt or a co-crystal, and includes both meanings. For example, in the case of a type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with succinic acid, N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide is This refers to a Type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide succinate or a Type III co-crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with succinic acid. In one embodiment of the present invention, there is provided a Type III co-crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with succinic acid and a method for producing the same, or a Type I co-crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with sorbic acid and a method for producing the same.

[0018] A crystal is a solid in which atoms and molecules are arranged in a regular repeating structure, and is different from an amorphous (non-crystalline) solid that does not have a repeating structure. Crystal or amorphous solids can be investigated by methods such as powder X-ray diffraction measurement (XRD measurement), differential scanning calorimetry (DSC measurement), simultaneous thermogravimetry-differential thermal analysis (TG-DTA), and single crystal analysis. Crystal polymorphs are the same molecule but have different atomic or molecular arrangements in the crystal, and it is known that the peaks obtained in XRD measurement differ between crystal polymorphs. It is also known that solubility, oral absorbability, and / or stability differ between crystal polymorphs.

[0019] In this specification, the terms "crystal" and "amorphous" are used in their usual sense, and the fact that a material is crystalline can be confirmed by X-ray diffraction spectroscopy.

[0020] Due to the nature of the data, when determining the identity of a crystal, the diffraction angle and overall pattern of a powder X-ray diffraction pattern are important. The relative intensities of a powder X-ray diffraction pattern may vary somewhat depending on the direction of crystal growth, particle size, measurement conditions, maintenance status of the measurement equipment, and the method of preparing the measurement sample, and therefore should not be interpreted strictly. In this specification, the phrase "a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in the figure" refers to a powder X-ray diffraction spectrum that a person skilled in the art would recognize as identical, taking into account slight variations in peak position and intensity relative to the powder X-ray diffraction spectrum shown in the figure. For example, the numerical values ​​of the diffraction angle (2θ) may have a measurement error of approximately ±0.2°.

[0021] In this specification, the term "compound (1)" simply refers to N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide, and is used to include both "crystal" and "amorphous." In this specification, the term "crystal of compound (1)" is used to include both a crystal of the free form of compound (1) and a crystal of compound (1) with an acid (a crystal of a salt of compound (1) and a co-crystal of compound (1)). In the present specification, crystals in which the molecules other than compound (1) constituting the crystal (other molecules constituting the salt or co-crystal) are not specified refer to crystals of the free form of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide, and are not limited to a single crystalline form such as free form Form I, but may include multiple free form crystals. In the present specification, the term "equivalent" refers to molar equivalents. In a crystal of compound (1) and an acid (a crystal or co-crystal of its salt), the equivalent of the acid relative to compound (1) can be analyzed by, for example, NMR or ion chromatography. In the present specification, the crystal may be either a hydrate or an anhydrous form.

[0022] The present invention also encompasses labeled forms of compound (1) or salts thereof, i.e., compound (1) or salts of compound (1), and compounds in which one or more atoms are substituted with a radioactive isotope or a non-radioactive isotope.

[0023] The crystal may be any crystal of compound (1), and may be a single crystal or a polymorphic mixture containing other crystals of compound (1). Specifically, the purity of the crystal may be 40% by weight or more (i.e., 40% by weight or more of single crystals). The purity of the crystal is preferably 50% by weight or more (i.e., 50% by weight or more of single crystals), more preferably 75% by weight or more (i.e., 75% by weight or more of single crystals), more preferably 90% by weight or more (i.e., 90% by weight or more of single crystals), even more preferably 95% by weight or more (i.e., 95% by weight or more of single crystals), even more preferably 98% by weight or more (i.e., 98% by weight or more of single crystals), and particularly preferably 99% by weight or more (i.e., 99% by weight or more of single crystals). This purity can be measured by analysis such as differential scanning calorimetry (DSC measurement).

[0024] In this specification, chemical purity refers to the purity measured by high performance liquid chromatography (HPLC), and when referring to the chemical purity of compound (1), it refers to the purity measured by HPLC of compound (1). In this case, the wavelength of the detector used for purity measurement can be appropriately set. Specifically, the chemical purity of the crystals of compound (1) is preferably 90% or more, more preferably 95% or more, even more preferably 98% or more, and particularly preferably 99% or more.

[0025] The numerical values ​​obtained from various patterns may have some error depending on the direction of crystal growth, particle size, measurement conditions, etc. Therefore, in this specification, the numerical value of the diffraction angle (2θ) in the powder X-ray diffraction pattern may have a measurement error of about ±0.2°. In other words, when the term "diffraction angle (2θ±0.2°)" is used in this specification, it means that a measurement error of ±0.2° is allowed for the numerical value of the diffraction angle (2θ). For example, when the diffraction angle (2θ±0.2°) is described as "6.6°," this means that a diffraction angle of up to 6.6°±0.2° is allowed, and includes diffraction angles of "6.4° to 6.8°." Furthermore, this value can be calculated using the Bragg formula (2d sinθ=nλ) and varies depending on the wavelength measured. In other words, it is also possible to convert it to a diffraction angle at a different measurement wavelength by substituting the measurement wavelength into the above formula. For example, the diffraction angles (2θ) at a wavelength λ of 1.54 Å, which is the characteristic X-ray of CuKα, are 6.6° and 8.8°, respectively, and if the values ​​of d and n are unchanged, the diffraction angles (2θ) at 0.75 Å are 3.2° and 4.3°, respectively.

[0026] The compound (1) used in the crystallization method of the present invention may be, for example, a compound produced by the method described herein. For crystallization, the compound (1) may be used either directly after synthesis without being extracted as crystals, or after being extracted as crystals (crude crystals).

[0027] In this specification, "room temperature" generally refers to about 18°C ​​to about 25°C.

[0028] In this specification, the term "lower alcohol" refers to an alcohol having 1 to 5 carbon atoms, which may be linear or branched. Examples include methanol, ethanol, propanol, isopropyl alcohol, butanol, and pentanol.

[0029] The endothermic peak in a thermogravimetric differential thermal analysis (TG-DTA) curve usually means ±5.0°C, although the measurement temperature may vary depending on the rate of temperature rise per minute, the chemical purity of the sample, etc. Therefore, when the crystal according to the present invention is measured by TG-DTA, an error in the peak (onset value) of ±5.0°C is taken into account. The term "around" used in this case means ±5.0°C.

[0030] One embodiment of the present invention relates to free-form crystals of Compound (1) (type II and type III crystals), crystals of Compound (1) with succinic acid (type III crystals), and crystals of Compound (1) with sorbic acid (type I crystals). The inventors have found that, among the free-form crystals of Compound (1), free-form crystals II and III crystals are stable and can be obtained with good reproducibility, and that free-form crystals II have advantageous properties in pharmaceutical production, such as low hygroscopicity and good oral absorbability. Furthermore, among crystalline forms or co-crystals with a specific acid, crystals with succinic acid and crystals with sorbic acid have been found to be stable, low hygroscopic, can be obtained with good reproducibility, and have good oral absorbability.

[0031] In the present specification, the stability of a crystal can be evaluated, for example, by a solid state stability test shown in the later-described Test Example 1. In one embodiment of the present invention, the change in chemical purity of a crystal of compound (1) after storage for 4 weeks under the conditions described in Test Example 1 is preferably ±0.15% or less, more preferably ±0.10% or less, and even more preferably ±0.05% or less.

[0032] In this specification, the hygroscopicity of a crystal can be evaluated by a dynamic moisture sorption / desorption (DVS) test shown in the following Test Example 2. When evaluated under the conditions described in Test Example 2, the crystal of compound (1) in one embodiment of the invention preferably exhibits a weight increase rate of less than 5%, more preferably less than 3%, and even more preferably less than 1%.

[0033] In this specification, the oral absorbability of the crystals can be evaluated by a plasma concentration measurement test shown in Test Example 5 below.

[0034] One embodiment of the present invention provides an antitumor agent comprising the above-mentioned crystal of compound (1) (i.e., a free form crystal of compound (1) or a crystal of compound (1) with an acid (a salt crystal or a co-crystal)). Another embodiment of the present invention provides a method for treating a tumor, comprising administering to a subject in need thereof an effective amount of the above-mentioned crystal of compound (1) (i.e., a free form crystal of compound (1) or a crystal of compound (1) with an acid (a salt crystal or a co-crystal)). One embodiment of the present invention provides use of the crystal of compound (1) (i.e., a free form crystal of compound (1) or a crystal of compound (1) with an acid (a salt crystal or a co-crystal)) for the manufacture of an antitumor agent. Another embodiment of the present invention provides a crystal of compound (1) (i.e., a free form crystal of compound (1) or a crystal of compound (1) with an acid (a salt crystal or a co-crystal)) for use in treating a tumor.

[0035] The free-form Form III crystal of Compound (1) in one embodiment of the present invention has advantageous properties in pharmaceutical production, such as excellent reproducibility of acquisition and solid-state stability, compared to other salts or other crystals of Compound (1). In addition, as shown in the test examples of the crystals obtained in the Examples, Reference Examples, and Comparative Examples, the free-form Form III crystal is also useful as an intermediate for the crystals according to the present invention (other forms of the free form, crystals with acids).

[0036] In one embodiment of the present invention, the free-form type II crystal of compound (1), the type III crystal with succinic acid, and the type I crystal with sorbic acid have advantageous properties in pharmaceutical production, such as low hygroscopicity, excellent reproducibility in preparation, solid-state stability, and oral absorbability, compared to other salts or other crystals of compound (1).

[0037] N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (compound (1)) Compound (1) is a compound having the following structure, which is disclosed in Patent Document 1 as a compound having excellent EGFR inhibitory activity. The compound (1) used in the present invention is not particularly limited, but for example, one produced by the following production method can be used.

[0038] (Method for producing compound (1)) Compound (1) can be produced, for example, by the method described in Patent Document 1 or the method described herein. Compound (1) can also be produced by combining known reactions using intermediates described in Patent Document 1 and the present specification as starting materials. The products obtained in each step can be isolated and purified by known separation and purification means, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography, etc., or can be subjected to the next step without isolation and purification. Furthermore, in the production methods below, regardless of whether they are described or not, introduction of a protecting group or deprotection may be performed as necessary, and the order of each step may be changed as appropriate.

[0039] This section further describes a method for preparing compound (1) using tert-butyl (4-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate as a starting material.

[0040] (Step 1) Synthesis of tert-butyl (4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate It can be obtained by subjecting tert-butyl (4-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate, obtained by the method described in Patent Document 1 or a known method, to Sonogashira coupling with an acetylene derivative protected with TES (triethylsilyl).

