CRYSTAL OF A 1,3,5-TRIAZINE DERIVATIVE OR SOLVATE THEREOF AND METHOD FOR PRODUCING THE SAME

Abstract

The present invention relates to a crystal of a 1,3,5-triazine derivative or a solvate thereof, and to a method for producing it. The present invention relates to a crystal of a compound represented by Formula (I) or a solvate thereof, and to a pharmaceutical composition containing it. The present invention also relates to a crystal of a compound represented by Formula (I), or to a solvate thereof.

Description

CRYSTAL OF 1,3,5-TRIAZINE DERIVATIVE OR SOLVATE THEREOF AND LfrRznn / zznz / E / YiAi METHOD FOR PRODUCING THE SAME Field of Invention The present invention relates to a crystal of a 1,3,5-triazine derivative or a solvate thereof and to a pharmaceutical composition containing it. The present invention relates to a method for producing a crystal of a 1,3,5-triazine derivative or a solvate thereof and to a pharmaceutical composition containing it. Background of the Invention Adenosine triphosphate (ATP) is known as an intracellular energy source and phosphorylated substrate. Furthermore, it is also known to act as an extracellular signaling molecule. ATP is released outside of cells in response to various stimuli, such as cell damage, inflammation, noxious stimuli, and reduced blood oxygen levels. It is also known to be released from primary sensory nerve endings along with other neurotransmitters. The ATP released outside of cells carries out various types of extracellular signaling via an ATP receptor (Non-Patent Document 4, Non-Patent Document 5). ATP receptors are roughly classified into the P2X ion channel family and the P2Y protein-coupled family Ref. 332179 G. The P2X receptor family is reported to have seven subtypes, which form a homotrimer or a heterotrimer with other P2X subtypes to function as a non-selective cation channel (Non-patent document 6). ATP is known to cause pain, and studies using P2X3 knockout and deactivation techniques have shown that the P2X3 receptor is involved in the transmission of chronic pain. The P2X3 receptor is specifically expressed in peripheral sensory nerves, forming a homocomplex or a heterocomplex with P2X2 (P2X2 / 3). (Non-patent document 1) Subsequently, it is suggested that the compound having antagonistic action on the P2X3 or P2X2 / 3 receptor is useful in: pain treatment (Patent Document 1, Non-Patent Document 3 and Non-Patent Document 7); treatment of diseases associated with dysfunctional urination (Non-Patent Document 2); treatment of respiratory diseases (Non-Patent Document 8, Non-Patent Document 9, Non-Patent Document 10, Patent Document 2 and Patent Document 3); treatment of chronic cough (Patent Document 4, Patent Document 5 and Non-Patent Document 11); treatment of hypertension (Non-Patent Document 12); treatment of pain associated with pancreatitis (Non-Patent Document 13); and treatment of pain associated with endometriosis (Non-Patent Document 14 and Non-Patent Document 15). Patent Document 6 then describes that a 1,3,5-triazine derivative represented by the following formula has P2Xs and / or P2X2 / 3 antagonist action, and is useful for the treatment and / or prevention of do 1o r: [Chemical formula 1] Patent Document 7 describes that a derivative of 1,3,5-triazine, represented by the following formula, has antagonistic action against P2X3 and / or P2X2 / 3, and is useful for the treatment and / or prevention of pain: [Chemical formula 2] (Rs)s Z1 (CR43R4b)n(VHh R2 Patent Document 8 describes that a derivative of 1,3,5-triazine, represented by the following formula, has antagonistic action against P2X3 and / or P2X2 / 3, and is useful for the treatment and / or prevention of pain: Lfrfiznn / zznz / B / YiAi [Chemical formula 3] Patent Document 9 describes that a derivative of 1,3,5-triazine represented by the following formula has antagonistic action against P2X3 and / or P2X2 / 3, and is useful