[0041] A catalyst can be used in this reaction, and for example, a palladium catalyst can be used alone or, if necessary, in combination with an activator. Examples of palladium catalysts include, but are not limited to, palladium on carbon (Pd—C), palladium on alumina, palladium immobilized on silica gel, palladium acetate, dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II), tetrakis(triphenylphosphine)palladium(0), dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II), and dichlorobis(triphenylphosphine)palladium(II). The catalyst ligand is not particularly limited, but examples thereof include tri(o-tolyl)phosphine, tri(tert-butyl)phosphine, triphenylphosphine, dichlorobis(triphenylphosphine), 2-di-tert-butylphospheno-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, [4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine, di-tert-butyl(4-dimethylaminophenyl)phosphine, tricyclohexylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (Xantphos), bis(2-(diphenylphosphino)phenyl)ether, etc. The catalyst ligand may be coordinated to the palladium catalyst in advance, or the palladium catalyst and the catalyst ligand may be separately introduced into a solvent and coordinated in the reaction solvent.

[0042] Examples of the palladium catalyst include those mentioned above, but dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) is preferred, and its ligand is preferably di-tert-butyl(4-dimethylaminophenyl)phosphine or tricyclohexylphosphine.

[0043] Examples of activators that can be used include copper catalysts, silver catalysts, quaternary ammonium salts, and aqueous amine solutions. Examples of copper catalysts include salts containing monovalent copper ions, such as copper(I) halides (copper(I) fluoride, copper(I) chloride, copper(I) bromide, copper(I) iodide, and copper(I) trifluoromethanesulfonate). Examples of silver catalysts include salts containing monovalent silver ions, such as silver(I) oxide. Examples of quaternary ammonium salts include quaternary ammonium hydroxides (tetra-n-butylammonium hydroxide (TBAOH), tetraethylammonium hydroxide (TEAOH), n-hexadecyltrimethylammonium hydroxide, and choline hydroxide). Examples of aqueous amine solutions include aqueous solutions of ammonia, primary amines, secondary amines, and tertiary amines. Examples of activators include copper catalysts, more preferably salts containing monovalent copper ions, even more preferably copper(I) bromide, copper(I) iodide, or copper(I) trifluoromethanesulfonate, and particularly preferably copper(I) iodide.

[0044] The base used in the Sonogashira coupling is not particularly limited as long as it is a base that can achieve the introduction of an alkyne group. Examples of the base include organic bases such as trimethylamine, diethylamine, diisopropylamine (DIPEA), triethylamine (TEA), N-methylmorpholine, diazabicyclononene (DBN), pyridine, 4-dimethylaminopyridine (DMAP), pyridine, morpholine, quinoline, piperidine, and diazabicycloundecene (DBU), and inorganic bases such as alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, calcium acetate, etc.), alkali metal carbonates (sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkaline earth metal carbonates (barium carbonate, calcium carbonate), alkali metal phosphates (sodium phosphate, potassium phosphate, etc.), and acetates (magnesium acetate, potassium acetate, calcium acetate, cesium acetate, etc.). Preferably it is an organic base, more preferably diisopropylethylamine.

[0045] The solvent for the Sonogashira coupling is not particularly limited as long as it is a solvent in which the reaction can be carried out, and examples thereof include N,N-diisopropylethylamine, N-methyl-2-pyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran-1,4-dioxane, and toluene. N-methyl-2-pyrrolidone, N,N-dimethylformamide, and N,N-dimethylacetamide are preferred.

[0046] The reaction time for the Sonogashira coupling is not particularly limited as long as it is a time that allows introduction of an alkyne group, and can be set appropriately, for example, 0.5 to 8 hours, preferably 0.5 to 5 hours, and more preferably 1 to 3 hours.

[0047] The reaction temperature for the Sonogashira coupling is not particularly limited as long as it is a temperature at which the introduction of an alkyne group can be achieved, and can be appropriately set, for example, from 25 to 120°C, preferably from 50 to 110°C, and more preferably from 80 to 100°C.

[0048] (Step 2) Synthesis of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine This compound can be obtained by deprotecting the Boc (tert-butoxycarbonyl) protecting group of the tert-butyl (4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate synthesized as described above. The amine protecting group can be deprotected by a known method appropriate for the protecting group. Examples include deprotection under acidic conditions, deprotection under reducing conditions, deprotection under basic conditions, and deprotection using a palladium catalyst. For example, in the case of Boc, deprotection is generally carried out under acidic conditions, and any acid may be used to set the acidic conditions as long as the deprotection proceeds. Preferred are trifluoroacetic acid, hydrochloric acid, and sulfuric acid. The amount of acid used to set the acidic conditions is not particularly limited as long as the reaction proceeds.

[0049] The solvent used in the deprotection reaction of the amine protecting group is not particularly limited as long as the reaction proceeds. It can be selected from the same solvents as those used in the deprotection step of the silicon-linked protecting group described below. Preferred are methanol, ethanol, 2-propanol, acetonitrile, and tetrahydrofuran, more preferably methanol, ethanol, and 2-propanol, and even more preferably methanol. The amount of solvent used is not particularly limited as long as the reaction proceeds, but is preferably 1 to 100 L, more preferably 5 to 50 L, and even more preferably 10 to 30 L per kg of reactant.

[0050] (Step 3) Synthesis of N-(4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide This compound can be obtained by condensing 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Step 2 with 5-methylpyrazine-2-carboxylic acid. There are no particular restrictions on the condensing agent used in the condensation reaction, as long as it allows the reaction to proceed. For example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride (WSC or EDC), dicyclohexylcarbodiimide (DCC), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide, etc. Carbodiimide condensation agents such as metho-p-toluenesulfonate (CMC), diisopropylcarbodiimide (DIC), and 1,3-bis(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC) are used in combination with 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), ethyl (hydroxyimino)cyanoacetate (Oxyma), N-hydroxysuccinimide (HOSu), and phenanthroline. combinations of alcohols for constructing activated esters such as tetrafluorophenol; uronium condensing agents such as O-(7-azabenzotriazo-1-yl)-N,N,N',N'-tetramethylhexauronium hexafluorophosphate (HATU) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU); 2-halo-N-alkylpyridinium salts (Mukaiyama condensation reagents) such as 2-chloro-6-methyl-1,3-diphenylpyridinium tetrafluoroborate and 1-methyl-2-chloropyridinium iodide; N,N'-carbonyldiimidazole (CDI), 1,1'-carbonyldi(1,2,imidazole condensing agents such as bromotripyrrolidinophosphonium hexafluorophosphate, chlorotripyrrolidinophosphonium hexafluorophosphate, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (Py Examples of suitable condensing agents include phosphonium condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and 4,6-dimethoxy-1,3,5-triazin-2-yl)-(octoxy-2-oxoethyl)dimethylammonium trifluoromethanesulfonate; triazine condensing agents such as 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P) and diphenylphosphoric azide (DPPA). A combination of a carbodiimide condensing agent and an alcohol for constructing an activated ester is preferred, and a combination of EDC and HOBt is more preferred. These condensing agents include polymer-supported reagents.

[0051] The solvent used in the condensation reaction is not particularly limited as long as it allows the reaction to proceed. It can be selected from the same solvents as those used in the deprotection step of the silicon-linked protecting group. Dichloromethane, chloroform, ethyl acetate, dimethyl sulfoxide, diethyl ether, tetrahydrofuran, 1,4-dioxane, acetone, N,N-dimethylformamide, N-methylpyrrolidone, toluene, acetonitrile, and tetrahydrofuran are preferred, with dichloromethane, chloroform, ethyl acetate, dimethyl sulfoxide, and N,N-dimethylformamide being even more preferred. The amount of solvent used is not particularly limited as long as the reaction proceeds, but is preferably 5 to 100 L, more preferably 15 to 50 L, and even more preferably 25 to 35 L per 1 kg of reactant.

[0052] (Step 4) Synthesis of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (compound (1)) It can be obtained by deprotecting the TES, which is the protecting group of the acetylene of N-(4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide obtained in Step 3, under basic conditions. The reagent for creating basic conditions is not particularly limited as long as the reaction proceeds. Examples of the inorganic base include metal hydroxides (sodium hydroxide, calcium hydroxide, etc.), metal hydrides (lithium hydride, sodium hydride, etc.), metal carbonates (sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, magnesium carbonate, sodium bicarbonate, etc.), and the like. Examples of the organic base include metal alkoxides (sodium methoxide, potassium tert-butoxide, etc.), metal amides (sodium amide, lithium diisopropylamide, etc.), alkyl metal compounds (n-butyllithium, trimethylaluminum, etc.), alkylamines (triethylamine, tetramethylethylenediamine, piperidine, 1,4-diazabicyclo[2.2.2]octane, etc.), heterocyclic amines (diazabicycloundecene, pyridine, imidazole, etc.), and quaternary ammonium fluoride (tetra-n-butylammonium fluoride). Preferably, the reagent for creating basic conditions is a reagent that does not contain fluoride ions, more preferably a metal carbonate, and even more preferably potassium carbonate. These can be used alone or in combination to adjust to the desired pH. The amount of the reagent used is not particularly limited as long as the reaction proceeds, but for example, 0.1 to 50 moles can be used per mole of the starting compound (compound represented by formula (II)). The amount is preferably 0.1 to 10 moles, and more preferably 0.1 to 2 moles.

[0053] The solvent used in the deprotection step is not particularly limited as long as it can maintain a basic pH and dissolve the compounds used in the reaction. Examples of the solvent include C5 to C10 hydrocarbons, C6 to C14 aromatic hydrocarbons, C1 to C6 alcohols, C3 to C10 aliphatic carboxylic acid esters, C3 to C10 ketones, C4 to C10 ethers, aprotic polar organic solvents, and mixed solvents thereof. In this specification, the term "C" refers to the number of carbon atoms, and refers to the total number of carbon atoms contained in the compound.

[0054] C5 to C10 hydrocarbons are hydrocarbons having 5 to 10 carbon atoms, and examples thereof include pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane.

[0055] The C6 to C14 aromatic hydrocarbons are aromatic hydrocarbons having 6 to 14 carbon atoms, and examples thereof include benzene, naphthalene, anthracene, toluene, xylene, cumene, styrene, and phenanthrene.

[0056] The C1 to C6 alcohol is an alcohol having 1 to 6 carbon atoms, and examples thereof include methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, n-pentanol, and n-hexanol.