for the treatment and / or prevention of pain: [Chemical formula 4] (C(R4a)(R4b))n Yo R2 In the Examples in Patent Document 9, the following compound is described (1-127), but a crystal of the compound is not described. [Chemical formula 5] Lfrfiznn / zznz / B / YiAi Furthermore, Patent Documents 6, 7, 8, and 9 describe a method for producing a 1,3,5-triazine derivative, but they do not describe the process according to the present invention and only describe a method for producing a similar compound. Additionally, Patent Document 10 describes a 1,3,5-triazine derivative that has a therapeutic effect on chronic cough, but it does not describe a crystal or a process according to the present invention. Additionally, Patent Document No. 16 describes an aza-Michael addition reaction of (S)-1-phenylethylamine and methyl methacrylate. REFERENCES TO THE PREVIOUS TECHNIQUE Patent document [Patent Document 1] International Publication WO 02 / 094767 A [Patent Document 2] International Publication WO 2006 / 012639 A [Patent document] 3] International publication WO LfrRznn / zznz / E / YiAi 2010 / 149578 A [Patent document] International publication WO 2015 / 027212 A [Patent document] 5] International publication WO 2017 / 058645 A [Patent document] International publication WO 2010 / 092966A [Patent document] 7] International publication WO 2012 / 020749 A [Patent document] International publication WO 2013 / 089212 A [Patent document] International publication WO 2014 / 200078A [Patent document] 10] International publication WO 2020 / 071530 A [Non-patent document] [Non-patent document] Neuroscientist 2005, vol. 11, pp. 345-356 [Non-patent document] 2] J. Physiol. 567.2 2005 pages 621-639 [Non-patent document] 3] Expert Opinion. Ther. Patens 2006 vol. 16, no. 8, pages 1113-1127 [Non-patent document 4] J. Physiol. 554.2 2003 pages 301-308 [Non-patent document 5] J. Physiol. 553.3 2003 pages 683-694 [Non-patent document 6] Pflungers Arch Eur J physiol 2006, pp. 452, 513-537 [Non-patent document 7] PNAS 2002, vol. 99, no. 26, pages 17179-17184 [Non-patent document 8] Brouns et al., Am J Respir Cell Mol Biol 2000, vol. 23, pages 52-61 [Non-patent document 9] Basoglu et al. Chest. 2005, vol. 128, No. 4, pages 1905-9 [Non-patent document 10] Adriaensen et al., THE ANATOMICAL RECORD PARC A 2003, Vol. 270A, pages 25-40 [Non-patent document 11] Lancet, 2015, vol. 385, pages 1198-205 [Non-patent document 12] Nat Med 2016, vol. 22, pages 1151-1159 [Non-patent document 13] Am J Physiol Gastrointest Liver Physiol 2015, vol. 308, pages 710-719 [Non-patent document 14] PLoS ONE 2017, vol. 12, no. 9 [Non-patent document 15] International Journal of Nanomedicine 2017, Volume 12, 8171-8183 [Non-patent document 16] Tetrahedron Asymmetry, vol. LfrRznn / zznz / E / YiAi 7, no. 3, pages 699-708 1996 Brief Description of the Invention PROBLEMS TO BE SOLVED BY THE INVENTION Pharmaceutically active ingredients can have substantially different physical properties depending on their respective solid form. Such differences in physical properties can affect, for example, the method of preparing or administering a pharmaceutically active ingredient, or a pharmaceutical composition comprising the pharmaceutically active ingredient. The present invention relates to a crystal of a 1,3,5-triazine derivative or a solvate thereof, which is very useful compared to other solid forms in a method for producing or administering a pharmaceutically active ingredient, or in a pharmaceutical composition comprising a pharmaceutically active ingredient. In general, the physical properties of a crystal of a compound useful as a pharmaceutical product have a significant influence on drug bioavailability, drug purity, formulation, and similar aspects, and are therefore extremely important in pharmaceutical development. Therefore, with regard to the compound represented by formula (I), it is necessary to study which crystalline