[0057] The C3 to C10 aliphatic carboxylic acid ester is an aliphatic carboxylic acid ester having 3 to 10 carbon atoms, and examples thereof include propyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate, propyl propionate, methyl butanoate, and ethyl butanoate.

[0058] The C3 to C10 ketones are ketones having 3 to 10 carbon atoms, and examples thereof include acetone, ethyl methyl ketone, diethyl ketone, isopropyl methyl ketone, and cyclohexanone.

[0059] The C4 to C10 ether is an ether having 4 to 10 carbon atoms, and examples thereof include diethyl ether, tert-butyl methyl ether, tetrahydrofuran, and 1,4-dioxane.

[0060] The aprotic polar organic solvent is a solvent that does not contain ionizable protons, and examples thereof include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, chloroform, and dichloromethane.

[0061] When compound (1) is produced according to steps 1 to 4 described herein, type III crystals of compound (1) may be produced.

[0062] Free Form III Crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) According to one aspect of the present invention, a free form III crystal of Compound (1) is provided. In one embodiment of the present invention, the free form III crystal of Compound (1) has a powder X-ray diffraction spectrum shown in FIG. 1 or a powder X-ray diffraction spectrum substantially identical thereto.

[0063] Here, in one embodiment of the present invention, characteristic peaks in the powder X-ray diffraction spectrum of the free form type III crystal of compound (1) can include one or more peaks selected from the diffraction angles (2θ±0.2°) of 6.6°, 8.8°, 11.6°, 12.3°, 13.8°, 17.9°, 18.6°, 21.3°, and 22.3°.

[0064] In one embodiment of the present invention, the free-form type III crystal of compound (1) has, in its powder X-ray diffraction spectrum, peaks at diffraction angles (2θ±0.2°) of: (i) one or more peaks selected from the group consisting of 8.8°, 11.6°, and 17.9°, and (ii) two or more peaks selected from the group consisting of 6.6°, 12.3°, 13.8°, 18.6°, 21.3°, and 22.3°. That is, it has a total of three or more peaks selected from group (i) and group (ii). In a preferred embodiment of the present invention, the free-form type III crystal of compound (1) has, in its powder X-ray diffraction spectrum, peaks at diffraction angles (2θ±0.2°) of four or more peaks selected from group (i) and group (ii), preferably five or more peaks, more preferably six or more peaks, and even more preferably seven or more peaks. In another embodiment of the present invention, the free-form III crystal of Compound (1) may have peaks at a total of eight or all diffraction angles (2θ±0.2°) selected from the above group (i) and the above group (ii) in the powder X-ray diffraction spectrum. In another embodiment, the free-form III crystal of Compound (1) may have peaks at two or more, three or more, or all peaks selected from the above group (i). In yet another embodiment, the free-form III crystal of Compound (1) may have peaks at three or more, four or more, five or more, or all peaks selected from the above group (ii). In yet another embodiment, it may further have peaks at one or more of the diffraction angles (2θ±0.2°) described in the examples other than those described above.

[0065] In one embodiment of the present invention, the free-form type III crystal of compound (1) has an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at 223 to 233° C., in other words, around 228° C. In another embodiment, the free-form type III crystal of compound (1) has a differential thermal analysis-thermogravimetry (TG-DTA) curve shown in FIG.

[0066] In one embodiment of the present invention, the free form Form III crystal of compound (1) has, in a powder X-ray diffraction spectrum, peaks at diffraction angles (2θ±0.2°) of: (i) one or more selected from the group consisting of 8.8°, 11.6°, and 17.9°, and (ii) two or more selected from the group consisting of 6.6°, 12.3°, 13.8°, 18.6°, 21.3°, and 22.3°, and has an exothermic peak (onset value) at around 228°C as determined by simultaneous differential thermal and thermogravimetry analysis. In a preferred embodiment of the present invention, the free-form type III crystal of compound (1) is a crystal having a powder X-ray diffraction spectrum in which the diffraction angle (2θ±0.2°) is a total of four or more peaks selected from group (i) and group (ii) above, and an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 228°C, preferably five or more peaks and an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 228°C, more preferably six or more peaks in total and an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 228°C, and even more preferably seven or more peaks and an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 228°C. In another embodiment of the present invention, the free-form type III crystal of compound (1) may have peaks at a total of eight or all diffraction angles (2θ±0.2°) selected from group (i) and group (ii) in a powder X-ray diffraction spectrum, and may have an exothermic peak (onset value) determined by differential thermal-thermogravimetry simultaneous measurement at around 228°C. In another embodiment, the free-form type III crystal of compound (1) may have peaks at two or more peaks selected from group (i) above and an exothermic peak (onset value) determined by differential thermal-thermogravimetry simultaneous measurement at around 228°C, or may have three or more peaks and an exothermic peak (onset value) determined by differential thermal-thermogravimetry simultaneous measurement at around 228°C, or may have peaks at all peaks and an exothermic peak (onset value) determined by differential thermal-thermogravimetry simultaneous measurement at around 228°C.In still another embodiment, the free form Type III crystal of Compound (1) may have three or more peaks selected from the above group (ii) and may have an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 228°C; may have four or more peaks and may have an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 228°C; may have five or more peaks and may have an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 228°C; or may have all peaks and may have an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 228°C.

[0067] (Method for Producing Free Form III Crystals of Compound (1)) In one embodiment of the present invention, free form III crystals of compound (1) can be obtained, for example, by stirring compound (1) in a methanol-containing solvent, for example, a mixed solvent of water and methanol. Examples of the methanol-containing solvent include a mixed solvent of methanol and water, as well as a combination of methanol and N-methyl-2-pyrrolidone. A mixed solvent of methanol and N-methyl-2-pyrrolidone is preferred. The amount of solvent is not particularly limited, but is preferably 5 to 50 times (volume / weight) the amount of compound (1), more preferably 5 to 30 times (volume / weight), and even more preferably 5 to 10 times (volume / weight). The stirring time can be set appropriately, but can be between 10 minutes and 120 hours. 1 to 24 hours is preferred, more preferably 1 to 5 hours, and even more preferably 1 to 3 hours. The stirring temperature can be set appropriately, but is preferably less than about 60°C. The temperature is preferably 10 to 50°C, more preferably 20 to 40°C, and even more preferably 20 to 30°C. To remove the solvent used, drying may be performed using a known drying method such as drying under reduced pressure. By producing by this method, the free-form type III crystal of compound (1) can be easily produced on a large scale.

[0068] Free Form II Crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) According to one aspect of the present invention, there is provided a free form II crystal of Compound (1). In one embodiment of the present invention, the free form II crystal of Compound (1) has a powder X-ray diffraction spectrum shown in FIG. 3 or a powder X-ray diffraction spectrum substantially identical thereto.

[0069] Here, characteristic peaks in the powder X-ray diffraction spectrum of the free form type II crystal of compound (1) in one embodiment of the present invention can include one or more peaks selected from the diffraction angles (2θ±0.2°) of 7.8°, 10.6°, 14.0°, 14.8°, 15.6°, 17.2°, 20.1°, 21.6°, 22.2°, 24.7°, 25.8°, and 28.9°.

[0070] In one embodiment of the present invention, the type II crystal of the free form of compound (1) has, in its powder X-ray diffraction spectrum, peaks at diffraction angles (2θ±0.2°) selected from the group consisting of: (i) one or more peaks selected from the group consisting of 15.6°, 20.1°, 24.7°, and 28.9°, and (ii) two or more peaks selected from the group consisting of 7.8°, 10.6°, 14.0°, 14.8°, 17.2°, 21.6°, 22.2°, and 25.8°. That is, it has a total of three or more peaks selected from group (i) and group (ii). In a preferred embodiment of the present invention, the type II crystal of the free form of compound (1) has, in its powder X-ray diffraction spectrum, peaks at diffraction angles (2θ±0.2°) selected from group (i) and group (ii) in a total of four or more, preferably five or more, more preferably six or more, and even more preferably seven or more peaks. In another embodiment of the present invention, the free-form type II crystal of compound (1) may have peaks in its powder X-ray diffraction spectrum at diffraction angles (2θ±0.2°) at a total of 8, 9, 10, 11, or all selected from group (i) and group (ii). In another embodiment, the free-form type II crystal of compound (1) may have peaks at two or more, three or more, or all of the angles selected from group (i). In yet another embodiment, the free-form type II crystal of compound (1) may have peaks at three or more, four or more, five or more, six or more, seven or more, or all of the angles selected from group (ii). In yet another embodiment, it may further have peaks at one or more of the diffraction angles (2θ±0.2°) described in the examples other than those described above.

[0071] In one embodiment of the present invention, the free-form type II crystal of compound (1) has an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at 231 to 241° C., in other words, around 236° C. In another embodiment, the free-form type II crystal of compound (1) has a simultaneous differential thermal analysis-thermogravimetry (TG-DTA) curve shown in FIG.

[0072] In one embodiment of the present invention, Type II crystal of the free form of compound (1) has, in a powder X-ray diffraction spectrum, peaks at diffraction angles (2θ±0.2°) of: (i) one or more selected from the group consisting of 15.6°, 20.1°, 24.7°, and 28.9°, and (ii) two or more selected from the group consisting of 7.8°, 10.6°, 14.0°, 14.8°, 17.2°, 21.6°, 22.2°, and 25.8°, and has an exothermic peak (onset value) at around 236°C as determined by simultaneous differential scanning calorimetry and thermogravimetry. In a preferred embodiment of the present invention, the type II crystal of the free form of compound (1) is a crystal having a powder X-ray diffraction spectrum in which the diffraction angle (2θ±0.2°) has a total of four or more peaks selected from group (i) and group (ii) above, and an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 236°C, preferably five or more peaks and an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 236°C, more preferably six or more peaks in total and an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 236°C, and even more preferably seven or more peaks and an exothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 236°C. In another embodiment of the present invention, the free-form type II crystal of compound (1) has peaks in a powder X-ray diffraction spectrum at diffraction angles (2θ±0.2°) of a total of 8, 9, 10, 11, or all selected from group (i) and group (ii) above, and may have an exothermic peak (onset value) determined by differential thermal-thermogravimetry simultaneous measurement around 236 ° C. In another embodiment, the free-form type II crystal of compound (1) may have peaks at two or more peaks selected from group (i) above and an exothermic peak (onset value) determined by differential thermal-thermogravimetry simultaneous measurement around 236 ° C., or may have three or more peaks and an exothermic peak (onset value) determined by differential thermal-thermogravimetry simultaneous measurement around 236 ° C., or may have peaks at all and an exothermic peak (onset value) determined by differential thermal-thermogravimetry simultaneous measurement around 236 ° C.In still another embodiment, the free form type II crystal of compound (1) may have three or more peaks selected from the group (ii) above, and may have an exothermic peak (onset value) determined by differential thermal analysis-thermogravimetry simultaneous measurement at around 236 ° C.; may have four or more peaks, and may have an exothermic peak (onset value) determined by differential thermal analysis-thermogravimetry simultaneous measurement at around 236 ° C.; may have five or more peaks, and may have an exothermic peak (onset value) determined by differential thermal analysis-thermogravimetry simultaneous measurement at around 236 ° C.; may have six or more peaks, and may have an exothermic peak (onset value) determined by differential thermal analysis-thermogravimetry simultaneous measurement at around 236 ° C.; may have seven or more peaks, and may have an exothermic peak (onset value) determined by differential thermal analysis-thermogravimetry simultaneous measurement at around 236 ° C.; or may have all peaks, and may have an exothermic peak (onset value) determined by differential thermal analysis-thermogravimetry simultaneous measurement at around 236 ° C.