form is most suitable as a pharmaceutical product. That is, since its physical properties depend on the attributes of the individual compounds, LfrRznn / zznz / E / YiAi It is generally difficult to predict a crystalline form of a pharmacological substance that has good physical properties, and it is necessary to examine each compound in a diverse way. Therefore, an objective of the present invention is to provide a crystalline form having good physical properties as a pharmacological substance for the compound represented by formula (I). Furthermore, Patent Document 9 does not describe a method for producing compound 1-127, but as a similar compound, Reference Example 3 of Patent Document 9 describes a method for producing a 1,3,5-triazine derivative as shown in the following formula. However, the process is still insufficient and can be further improved. [Chemical Formula 6] Lfrfiznn / zznz / B / YiAi [MEANS TO SOLVE THE PROBLEM] As a result of intensive studies, the inventors of the present invention have discovered that, as crystalline forms of the compound represented by Formula (I), there exist an anhydrous Form I, an anhydrous Form II, and a dihydrate. Furthermore, they have found that the anhydrous Form I and the dihydrate crystal are more stable than other crystal forms. In addition, they have found that the Form I of the anhydrous crystal has a low crystal compressibility index (%) and has favorable crystal fluidity compared to other crystal forms. Furthermore, the present inventors have found an intermediate having high chemical and / or optical purity, a method for producing the intermediate, and a method for producing an optically active 1,3,5-triazine derivative having P2Xs and / or P2X2 / 3 antagonistic action. The present invention relates to the following elements (1'), (2'), (2Ά), (2'B), (3'), (3Ά), (3'B), (4') to (35'), (3), (5) and (36) to (42). (1') A crystal of a compound represented by Formula (I): [Chemical Formula 7] or a solvate of the same. (2') An anhydrous crystal Form I of the compound according to point (I') above, having, in a powder X-ray diffraction spectrum, characteristic peaks at: diffraction angles (2Θ) of 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2° and 19.4°±0.2°; or diffraction angles (2Θ) of 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2° and 19.4°±0.2°. (2' A) An anhydrous crystal form I of the compound according to point (1') above, having characteristic peaks at diffraction angles (2Θ) of 15.8°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2° and 25.4°±0.2° in a powder X-ray diffraction spectrum. (2'B) An anhydrous crystal form I of the compound according to point (1') above, having characteristic peaks at diffraction angles (2Θ) of 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2° and 19.4°±0.2° in a powder X-ray diffraction spectrum. (3') An anhydrous crystal form I of the compound according to point (1') above, having, in a powder X-ray diffraction spectrum, characteristic peaks at: diffraction angles (2Θ) of 12.6°±0.2°, 12.9°±0.2°, 15.8°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2°, 25.4°±0.2°, 26.6°±0.2°, 27.8°±0.2° and 32.8°±0.2°; or diffraction angles (2Θ) of 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2°, 17.2°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°+0.2°, 25.4°±0.2° and 27.8°±0.2°. (3' A) An anhydrous crystal form I of the compound according to the previous point (1'), having characteristic peaks at diffraction angles (2Θ) of 12.6°±0.2°, LfrRznn / zznz / E / viaA 12.9°±0.2°, 15.8°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2°, 25.4°±0.2°, 26.6°±0.2°, 27.8°±0.2° and 32.8°±0.2° in a powder X-ray diffraction spectrum. (3'B) An anhydrous crystal form I of the compound according to point (1') above, having characteristic peaks at diffraction angles (2Θ) of 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2, 15.8°±0.2°, 17.2°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2°, 25.4°±0.2° and 27.8°±0.2° in a powder X-ray diffraction spectrum. (3) An anhydrous crystal form I of the compound according to point (1') above, having absorption peaks at 829 0^12 cm-1, 989 cm-1±2 cm-1, 1013 cm-1±2 cm-1, 1128 cm-1!! cir1y 1370 cm-1±2 cirn1 in Raman spectrum. (4') A dihydrated crystal of the compound according to the previous point (1'5), having characteristic peaks at diffraction angles (2Θ) of 5.7°±0.2°, 7.7°±0.2°, 11.8°±0.2°, 15.2° ±0.2° and 17.7°±0.2° in a powder X-ray diffraction spectrum. (5') A dihydrated crystal of the compound according to the previous point (1'), having characteristic peaks at diffraction angles (2Θ) of 5.7°±0.2°, 7.7°±0.2°, 11.8°±0.2°, 15.2° +0.2°, 17.7°+0.2°, 20.6°+0.2°, 20.8°±0.2°, 26.5°±0.2°, 27.1°±0.2° and 29.1°±0.2° in a powder X-ray diffraction spectrum. (5) A dihydrate crystal of the compound according to LfrRznn / zznz / E / viA the previous point (1'), which has absorption peaks at 871 cm!±2 cm-1, 996 cm-1±2 cm-1, 1114 cm-1±2 cm-1, 1234 cm-1±2cm-1, 1340 cm-1±2 cm-1 and 157 7 cm-1±2 cm-1 in Raman spectrum. (6') A pharmaceutical composition containing the crystal according to any of the above points (1'), (2'), (2Ά), (2'B), (3'), (3Ά), (3'B), (4'), (5'), (3) and (5). (7') A method for producing the crystal according to any of the above points (1'), (2'), (2Ά), (2'B), (3') ), (3Ά) , (3'B) , (4') , (5') , (3) and (5) . (8') The pharmaceutical composition in accordance with point (6') above, the pharmaceutical composition being a P2Xs and / or P2X2 / 3 antagonist. (9') The pharmaceutical composition in accordance with point (6') above, the pharmaceutical composition being used to treat and / or prevent chronic cough. (10') The pharmaceutical composition in accordance with point (6') above, the pharmaceutical composition being used to treat and / or prevent refractory chronic cough. (11') An antagonist of P2Xs and / or P2X2 / 3, characterized by containing a crystal according to any of the above points (1'), (2'), (2Ά), (2'B), (3'), (3Ά), (3'B), (4' ) , (5' ) , (3) and (5) . (12') A therapeutic and / or preventive agent for chronic cough, characterized by containing the crystal in accordance with any of the above points (1'), (2'), (2Ά) , (2'B), LfrRznn / zznz / E / YiAi (3' ) , (3Ά) , (3'Β) , (4' ) , (5' ) , (3) and (5) . (13') A therapeutic and / or preventive agent for refractory chronic cough, characterized by containing the crystal in accordance with any of the above points (1' ), (2'), (2Ά), (2'B) , (3'), (3Ά), (3'B), (4' ), (5'), (3) and (5). (14') A method for the treatment and / or prevention of chronic cough, characterized by administering a pharmaceutical composition containing the crystal in accordance with any of the above points (1'), (2'), (2Ά) , (2'B), (3' ) , (3Ά), (3'B), (4' ) , (5' ) , (3) and (5) . (15') A method for the treatment and / or prevention of refractory chronic cough, characterized by administering a pharmaceutical composition containing the crystal in accordance with any of the above points (1'), (2'), (2Ά), (2'B), (3'), (3Ά), (3'B), (4'), (5'), (3) and (5). (16') Use of the crystal in accordance with any of the above points (1'), (2'), (2'B), (3'), (3' A), (3'B), (4'), (5'), (3) and (5) to produce a medicine for the treatment and / or prevention of chronic cough. (17') Use of the crystal in accordance with any of the above points (1'), (2'), (2Ά), (2'B), (3'), (3Ά), (3'B), (4'), (5'), (3) and (5) to produce a drug for the treatment and / or prevention of refractory chronic cough. (18') The crystal in accordance with any of the above points (1' ) , (2'), (2Ά), (2'B), (3'), (3Ά), (3' B) , (4'), LfrRznn / zznz / E / viA (5'), (3) and (5) for the treatment and / or prevention of chronic cough. (19') The crystal in accordance with any of the above points (1'), (2'), (2Ά), (2'B), (3' ) , (3Ά) , (3' B) , (4 ) , (5'), (3) and (5) for the treatment and / or prevention of refractory chronic cough. (20') The crystal according to the previous point (1'), characterized by a powder X-ray diffraction spectrum substantially identical to that shown in Figure 1. (21' ) The crystal according to the previous point (2'), characterized by a powder X-ray diffraction spectrum substantially identical to that shown in Figure 1. (22') The crystal according to the previous point (2Ά) , characterized by a powder X-ray diffraction spectrum substantially identical to that shown in Figure 1. (23') The crystal according to the previous point (2'B), characterized by a powder X-ray diffraction spectrum substantially identical to that shown in Figure 1. (24') The crystal according to the previous point (3'), characterized by a powder X-ray diffraction spectrum substantially identical to that shown in Figure 1. (25') The crystal according to the previous point (3Ά), characterized by a powder X-ray diffraction spectrum substantially identical to that shown in Figure 1. (26') The crystal according to the previous point (3'B), characterized by a powder X-ray diffraction spectrum substantially identical to that shown in Figure 1. (27') The crystal according to the previous point (4'), characterized by a powder X-ray diffraction spectrum substantially identical to that shown in Figure 4. (28' ) The crystal according to the previous point (5'), characterized by a powder X-ray diffraction spectrum substantially identical to that shown in Figure 4. (29') The crystal according to the previous point (1'), characterized by a Raman spectrum substantially identical to that shown in Figure 2. (30') An anhydrous crystalline Form I of the compound according to point (1') above, characterized by one or more physicochemical properties selected from the group consisting of the following (i) and (ii): i) that has, in a powder X-ray diffraction spectrum, characteristic peaks at: diffraction angles (2Θ) of 15.8°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2° and 25.4°±0.2°, or diffraction angles (2Θ) of 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2° and 19.4°±0.2°; and (ii) that it has absorption peaks at 829 cm-1+2 cnr1, 989 cm-1±2 cnr1, 1013 cm-1±2 cnr1, 1128 cm-1±2 cm-1 and 1370 cm-1±2 cm-1 in the Raman spectrum. (31') An anhydrous crystalline Form I of the compound of Lfrfiznn / zznz / B / YiAi in accordance with point (1') above, characterized by one or more physicochemical properties selected from the group consisting of the following (i) and (ii): (i) that it has characteristic peaks at diffraction angles (2Θ) of 15.8°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2° and 25.4°±0.2° in a powder X-ray diffraction spectrum; and (ii) that it has absorption peaks at 829 cm-1±2 cm-1, 989 cm-1 cm-1, 1013 cm-1 cm-1, 1128 cm-1 and 1370 cm-1 cm-1 in a Raman spectrum. (32') An anhydrous crystalline Form I of the compound according to point (1') above, characterized by one or more physicochemical properties selected from the group consisting of the following (i) and (ii): (i) that it has characteristic peaks at diffraction angles (2Θ) of 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2° and 19.4°±0.2° in a powder X-ray diffraction spectrum; and (ii) that it has absorption peaks at 829 cm-1±2 cm-1, 989 cm-1±2 cm-1, 1013 cm-1, 1128 cm-1 and 1370 cm-1 in a Raman spectrum. (33') An anhydrous crystalline Form I of the compound according to point (1') above, characterized by one or more physicochemical properties selected from the group consisting of the following (i) and (ii): LfrRznn / zznz / E / YiAi (i) having, in a powder X-ray diffraction spectrum, characteristic peaks at: diffraction angles (2Θ) of 12.6°±0.2°, 12.9°±0.2°, 15.8°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2°, 25.4°±0.2°, 26.6°±0.2°, 27.8°±0.2° and 32.8°±0.2°, or diffraction angles (2Θ) of 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2°, 