[0073] (Method for Producing Free Form Type II Crystal of Compound (1)) In one embodiment of the present invention, the free form Type II crystal of Compound (1) can be obtained, for example, by stirring Compound (1) in a solvent such as tetrahydrofuran. Examples of the solvent used include, in addition to tetrahydrofuran, lower alcohols having 3 or more carbon atoms, acetone, ethyl acetate, and N-methyl-2-pyrrolidone, and these may be used alone or in mixtures. Tetrahydrofuran is preferred. The amount of solvent is not particularly limited, but is preferably 5 to 50 times (volume / weight) the amount of Compound (1), more preferably 5 to 30 times (volume / weight), and even more preferably 5 to 20 times (volume / weight). The stirring time can be set appropriately, but can be between 10 minutes and 120 hours. 2 to 48 hours is preferred, and 5 to 24 hours is more preferred. The stirring temperature can be set appropriately, but is preferably less than about 60°C. It is preferably 20 to 50°C, more preferably 20 to 30°C, and even more preferably 25°C. To remove the solvent used, drying may be carried out using a known drying method such as drying under reduced pressure.

[0074] Form III Crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) with Succinic Acid According to one aspect of the present invention, a Form III crystal of Compound (1) with succinic acid is provided. In one embodiment of the present invention, the Form III crystal of Compound (1) with succinic acid has a powder X-ray diffraction spectrum shown in FIG. 13 or a powder X-ray diffraction spectrum substantially identical thereto.

[0075] Here, in one embodiment of the present invention, characteristic peaks in the powder X-ray diffraction spectrum of the type III crystal of compound (1) with succinic acid can include one or more peaks selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5° as diffraction angles (2θ±0.2°).

[0076] In one embodiment of the present invention, the type III crystal of compound (1) with succinic acid is a crystal having three or more peaks selected from the above characteristic peaks, preferably a crystal having four or more peaks selected from the above characteristic peaks, more preferably a crystal having five or more peaks selected from the above characteristic peaks, even more preferably a crystal having six or more peaks selected from the above characteristic peaks, and even more preferably a crystal having seven or more peaks selected from the above characteristic peaks. In another embodiment of the present invention, the type III crystal of compound (1) with succinic acid may have eight or more, nine or more, or all peaks selected from the above characteristic peaks. In yet another embodiment, it may further have peaks at one or more of the diffraction angles (2θ±0.2 °) described in the examples other than those described above.

[0077] In one embodiment of the present invention, the type III crystal of compound (1) with succinic acid has an endothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at 197 to 207° C., in other words, around 202° C. In another embodiment, the type III crystal of compound (1) with succinic acid has the curve of simultaneous differential thermal analysis-thermogravimetry (TG-DTA) shown in FIG.

[0078] In one embodiment of the present invention, the type III crystal of compound (1) with succinic acid has characteristic peaks in a powder X-ray diffraction spectrum at diffraction angles (2θ±0.2°) of one or more selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5°, and has an endothermic peak (onset value) at around 202°C as determined by simultaneous differential thermal and thermogravimetry analysis. In one embodiment of the present invention, the type III crystal of compound (1) with succinic acid is a crystal having three or more peaks selected from the above characteristic peaks, and an endothermic peak (onset value) determined by simultaneous differential thermal analysis and thermogravimetry at around 202°C, preferably a crystal having four or more peaks selected from the above characteristic peaks, and an endothermic peak (onset value) determined by simultaneous differential thermal analysis and thermogravimetry at around 202°C, more preferably a crystal having five or more peaks selected from the above characteristic peaks, and an endothermic peak (onset value) determined by simultaneous differential thermal analysis and thermogravimetry at around 202°C, even more preferably a crystal having six or more peaks selected from the above characteristic peaks, and an endothermic peak (onset value) determined by simultaneous differential thermal analysis and thermogravimetry at around 202°C, and even more preferably a crystal having seven or more peaks selected from the above characteristic peaks, and an endothermic peak (onset value) determined by simultaneous differential thermal analysis and thermogravimetry at around 202°C. In another embodiment of the present invention, the type III crystal of compound (1) with succinic acid may have eight or more, nine or more, or all of the characteristic peaks selected from the above-mentioned characteristic peaks, and may have an endothermic peak (onset value) at around 202°C as determined by simultaneous differential thermal and thermogravimetry analysis.

[0079] In the present specification, the type III crystal of compound (1) and succinic acid may be a salt or co-crystal of compound (1) and succinic acid. Preferably, the equivalent ratio of compound (1) to succinic acid is 1:1 to 10, preferably 1:1 to 5, more preferably 1:1 to 3, and even more preferably 1:1 or 1:3.

[0080] (Method for Producing Type III Crystals of Compound (1) with Succinic Acid) In one embodiment of the present invention, Type III crystals of compound (1) with succinic acid can be obtained, for example, by stirring compound (1) together with succinic acid in a solvent such as acetonitrile. Examples of the solvent used include, in addition to acetonitrile, lower alcohols having two or more carbon atoms, methyl ethyl ketone, tetrahydrofuran, and 2-methyltetrahydrofuran. Acetonitrile, tetrahydrofuran, and 2-methyltetrahydrofuran are preferred. The amount of solvent is not particularly limited, but is preferably 5 to 50 times (volume / weight) the amount of compound (1), more preferably 5 to 20 times (volume / weight), and even more preferably 5 to 9 times (volume / weight). The stirring time can be set appropriately, but is preferably 10 minutes to 24 hours, more preferably 30 minutes to 3 hours, and even more preferably 1 to 2 hours. The stirring temperature can be set appropriately, but is preferably less than about 60°C. The temperature is preferably 30 to 50° C., more preferably 40 to 50° C., and even more preferably 50° C. To remove the solvent used, drying may be carried out using a known drying method such as drying under reduced pressure.

[0081] Form I Crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) with Sorbic Acid According to one aspect of the present invention, Form I crystal of Compound (1) with sorbic acid is provided. In one embodiment of the present invention, Form I crystal of Compound (1) with sorbic acid has the powder X-ray diffraction spectrum shown in FIG. 15 or a powder X-ray diffraction spectrum substantially identical thereto.

[0082] Here, in one embodiment of the present invention, characteristic peaks in the powder X-ray diffraction spectrum of type I crystals of compound (1) with sorbic acid can include one or more peaks selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4° as diffraction angles (2θ±0.2°).

[0083] In one embodiment of the present invention, the type I crystal of compound (1) with sorbic acid is a crystal having three or more peaks selected from the above characteristic peaks, preferably a crystal having four or more peaks selected from the above characteristic peaks, more preferably a crystal having five or more peaks selected from the above characteristic peaks, even more preferably a crystal having six or more peaks selected from the above characteristic peaks, and even more preferably a crystal having seven or more peaks selected from the above characteristic peaks. In another embodiment of the present invention, the type I crystal of compound (1) with sorbic acid may have eight or more, nine or more, or all peaks selected from the above characteristic peaks. In yet another embodiment, it may further have peaks at one or more of the diffraction angles (2θ±0.2°) described in the examples other than those described above.

[0084] In one embodiment of the present invention, the type I crystal of compound (1) with sorbic acid has an endothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at 168 to 178° C., in other words, around 173° C. In another embodiment, the type I crystal of compound (1) with sorbic acid has the curve of simultaneous differential thermal analysis-thermogravimetry (TG-DTA) shown in FIG.

[0085] In one embodiment of the present invention, the type I crystal of compound (1) with sorbic acid has characteristic peaks in a powder X-ray diffraction spectrum at diffraction angles (2θ±0.2°) of one or more selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4°, and has an endothermic peak (onset value) at around 173°C as determined by simultaneous differential thermal and thermogravimetry analysis. In one embodiment of the present invention, the type I crystal of compound (1) with sorbic acid is a crystal having three or more peaks selected from the above characteristic peaks and having an endothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 173°C, preferably a crystal having four or more peaks selected from the above characteristic peaks and having an endothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 173°C, more preferably a crystal having five or more peaks selected from the above characteristic peaks and having an endothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 173°C, even more preferably a crystal having six or more peaks selected from the above characteristic peaks and having an endothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 173°C, and even more preferably a crystal having seven or more peaks selected from the above characteristic peaks and having an endothermic peak (onset value) determined by simultaneous differential thermal analysis-thermogravimetry at around 173°C. In another embodiment of the present invention, the type I crystal of compound (1) with sorbic acid may have eight or more, nine or more, or all of the characteristic peaks selected from the above-mentioned characteristic peaks, and may have an endothermic peak (onset value) at around 173°C as determined by simultaneous differential thermal and thermogravimetry analysis.

[0086] In this specification, the type I crystal of compound (1) and sorbic acid may be a salt or co-crystal of compound (1) and sorbic acid. Preferably, the equivalent ratio of compound (1) to sorbic acid is 1:1 to 10, preferably 1:1 to 5, more preferably 1:1 to 3, and even more preferably 1:1.

[0087] (Method for Producing Type I Crystals of Compound (1) with Sorbic Acid) In one embodiment of the present invention, Type I crystals of Compound (1) with sorbic acid can be obtained, for example, by stirring Compound (1) together with sorbic acid in acetonitrile. Examples of the solvent used include, in addition to acetonitrile, lower alcohols, tetrahydrofuran, acetone, methyl ethyl ketone, water, and ethyl acetate. Preferred are acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, and water. The amount of solvent is not particularly limited, but is preferably 5 to 50 times (volume / weight) the amount of Compound (1), more preferably 5 to 20 times (volume / weight), and even more preferably 5 to 10 times (volume / weight). The stirring time can be set as appropriate, but is preferably 10 minutes to 120 hours, more preferably 1 to 10 hours, and even more preferably 2 to 7.5 hours. The stirring temperature can be set as appropriate, but is preferably less than about 60°C. It is preferably 30 to 50°C, more preferably 40 to 50°C, and even more preferably 50°C. To remove the solvent used, drying may be carried out using a known drying method such as drying under reduced pressure.

[0088] (Purification of Crystals and Other Operations) The precipitated crystals can be isolated and purified from the solution in which the crystals are dissolved, the mixed solution, etc., by known separation and purification means, for example, filtration, washing with water or an organic solvent, drying under reduced pressure, etc. Examples of organic solvents used for washing include lower alcohols, acetone, acetonitrile, etc.

[0089] Each crystal can also be produced by adding the desired crystal as a seed crystal to a specific solvent, which can be the solvent used to obtain each crystal listed above.

[0090] (Activity and Use) The crystal of compound (1) in one embodiment of the present invention has excellent EGFR inhibitory activity. In particular, it has excellent inhibitory activity against EGFR (Del19 / C797S), EGFR (L858R / C797S), EGFR (Del19 / T790M / C797S), and EGFR (L858R / T790M / C797S), and is useful as an antitumor agent. Furthermore, the crystal of compound (1) in one embodiment of the present invention has the advantage of having excellent selectivity against mutant EGFR and having fewer side effects caused by wild-type EGFR and other kinases.

[0091] As used herein, "wild-type EGFR" refers to, for example, the amino acid sequence of GenBank Accession No. NP_005219.2. As used herein, "exon 19" refers to the region from 729 to 823 in the amino acid sequence of wild-type EGFR (for example, GenBank Accession No. NP_005219.2).

[0092] As used herein, "Del19" refers to a mutation in which one or more amino acids are deleted in the exon 19 region of wild-type EGFR. It also encompasses mutations in which one or more arbitrary amino acids are inserted in addition to the deletion of the region. Examples of exon 19 deletion mutations include a mutation in which five amino acids from glutamic acid at position 746 to alanine at position 750 in the exon 19 region are deleted (Del E746-A750 (also referred to as d746-750)), a mutation in which seven amino acids from leucine at position 747 to proline at position 753 in the exon 19 region are deleted followed by an insertion of serine (Del L747-P753insS), a mutation in which five amino acids from leucine at position 747 to threonine at position 751 in the exon 19 region are deleted (Del L747-T751), and a mutation in which four amino acids from leucine at position 747 to alanine at position 750 in the exon 19 region are deleted followed by an insertion of proline (Del L747-A750insP). A preferred mutation is a deletion of five amino acids from glutamic acid at position 746 to alanine at position 750 in the exon 19 region (Del E746-A750).

[0093] The crystals of the present invention may be used for postoperative adjuvant chemotherapy, which is carried out to prevent recurrence after surgical removal of a tumor, or for neoadjuvant chemotherapy, which is carried out before surgical removal of a tumor.

[0094] The tumors that are the subject of the present invention are not particularly limited, and examples thereof include head and neck cancer, digestive cancers (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder / bile duct cancer, etc.), pancreatic cancer, colon cancer (colorectal cancer, colon cancer, rectal cancer, anal cancer, etc.)), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma (pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, testicular mesothelioma, etc.)), breast cancer, reproductive cancers (ovarian cancer, vulvar cancer, uterine cancer (cervical cancer, uterine cancer, endometrial cancer, etc.)), urinary cancers (kidney cancer, bladder cancer, prostate cancer, testicular tumor, urothelial carcinoma, renal pelvis cancer, urethral cancer, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, rhabdomyosarcoma, skin cancer, brain tumors, malignant neurinoma, neuroendocrine tumors, thyroid cancer, etc. Preferred are head and neck cancer, breast cancer, colon cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, renal cancer, bladder cancer, skin cancer, and brain cancer, and particularly preferred is lung cancer. Here, cancer includes not only primary tumors but also cancers that have metastasized to other organs (such as the liver). Furthermore, crystals of compound (1) according to one embodiment of the present invention have excellent inhibitory activity against mutant EGFR. Examples of such mutant EGFR include drug-resistant mutant EGFR and highly sensitive mutant EGFR. Therefore, the compound of the present invention or a salt thereof is useful as an antitumor agent against the aforementioned malignant tumors having mutant EGFR.

[0095] As used herein, the term "effective amount" of a compound refers to an amount of a compound of the present invention that elicits a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity, or that improves symptoms, alleviates a condition, or slows or delays the progression of a disease (a therapeutically effective amount). As used herein, the term "subject" includes mammals and non-mammals. In one embodiment, the subject is a human, and may be a human diagnosed with a need for treatment for a symptom, condition, or disease disclosed herein.

[0096] When using crystals or cocrystals of compound (1) or its salt as a pharmaceutical, various administration forms can be adopted depending on the therapeutic purpose, with or without pulverization of the crystals, and they can be used in dosage forms generally used for pharmaceuticals. Examples of such forms include oral preparations such as tablets, capsules, granules, fine granules, powders, and dry syrups; and parenteral preparations such as suppositories, inhalants, nasal drops, ointments, patches, and injections. Pharmaceutical compositions suitable for these administration forms can be prepared using pharmaceutically acceptable carriers by formulation methods commonly known and commonly used by those skilled in the art.

[0097] One embodiment of the present invention provides an orally administered antitumor agent comprising the above-mentioned crystal of compound (1) (i.e., a crystal of the free form of compound (1) or a crystal of compound (1) with an acid (a salt crystal or a co-crystal)). Another embodiment of the present invention provides a method for treating a tumor, comprising orally administering to a subject in need thereof an effective amount of the above-mentioned crystal of compound (1) (i.e., a crystal of the free form of compound (1) or a crystal of compound (1) with an acid (a salt crystal or a co-crystal)). Another embodiment of the present invention provides use of the above-mentioned crystal of compound (1) (i.e., a crystal of the free form of compound (1) or a crystal of compound (1) with an acid (a salt crystal or a co-crystal)) for the manufacture of an orally administered antitumor agent. Another embodiment of the present invention provides the above-mentioned crystal of compound (1) (i.e., a crystal of the free form of compound (1) or a crystal of compound (1) with an acid (a salt crystal or a co-crystal)) for use in the treatment of a tumor by oral administration.

[0098] One embodiment of the present invention provides a pharmaceutical composition comprising the above-described crystal of compound (1) (i.e., a crystal of the free form of compound (1) or a crystal of compound (1) with an acid (a crystal of a salt or a co-crystal)). One embodiment of the present invention comprises the above-described crystal of compound (1) (i.e., a crystal of the free form of compound (1) or a crystal of compound (1) with an acid (a crystal of a salt or a co-crystal)), and a pharmaceutically acceptable carrier. Another embodiment of the present invention provides use of the above-described crystal of compound (1) (i.e., a crystal of the free form of compound (1) or a crystal of compound (1) with an acid (a crystal of a salt or a co-crystal)) for the manufacture of a pharmaceutical composition. Another embodiment of the present invention provides the above-described crystal of compound (1) (i.e., a crystal of the free form of compound (1) or a crystal of compound (1) with an acid (a crystal of a salt or a co-crystal)) for use as a pharmaceutical.

[0099] Pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as formulation materials, and include excipients, binders, disintegrants, lubricants, coating agents, etc. in solid formulations, and are incorporated as solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers, etc. can also be used as needed.

[0100] Examples of excipients include starches, sugars, polysaccharides, inorganic compounds, and the like. Examples of starches include potato starch, corn starch, rice starch, and partially pregelatinized starch. Examples of sugars include monosaccharides, disaccharides, trisaccharides, and sugar alcohols. Examples include lactose, sucrose, trehalose, D-mannitol, raffinose, xylitol, and erythritol. Examples of polysaccharides include cellulose and dextran. Examples include crystalline cellulose, hydroxypropyl cellulose, and hydroxypropylmethylcellulose. Examples of inorganic compounds include silicic acids, such as light anhydrous silicic acid and calcium silicate. Examples of binders include hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, candy powder, and hypromellose. Examples of disintegrants include sodium starch glycolate, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and partially pregelatinized starch. Examples of lubricants include talc, magnesium stearate, sucrose fatty acid esters, stearic acid, and sodium stearyl fumarate. Examples of coating agents include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hypromellose, and sucrose. Examples of solvents include water, propylene glycol, and physiological saline. Examples of solubilizers include polyethylene glycol, alcohols such as ethanol, cyclodextrins, cyclodextrin derivatives, ionic surfactants, and nonionic surfactants, such as sorbitan fatty acid esters such as polysorbate 80, sucrose fatty acid esters, and sodium lauryl sulfate. Examples of suspending agents include carrageenan, crystalline cellulose-carmellose sodium, polyoxyethylene hydrogenated castor oil, gum arabic, and sodium alginate. Examples of isotonic agents include sodium chloride, glycerin, and potassium chloride. Examples of pH adjusters and buffers include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, and sodium dihydrogen phosphate. Examples of soothing agents include procaine hydrochloride and lidocaine.Examples of preservatives include ethyl parahydroxybenzoate, cresol, and benzalkonium chloride. Examples of antioxidants include sodium sulfite, ascorbic acid, and natural vitamin E. Examples of colorants include titanium oxide, ferric oxide, Food Blue No. 1, and copper chlorophyll. Examples of flavoring and odor correcting agents include aspartame, saccharin, sucralose, l-menthol, and mint flavor. Examples of stabilizers include sodium metabisulfite, sodium edetate, erythorbic acid, magnesium oxide, and dibutylhydroxytoluene.

[0101] When preparing oral solid preparations, excipients, and if necessary binders, disintegrants, lubricants, colorants, flavorings, and odor-correcting agents, etc., are added to crystals of compound (1) (i.e., crystals of the free form of compound (1) or crystals of compound (1) with an acid (crystals of a salt or co-crystal)), and tablets, coated tablets, granules, powders, capsules, etc. can be produced by conventional methods. When preparing injections, pH adjusters, buffers, stabilizers, isotonicity agents, local anesthetics, etc. are added to crystals of compound (1) (i.e., crystals of the free form of compound (1) or crystals of compound (1) with an acid (crystals of a salt or co-crystal)), and subcutaneous, intramuscular, and intravenous injections can be produced by conventional methods.