17.2°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2°, 25.4°±0.2° and 27.8°±0.2°; and (ii) that it has absorption peaks at 829 cm-1±2 cm-1, 989 cm-1±2 cm-1, 1013 cm-1, 1128 cm-1 and 1370 cm-1 in the Raman spectrum. (34') An anhydrous crystalline Form I of the compound according to point (1') above, characterized by one or more selected physicochemical properties of the group consisting of the following (i) and (ii): (i) that it has characteristic peaks at diffraction angles (2Θ) of 12.6°±0.2°, 12.9°±0.2°, 15.8°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2°, 25.4°±0.2°, 26.6°±0.2°, 27.8°±0.2° and 32.8°±0.2° in a powder X-ray diffraction spectrum; and (ii) that it has absorption peaks at 829 cm⁻¹±2 cm⁻¹, 989 cm⁻¹±2 cm⁻¹, 1013 cm⁻¹·cnu⁻¹, 1128 cm⁻¹±2 cm⁻¹ and 1370 cm⁻¹·cnu⁻¹ cm-1 in Raman spectrum. (35' ) An anhydrous crystalline Form I of the compound according to point (1') above, characterized by one or more physicochemical properties selected from the group that Lfrfiznn / zznz / B / YiAi consists of the following (i) and (ii): (i) with characteristic peaks at diffraction angles (2Θ) of 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2°, 17.2°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2°, 25.4°±0.2° and 27.8°±0.2° in a powder X-ray diffraction spectrum; and (ii) which has absorption peaks at 829 cm-1±2 cm1, 989 cmr±2 cm1, 1013 cm2±2 cm1, 112 8 cmΣ±2 cm1 and 137 0 cm1±2 cm1 in Raman spectrum. (36) An anhydrous crystal Form I of the compound according to point (1') above, characterized by one or more spectra and / or curves selected from the group consisting of the following (a) and (b): (a) a powder X-ray diffraction spectrum substantially identical to that shown in Figure 1; and (b) a Raman spectrum substantially identical to that shown in Figure 2. (37) The crystal according to the previous point (1') , characterized by a Raman spectrum substantially identical to that shown in Figure 6. (38) A dihydrated crystal of the compound according to point (1') above, characterized by one or more physicochemical properties selected from the group consisting of the following (i) and (ii): i) that has characteristic peaks at diffraction angles (2Θ) of 5.7°±0.2°, 7.7°±0.2°, 11.8°±0.2°, LfrRznn / zznz / E / YiAi (ii) with absorption peaks at 871 cm-1±2 cnr1, 996 cm-1±2 crtr1, 1114 cm-1±2 cm-1, 1234 cm-1±2 cmr1, 1340 cm-1±2 cm-1 and 1577 cm-1±2 cm-1 in Raman spectrum. (39) A dihydrate crystal of the compound according to point (1') above, characterized by one or more physicochemical properties selected from the group consisting of the following (i) and (ii): i) that has characteristic peaks at diffraction angles (2Θ) of 5.7°±0.2°, 7.7°±0.2°, 11.8°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 26.5°±0.2°, 27.1°±0.2° and 29.1°±0.2° in a powder X-ray diffraction spectrum; and (ii) with absorption peaks at 871 cm-1±2 cm-1, 996 cm-1±2 cnr1, 1114 cm-1±2 cnr1, 12 34 cm-1±2 cnr1, 134 0 cm-1±2 cnr1 and 157 7 cm-1±2 cnr1 in Raman spectrum. (40) A dihydrate crystal of the compound according to point (1') above, characterized by one or more spectra and / or curves selected from the group consisting of the following (a) and (b): (a) a powder X-ray diffraction spectrum substantially identical to that shown in Figure 4; and (b) a Raman spectrum substantially identical to that shown in Figure 6. Lfrfiznn / zznz / B / YiAi (41) An anhydrous crystal form I of the compound of the previous point (I'), which when measured at 298.15 K is substantially in agreement with the following crystallographic data: Space group: P1 a = 9.8720 (5)Á b = 10.9952 (5)A c = 12.2781 (6)Á a = 67.712 (4)° β = 80.870 (4)° Y = 80.870 (4)° (42) An anhydrous crystal form I of the compound of the previous point (1'), which when measured at 298.15 K is characterized by the following crystallographic data: Space group: P1 a=9.9Á±0.5Á b = 11.0 A ± 0.5Á c = 12.3 Á ± 0.5Á a = 67.7° ± 0.5° β = 80.9° ± 0.5° Y = 