[0102] The amount of crystals of compound (1) (i.e., crystals of the free form of compound (1) or crystals of compound (1) with an acid (salt crystals or co-crystals)) to be incorporated into each dosage unit form varies depending on the symptoms of the patient to whom it is to be administered or on the dosage form, etc., but generally, it is desirable that the amount per dosage unit form be about 0.05 to 1000 mg, in terms of the free form of compound (1), for oral agents, about 0.1 to 500 mg for injections, and about 1 to 1000 mg for suppositories or external preparations.

[0103] Furthermore, the daily dose of a crystal of compound (1) (i.e., a crystal of the free form of compound (1) or a crystal of compound (1) with an acid (a salt crystal or a co-crystal)) for a drug having each dosage form varies depending on the symptoms, body weight, age, sex, etc. of the patient and cannot be determined in general, but is usually about 0.05 to 5000 mg, preferably 0.1 to 1000 mg, of compound (1) in free form per day for an adult (body weight 50 kg).

[0104] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. Although the present invention has been fully explained with reference to examples, it is understood that various changes and / or modifications may be made by those skilled in the art. Therefore, as long as such changes and / or modifications do not deviate from the scope of the present invention, they are included in the present invention.

[0105] In the following compound examples, % means weight percent unless otherwise specified.

[0106] Powder X-ray Diffraction Measurement Powder X-ray diffraction was measured according to one of the following test conditions after lightly crushing an appropriate amount of the test substance in an agate mortar as required.

[0107] Equipment: PANalytical EMPYREAN (Method A) Reflection method (focusing method) Target: Cu X-ray tube current: 40 mA X-ray tube voltage: 45 kV Scan range: 2θ = 5.0 to 40.0° Step: 2θ = 0.0131° Averaging time / step: 8.670 s Scan speed: 0.0015° / s Divergence slit: 1° Scattering slit: 2.0 mm Receiving slit: 8.0 mm Equipment: PANalytical EMPYREAN (Method B) Transmission method Target: Cu X-ray tube current: 40 mA X-ray tube voltage: 45 kV Scan range: 2θ = 2.0 to 40.0° Step: 2θ = 0.0066° Averaging time / step: 8.670 s Scan speed: 0.0008° / s Divergence slit: 1 / 2° Scattering slit: 2.0 mm Receiving slit: None

[0108] The operation of the equipment, including data processing, followed the methods and procedures specified for each device. The values ​​obtained from various spectra may vary slightly depending on the crystal growth direction, particle size, measurement conditions, etc. Therefore, these values ​​should not be interpreted strictly.

[0109] Simultaneous differential thermal analysis and thermogravimetry (TG-DTA measurement) was performed on 1 to 5 mg of test substance under the following test conditions: Apparatus: TG / DTA7200 manufactured by Hitachi High-Tech Science Corporation Sample container: made of aluminum Heating rate: 25 to 400°C at 10°C / min Ambient gas: air (200 mL / min) Reference substance: empty pan The device was handled, including data processing, in accordance with the methods and procedures specified for each device.

[0110] Example 1: Preparation of Type III Crystals of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1))) (Step 1) Synthesis of tert-butyl (4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate. tert-butyl (4-(4-amino-6-bromo-5-(quinolin-3-yl))-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate was synthesized by the method described in Patent Document 1. N-methylpyrrolidone (1500 mL) was added to 7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (65.9 g) and the mixture was stirred at 90°C for 30 minutes under a nitrogen atmosphere to dissolve. After cooling to 35°C, diisopropylethylamine (46.5 g), triethylsilylacetylene (33.7 g), copper(I) iodide (4.57 g), dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) (8.50 g), and N-methylpyrrolidone (80 mL) were added and the mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere. After cooling to 40°C, a 10% aqueous solution of sodium dihydrogen phosphate and ethyl acetate were added. The organic layer was washed with dilute aqueous ammonia and water, and activated carbon (33.0 g) and SH silica gel (65.9 g) were added, followed by stirring at 40°C for 1 hour and at room temperature for 2 hours. After filtering off insoluble matter through Celite, the solvent was evaporated under reduced pressure, and acetonitrile was added to the resulting residue, followed by stirring at room temperature for 15 hours. The precipitated solid was collected by filtration, washed with acetonitrile, and dried under reduced pressure to obtain the title compound (37.4 g).

[0111] (Step 2) Synthesis of 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. 5-10% hydrochloric acid in methanol (520 mL) was added to the tert-butyl (4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)carbamate (65.0 g) synthesized as described above, and the mixture was stirred at 50°C for 3 hours under a nitrogen atmosphere. 2 mol / L aqueous sodium hydroxide solution was added dropwise under ice cooling to adjust the pH to around 12. The precipitated solid was collected by filtration, washed with 50% methanol, and dried under reduced pressure to obtain the title compound (50.3 g).

[0112] (Step 3) Synthesis of N-(4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide 7-(4-aminobicyclo[2.2.1]heptan-1-yl)-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl) obtained in Step 2 To a mixture of 7H-pyrrolo[2,3-d]pyrimidin-4-amine (48.3 g), 5-methylpyrazine-2-carboxylic acid (13.4 g), 1-hydroxybenzotriazole monohydrate (16.0 g), diisopropylethylamine (24.6 g), and methylene chloride (1450 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.9 g) under a nitrogen atmosphere and stirred for 17 hours. The reaction solution was washed with 10% aqueous sodium dihydrogen phosphate, saturated aqueous sodium carbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the solvent was evaporated under reduced pressure. To the resulting residue, methanol was added and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with methanol, and dried under reduced pressure to obtain the title compound (54.8 g).

[0113] (Step 4) Synthesis of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) To a mixture of N-(4-(4-amino-5-(quinolin-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (80.0 g) obtained in Step 3, methylene chloride (1,000 mL), and methanol (1,000 mL) was added potassium carbonate (7.03 g) under a nitrogen atmosphere and stirred for 18 hours. The insoluble matter was filtered off through Celite, and the solvent was evaporated under reduced pressure. Methanol and water were added to the resulting residue, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration, washed with 50% methanol, and dried under reduced pressure to obtain the title compound (64.5 g) as a pale yellow solid (type III crystals). The structure of the resulting pale yellow solid was analyzed by 1H-NMR (Bruker AVNEO400, 400 MHz SCANS4 DMSO-d6 instrument), confirming that it was N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (compound (1)).

[0114] The powder X-ray diffraction spectrum (Method A) of the Form III crystal obtained in Step 4 was obtained by the above procedure and is shown in Figure 1. Characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks. Characteristic diffraction angles (2θ±0.2°): 6.6°, 8.8°, 11.6°, 12.3°, 13.8°, 17.9°, 18.6°, 21.3°, and 22.3°. Other peaks are as shown in Table 1 below. The differential thermal-thermogravimetric simultaneous measurement curve of the crystals obtained in step 4 was obtained by the above procedure and is shown in Figure 2. An exothermic peak (onset value) was observed at around 228°C in the differential thermal-thermogravimetric simultaneous measurement curve.

[0115] Example 2 Preparation of Form II Crystals of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1))) Form III crystals of free form of Compound (1) were synthesized in the same manner as in Example 1. The same applies to other Examples, Reference Examples, and Comparative Examples described later. Tetrahydrofuran (6 mL) was added to Form III crystals of free form of Compound (1) (300 mg), and the suspension was stirred at 25°C for about 24 hours, and then filtered to recover the solid, which was then dried under reduced pressure at room temperature for about 30.5 hours to obtain 199.3 mg of the title crystals.

[0116] The powder X-ray diffraction spectrum (Method A) of the resulting crystals was obtained by the above procedure and is shown in Figure 3. Characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ±0.2°): 7.8°, 10.6°, 14.0°, 14.8°, 15.6°, 17.2°, 20.1°, 21.6°, 22.2°, 24.7°, 25.8°, and 28.9°. Other peaks are as shown in Table 2 below. The differential thermal-thermogravimetric simultaneous measurement curve of the obtained crystals was obtained by the above procedure and is shown in Figure 4. An exothermic peak (onset value) was observed at around 236°C in the differential thermal-thermogravimetric simultaneous measurement curve.

[0117] Reference Example 1 Preparation of Form VII Crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1))) A water-ethanol mixture (1:1 v / v) (6 mL) was added to Form III crystal of free form of Compound (1) (300 mg), and the suspension was stirred at 50°C for about 2 hours. The solid was then collected by filtration to obtain Form VII of free form. This was dried under reduced pressure at room temperature for about 65 hours to obtain 286.9 mg of the title crystal.

[0118] The powder X-ray diffraction spectrum (Method B) of the obtained crystals was obtained by the above procedure and is shown in Figure 5. Characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks. Characteristic diffraction angles (2θ±0.2°): 7.1°, 7.7°, 13.0°, 17.2°, 18.5°, 21.3°, 22.6°, 23.5°, 24.2°, and 26.1°. The differential thermal-thermogravimetric simultaneous measurement curve of the obtained crystals was obtained by the above procedure and is shown in Figure 6. An exothermic peak (onset value) was observed in the differential thermal-thermogravimetric simultaneous measurement curve at around 225°C.

[0119] Comparative Example 1 Preparation of Type VIII Crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) Free-form Type III crystal of Compound (1) (10.0 g) was dissolved in dimethyl sulfoxide (140 mL) at 45°C, and then cooled to 30 to 35°C. Thereafter, dimethyl sulfoxide (10 mL) and water (37.5 mL) were added, and the mixture was stirred at room temperature for 5.5 hours. The solid was then filtered off and collected, and dried under reduced pressure at 50°C to obtain 9.6 g of the title crystal.

[0120] The powder X-ray diffraction spectrum (Method B) of the obtained crystals was obtained by the above procedure and is shown in Figure 7. Characteristic diffraction angles observed in the powder X-ray diffraction spectrum were as follows: Characteristic diffraction angles (2θ±0.2°): 7.1°, 7.8°, 12.8°, 13.6°, 14.2°, 14.8°, 17.0°, 18.3°, 21.2°, 22.5°, 24.0°, and 25.9°. The differential thermal-thermogravimetric simultaneous measurement curve of the obtained crystals was obtained by the above procedure and is shown in Figure 8. An exothermic peak (onset value) was observed in the differential thermal-thermogravimetric simultaneous measurement curve at around 207°C.

[0121] Test Example 1: Solid-state stability test The free-form type II crystals, free-form type III crystals, free-form type VII crystals, and free-form type VIII crystals of compound (1) obtained in the Examples, Reference Examples, and Comparative Examples were stored for 4 weeks and their solid-state stability was evaluated by the following procedure. Storage conditions: 80°C (closed system) (HIFLEX (high-temperature storage device manufactured by ETAC)) Storage period: 4 weeks Storage amount: about 30 mg Storage container: glass bottle The results are shown in Table 3 below.

[0122] The change in the amount of related substances (the amount of substances detected other than compound (1)) was analyzed by HPLC using the following method. For the analytical sample, approximately 8 mg of each sample was weighed and dissolved in 1 mL of a chloroform-methanol mixture (1:1 v / v). 50 μL of this solution was measured and diluted with 950 μL of an acetonitrile-water mixture (7:3). 5 μL of this solution was accurately measured and used. HPLC Measurement Method (Stability Test) The amount of related substances in the sample solution was measured by HPLC analysis. The handling of the equipment, including data processing, followed the methods and procedures specified for each equipment. Column: InertSustainSwift C18 (2.1 x 50 mm, 1.9 µm) manufactured by GL Sciences UV detection: 220 nm Column temperature: 40°C Flow rate: 0.3 mL / min Sample cooler: 10°C Sample concentration: 0.1 mg / mL Mobile phase A: 10 mmol / L phosphate buffer (pH 6.8) / acetonitrile (95:5) mixture Mobile phase B: acetonitrile The gradient is shown in Table 4.

[0123] As a result, it was found that the free form II crystal, free form III crystal and free form VII crystal of Compound (1) showed almost no increase in related substances and were extremely stable crystals.

[0124] Test Example 2 Dynamic moisture adsorption / desorption (DVS) test A moisture adsorption / desorption test was carried out using the free form II crystal, free form III crystal, free form VII crystal, and free form VIII crystal of compound (1) obtained in the Examples, Reference Examples, and Comparative Examples. The moisture adsorption / desorption test was carried out under the following conditions. Approximately 10 mg of sample was filled into a dedicated quartz holder, and the weight of the sample at each humidity was continuously measured and recorded under the following conditions. The operation of the device, including data processing, was carried out in accordance with the method and procedure specified for each device. Apparatus: VTI SA+ (manufactured by TA Instruments) Drying temperature: 60°C Heating rate: 1°C / min Drying equilibrium: Confirm that there is no decrease of 0.01 wt% in 5 minutes, within a range not exceeding 300 minutes Measurement temperature: 25°C Humidification equilibrium: Confirm that there is no increase of 0.01 wt% in 5 minutes, within a range not exceeding 120 minutes Relative humidity program: Increase in 5% RH increments from 5 to 95% RH, and decrease in 5% RH increments from 95% RH to 5% RH The weight changes within the measurement condition ranges obtained in these tests are shown in Figures 9 to 12.

[0125] As shown in the figure, the free-form type II crystal of compound (1) showed a weight increase of 0.16% at 95% relative humidity in a moisture adsorption / desorption test, which is less than 1%, and was therefore determined to be almost non-hygroscopic. The free-form type III crystal of compound (1) exhibited rapid hygroscopicity when the RH exceeded 65%, but moisture desorption occurred when the humidity was reduced, indicating that this adsorption was reversible. On the other hand, as shown in the figure, the free-form type VII crystal and the free-form type VIII crystal showed a mass increase of 1% or more at 95% relative humidity in a moisture adsorption / desorption test, demonstrating their high moisture absorption. Furthermore, these crystals did not desorb moisture even when the humidity was reduced, indicating that the reaction was irreversible.

[0126] From the above results, it can be said that the free form II crystal of compound (1) has lower hygroscopicity than the free form III crystal, free form VII crystal, and free form VIII crystal of compound (1), and is superior as a candidate compound for pharmaceutical development from the viewpoint of industrial production of pharmaceuticals with stable quality. Since the free form III crystal has low hygroscopicity when the RH is less than 65%, it was considered to be useful as a candidate compound for pharmaceuticals, similar to the free form II crystal, in a humidity-controlled environment. It was confirmed that the free form II crystal and the free form III crystal of compound (1) have excellent properties as pharmaceuticals or pharmaceutical ingredients.

[0127] Example 3 Preparation of Type III Crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) with Succinic Acid Succinic acid (6.88 g) and acetonitrile (90 mL) were added to Type III crystal (10 g) of free form of Compound (1), and the suspension was stirred at 50°C for about 1 hour, and then filtered to recover the solid. This was suspended and washed twice in ethanol, and dried under reduced pressure at 40°C for about 19.5 hours to obtain 11.71 g of the title crystal.

[0128] The powder X-ray diffraction spectrum (Method A) of the resulting crystals was obtained by the above procedure and is shown in Figure 13. Characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ±0.2°): 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5°. Other peaks are as shown in Table 5 below. The differential thermal-thermogravimetric simultaneous measurement curve of the obtained crystals was obtained by the above procedure and is shown in Figure 14. An endothermic peak (onset value) was observed at around 202°C in the differential thermal-thermogravimetric simultaneous measurement curve.

[0129] Example 4 Preparation of Type I Crystals of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) with Sorbic Acid Sorbic acid (109 mg) and acetonitrile (5 mL) were added to Type III crystals (500 mg) of the free form of Compound (1), and the suspension was stirred at 50°C for about 7.5 hours. The solid was then collected by filtration and dried under reduced pressure at 40°C for about 13.5 hours to obtain 568.4 mg of the title crystals.

[0130] The powder X-ray diffraction spectrum (Method A) of the resulting crystals was obtained by the above procedure and is shown in Figure 15. Characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ±0.2°): 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4°. Other peaks are as shown in Table 6 below. The differential thermal-thermogravimetric simultaneous measurement curve of the obtained crystals was obtained by the above procedure and is shown in Figure 16. An endothermic peak (onset value) was observed at around 173°C in the differential thermal-thermogravimetric simultaneous measurement curve.

[0131] Comparative Example 2 Preparation of Type I Crystals of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) with Citric Acid Citric acid (560 mg) and 10 mL of ethanol were added to Type III crystals (500 mg) of the free form of Compound (1), and the suspension was stirred at 25°C for about 5.5 hours, and then filtered to recover the solid, which was then dried under reduced pressure at 40°C for about 13.5 hours to obtain 664.3 mg of the title crystals.

[0132] The powder X-ray diffraction spectrum (Method A) of the obtained crystals was obtained by the above procedure and is shown in Figure 17. Characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks. Characteristic diffraction angles (2θ±0.2°): 5.6°, 8.7°, 9.6°, 11.2°, 13.0°, 13.9°, 15.2°, 16.8°, 20.9°, and 24.2°. The differential thermal-thermogravimetric simultaneous measurement curve of the obtained crystals was obtained by the above procedure and is shown in Figure 18. An endothermic peak (onset value) was observed in the differential thermal-thermogravimetric simultaneous measurement curve at around 191°C.

[0133] Comparative Example 3 Preparation of Type IV Crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) with Citric Acid Citric acid (37.3 mg) and tetrahydrofuran (3 mL) were added to Type III crystal (100 mg) of free form of Compound (1), and the suspension was stirred at 50°C for about 47.5 hours, and then filtered to recover the solid, which was then dried under reduced pressure at 40°C for about 18.5 hours to obtain 85.6 mg of the title crystal.

[0134] The powder X-ray diffraction spectrum (Method B) of the obtained crystals was obtained by the above procedure and is shown in Figure 19. Characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks. Characteristic diffraction angles (2θ±0.2°): 5.4°, 11.0°, and 19.1°. The differential thermal-thermogravimetric simultaneous measurement curve of the obtained crystals was obtained by the above procedure and is shown in Figure 20. An endothermic peak (onset value) was observed in the differential thermal-thermogravimetric simultaneous measurement curve at around 149°C.

[0135] Comparative Example 4 Preparation of Type I Crystals of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1)) with Phosphoric Acid) Phosphoric acid (39.7 μL) and tetrahydrofuran (6 mL) were added to Type III crystals (300 mg) of the free form of Compound (1), and the suspension was stirred at 50° C. for about 3 hours. The solid was then collected by filtration and dried under reduced pressure at room temperature for about 40 minutes to obtain 111.6 mg of the title crystals.

[0136] The powder X-ray diffraction spectrum (Method B) of the obtained crystals was obtained by the above procedure and is shown in Figure 21. Characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks. Characteristic diffraction angles (2θ±0.2°): 5.3°, 8.6°, 10.6°, 11.1°, 12.5°, 13.5°, 17.3°, 19.7°, 22.3°, and 23.1°. The differential thermal-thermogravimetric simultaneous measurement curve of the obtained crystals was obtained by the above procedure and is shown in Figure 22. An exothermic peak (onset value) was observed in the differential thermal-thermogravimetric simultaneous measurement curve at around 205°C.

[0137] Test Example 3: Solid State Stability Test The solid state stability of the Type III crystals with succinic acid, Type I crystals with citric acid, Type IV crystals with citric acid, Type I crystals with sorbic acid, and Type I crystals with phosphoric acid obtained in the Examples, Reference Examples, and Comparative Examples was evaluated after storage for 4 weeks. The evaluation method, storage, and measurement conditions were the same as in Test Example 1. The results are shown in Table 7 below.

[0138] As a result, it was found that the type III crystal of compound (1) with succinic acid and the type I crystal of compound (1) with sorbic acid showed almost no increase in related substances and were extremely stable crystals. On the other hand, the type I crystal of compound (1) with citric acid, the type IV crystal of compound (1) with citric acid, and the type I crystal of compound (1) with phosphoric acid showed a decrease in purity and were found to be unstable crystals.

[0139] Test Example 4 Dynamic Moisture Sorption / Desorption (DVS) Test A moisture sorption / desorption test was carried out using type III crystals with succinic acid, type I crystals with citric acid, type IV crystals with citric acid, type I crystals with sorbic acid, and type I crystals with phosphoric acid of Compound (1) obtained in the Examples, Reference Examples, and Comparative Examples. The moisture sorption / desorption test was carried out under the same conditions as in Test Example 2. The weight changes obtained in this test within the range of measurement conditions are shown in Figures 23 to 27.

[0140] As shown in the figure, the Type III crystal of compound (1) with succinic acid and the Type I crystal of compound (1) with sorbic acid showed weight increases of 0.28% and 0.26%, respectively, at 95% relative humidity in a moisture adsorption / desorption test, which is less than 1%, and therefore they were determined to have almost no hygroscopicity. On the other hand, the Type I crystal of compound (1) with citric acid, the Type IV crystal of compound (1) with citric acid, and the Type I crystal of compound (1) with phosphoric acid showed mass increases of 1% or more at 95% relative humidity in a moisture adsorption / desorption test, as shown in the figure, demonstrating that they have high hygroscopicity.

[0141] From the above results, it can be said that the Type III crystals of compound (1) with succinic acid and the Type I crystals of compound (1) with sorbic acid have lower hygroscopicity than the Type I crystals of compound (1) with citric acid, the Type IV crystals of compound (1) with citric acid, and the Type I crystals of compound (1) with phosphoric acid, and are superior as candidate compounds for pharmaceutical development from the viewpoint of industrial production of pharmaceuticals with stable quality. It was confirmed that the Type III crystals of compound (1) with succinic acid and the Type I crystals of compound (1) with sorbic acid have excellent properties as pharmaceuticals or pharmaceutical active ingredients.

[0142] Test Example 5 Plasma Concentration Measurement Test For the free form (type II crystal) of compound (1) obtained in the Examples, type III crystal of compound (1) with 1 equivalent of succinic acid, and type I crystal of compound (1) with 1 equivalent of sorbic acid, a plasma concentration measurement test was carried out after oral administration to male beagle dogs set under low gastric conditions.

[0143] (Selection of Beagles) To select three male beagles for use in the study, plasma concentrations were measured in five male beagles maintained under low gastric conditions after solution administration and capsule administration. Three dogs with large differences in AUClast (area under the plasma concentration-time curve from 0 hours after administration to the time point at which the final concentration could be calculated, calculated using the linear trapezoidal method before Tmax and the logarithmic trapezoidal method after Tmax) and Cmax (maximum plasma concentration) after solution administration and capsule administration were selected, and plasma concentrations were measured after oral administration of the free form (type II crystal) of compound (1), the type III crystal of compound (1) with one equivalent of succinic acid, and the type I crystal of compound (1) with one equivalent of sorbic acid, all packed into capsules. Preparation of the administration solution, capsule filling, and animal experiments were performed according to the following procedures.

[0144] (Preparation of Dosage Solution, Capsule Filling, and Animal Experiment Method) The free form of Compound (1) was dissolved in 20% HP-β-CD solution containing 0.1 N hydrochloric acid to prepare a 20 mg / 5 mL solution. The free form of Compound (1) (type II crystal), type III crystal with 1 equivalent of succinic acid, and type I crystal with 1 equivalent of sorbic acid were each filled into gelatin capsules so that the molecular weight equivalent of Compound (1) (free form) was 20 mg / kg. The male beagle dogs used in the test were fasted from 11:00 AM to 12:00 PM on the day before administration of Compound (1), and were fed after blood sampling 8 hours after compound administration. Water was withheld from 30 minutes before compound administration until 2 hours after administration, with free access at other times. Thirty minutes before compound administration, atropine (atropine sulfate injection 0.5 mg "Fuso") was administered intravenously at 0.02 mg / kg, followed by intramuscular administration of pentagastrin at 0.01 mg / kg. Thirty minutes after atropine administration, a capsule filled with the compound was administered orally by force, and the animal was allowed to self-swallow the capsule with 5 mL of distilled water. 50 mL of distilled water was then administered orally by force using a catheter. Alternatively, a solution containing the compound was orally administered at a dose of 20 mg / 5 mL / kg using a catheter, and the catheter was immediately washed with 10 mL of distilled water. After blood samples were taken 15 minutes and 1 hour after compound administration, pentagastrin was again administered intramuscularly at 0.01 mg / kg. Before and after administration (0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours later), the blood collector grasped the dog's forelimbs and engorged the blood vessels with a clothespin or similar tool. The blood collection site was then disinfected with alcohol swabs, and approximately 0.2 mL of blood was collected using a heparinized syringe and needle. After blood collection, the puncture site was held down with absorbent cotton to ensure adequate hemostasis. The collected blood was cooled on ice, and plasma was separated by centrifugation as quickly as possible. The separated plasma was promptly frozen on dry ice and then frozen and stored in a freezer set at -80°C. Using LC / MS / MS, the concentration of compound (1) in each plasma sample was measured by MRM and quantified from the calibration curve. From this, AUClast, Cmax, and Tmax (time to reach maximum blood concentration) were calculated using Phoenix WinNonlin (v7.0.0, Certara USA, Inc.).

[0145] The results are shown in Table 8. It was assumed that the free-form type II crystals of compound (1), the type III crystals with succinic acid, and the type I crystals with sorbic acid are crystalline forms that exert pharmacological effects in vivo. From the above, it was confirmed that all crystalline forms are orally administrable.

[0146] All documents and publications mentioned herein are incorporated by reference in their entirety, regardless of their purpose. This specification also encompasses the disclosures of the claims, specification, and drawings of Japanese Patent Application No. 2022-071154 (filed April 22, 2022), the priority application of which this application claims priority. While several embodiments of the present invention have been described, these embodiments are presented as examples and are not intended to limit the scope of the invention. These novel embodiments may be embodied in various other forms, and various omissions, substitutions, and modifications may be made without departing from the spirit of the invention. These embodiments and their variations are within the scope and spirit of the invention, as well as within the scope of the inventions and their equivalents.

Claims

1. A type II crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide, which has peaks in its powder X-ray diffraction spectrum at diffraction angles (2θ±0.2°) selected from the group consisting of: (i) one or more peaks selected from the group consisting of 15.6°, 20.1°, 24.7°, and 28.9°, and (ii) two or more peaks selected from the group consisting of 7.8°, 10.6°, 14.0°, 14.8°, 17.2°, 21.6°, 22.2°, and 25.8°.

2. The crystal according to claim 1, which has, in its powder X-ray diffraction spectrum, peaks at diffraction angles (2θ±0.2°) at a total of five or more peaks selected from group (i) and group (ii).

3. The crystal according to claim 1 or 2, which has, in its powder X-ray diffraction spectrum, peaks at diffraction angles (2θ±0.2°) at a total of seven or more peaks selected from group (i) and group (ii).

4. The crystal according to any one of claims 1 to 3, which has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 3.

5. The crystal according to any one of claims 1 to 4, which has an exothermic peak at about 236°C as determined by simultaneous differential thermal and thermogravimetric measurements.

6. The crystal according to any one of claims 1 to 5, having a crystal purity of 95% by weight or more.

7. The crystal according to any one of claims 1 to 6, having a chemical purity of 95% or more.

8. A method for producing Type II crystals of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide according to any one of claims 1 to 7, characterized by stirring N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide in a single solvent selected from lower alcohols having 3 or more carbon atoms, tetrahydrofuran, acetone, and ethyl acetate, or in a mixed solvent containing two or more of these solvents.

9. A type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with succinic acid, which has peaks in a powder X-ray diffraction spectrum at three or more diffraction angles (2θ±0.2°) selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5°.

10. The crystal according to claim 9, which has peaks at five or more diffraction angles (2θ±0.2°) selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5° in a powder X-ray diffraction spectrum.

11. The crystal described in claim 10 or 11, which has peaks at seven or more diffraction angles (2θ±0.2°) selected from the group consisting of 10.4°, 13.3°, 14.6°, 15.7°, 17.2°, 18.3°, 19.7°, 20.8°, 22.3°, and 27.5° in a powder X-ray diffraction spectrum.

12. The crystal according to any one of claims 9 to 11, which has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 13.

13. The crystal according to any one of claims 9 to 12, which exhibits an endothermic peak at around 202°C as determined by simultaneous differential thermal and thermogravimetric measurements.

14. The crystal according to any one of claims 9 to 13, having a crystal purity of 95% by weight or more.

15. The crystal according to any one of claims 9 to 14, having a chemical purity of 95% or more.

16. N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and succinic acid in an equivalent ratio of 1:1 to 10, in a solvent containing acetonitrile, a lower alcohol having two or more carbon atoms, methyl ethyl ketone, tetrahydrofuran, and 2-methyltetrahydrofuran. The method for producing a type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and succinic acid according to any one of claims 9 to 15, characterized in that the mixture is stirred in a single solvent selected from the group consisting of quinolin-3-yl, ...

17. A type I crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide with sorbic acid, having peaks at three or more diffraction angles (2θ±0.2°) selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4° in a powder X-ray diffraction spectrum.

18. The crystal described in claim 17, which has peaks at five or more diffraction angles (2θ±0.2°) selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8°, and 27.4° in a powder X-ray diffraction spectrum.

19. A crystal according to claim 17 or 18, which has peaks at seven or more diffraction angles (2θ±0.2°) selected from the group consisting of 12.6°, 14.7°, 15.4°, 15.9°, 17.1°, 18.9°, 22.2°, 24.1°, 25.8° and 27.4° in a powder X-ray diffraction spectrum.

20. The crystal according to any one of claims 17 to 19, which has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 15.

21. The crystal according to any one of claims 17 to 20, which exhibits an endothermic peak at around 173°C as determined by simultaneous differential thermal and thermogravimetric measurements.

22. The crystal according to any one of claims 17 to 21, having a crystal purity of 95% by weight or more.

23. The crystal according to any one of claims 17 to 22, having a chemical purity of 95% or more.

24. A method for producing Type I crystals of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and sorbic acid according to any one of claims 17 to 23, characterized by stirring N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and sorbic acid in an equivalent ratio of 1:1 to 10 in a single solvent selected from acetonitrile, a lower alcohol, tetrahydrofuran, acetone, methyl ethyl ketone, water, and ethyl acetate, or a mixed solvent containing two or more of these.

25. A type III crystal of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide, having peaks in a powder X-ray diffraction spectrum at diffraction angles (2θ±0.2°) selected from the group consisting of: (i) one or more peaks selected from the group consisting of 8.8°, 11.6°, and 17.9°, and (ii) two or more peaks selected from the group consisting of 6.6°, 12.3°, 13.8°, 18.6°, 21.3°, and 22.3°.

26. The crystal described in claim 25, which has a total of five or more peaks selected from group (i) and group (ii) at diffraction angles (2θ±0.2°) in its powder X-ray diffraction spectrum.

27. A crystal described in claim 25 or 26, which has, in its powder X-ray diffraction spectrum, peaks at diffraction angles (2θ±0.2°) at a total of seven or more peaks selected from group (i) and group (ii).

28. The crystal according to any one of claims 25 to 27, which has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 1.

29. The crystal according to any one of claims 25 to 28, which has an exothermic peak at around 228°C as determined by simultaneous differential thermal and thermogravimetric measurements.

30. The crystal according to any one of claims 25 to 29, having a crystal purity of 95% by weight or more.

31. The crystal according to any one of claims 25 to 30, having a chemical purity of 95% or more.

32. A method for producing Type III crystals of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide according to any one of claims 25 to 31, comprising stirring N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide in a solvent containing methanol.

33. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 7, 9 to 15, 17 to 23 and 25 to 31.