86.9° ± 0.5° The present invention also relates to the following points (1) to (34) . (1) A crystal of a compound represented by the Formula LfrRznn / zznz / E / YiAi [Chemical formula 8]. or a solvate of the same. (2) A crystal of the compound according to point (1) above, having characteristic peaks at diffraction angles (2Θ) of 15.8°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2°, 25.4°±0.2° or 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2° and 19.4°±0.2° in a powder X-ray diffraction spectrum. (3) A crystal of the compound according to point (1) above, having, in a powder X-ray diffraction spectrum, characteristic peaks at: diffraction angles (2Θ) of 12.6°±0.2°, 12.9°±0.2°, 15.8°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2°, 25.4°±0.2°, 26.6°±0.2°, 27.8°±0.2° and 32.8°±0.2°; or differential angles (2Θ) of 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2°, 17.2°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2°, 25.4°±0.2° and 27.8°±0.2°. (4) A pharmaceutical composition containing the crystal in accordance with any of points (1) to (3) above. (5) A process for producing the crystal in accordance with any of the above points (1) to (3). (6) A process for producing a compound represented by Formula (IV): where R1 is a C1-C4 alkyl, or one of its salts, characterized by causing a reaction between a compound represented by formula (II): [Chemical formula 10] H Chh w ( || ) or one of its salts, and a compound represented by Formula (III) : [Chemical formula 11] EITHER ) wherein R1 is C1-C4 alkyl, or one of its salts, in the presence of one or more additives selected from the group consisting of lithium chloride, calcium chloride, magnesium chloride, lithium bromide, p-toluenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid. (7) The process in accordance with point (6) above, wherein the additive is lithium chloride. (8) A process for producing a ptoluenesulfonic acid salt from a compound represented by Formula (IV-A): [Chemical Formula 12] H CH3O --¾. / A / ti iai íf NXO ( IV-A )MH CHs where R1 is C1-C4 alkyl, characterized by: obtain a compound represented by Formula (IV) or a salt thereof by the process according to point (6) or (7) above, and add p-toluenesulfonic acid. (9) A process for producing a ptoluenesulfonic acid salt from a compound represented by Formula (IV-A): [Chemical Formula 13] LfrRznn / zznz / E / YiAi where R1 is a C1-C4 alkyl, characterized in that the additive is ptoluenesulfonic acid in the process according to point (6). (10) The process in accordance with any of points (6) to (9) above, wherein R1 is methyl. (11) A p-toluenesulfonic acid salt of a compound represented by Formula (IV-B): [Chemical Formula 14] (12) A process for producing 1 / 2 sulfuric acid salt from a compound represented by Formula (V): [Chemical Formula 15]. H2N* X or -(V) H CH3characterized because: a p-toluenesulfonic acid salt of a compound represented by Formula (IV-B): [Chemical Formula 16] is subjected to a hydrogenolysis reaction; and sulfuric acid is added. (13) 1 / 2 sulfuric acid salt of a compound represented by Formula (V): [Chemical Formula 17]. H CH3(14) A process for producing a represented compound by Formula (I): [Chemical Formula 18] 10 ííj ηνL 15 or one of its salts, characterized in that: a compound [Chemical Formula 19] hL J 2° 0 HN O represented by Formula (VI): 0 k * ( VI ) Ό is subjected where R1 is a C1-C4 alkyl, or one of its salts, to a hydrolysis reaction in the presence of one or more solvents selected from the group consisting of isopropyl alcohol, tetrahydrofuran, and t-butanol. (15) The process according to point (14) above, wherein R1 is methyl. (16) A process for producing a compound represented by the formula (VI): [Chemical formula 20] where R1 is methyl, or one of its salts, where the process comprises the step of: produce a p-toluenesulfonic acid salt from a compound represented by formula (IV-B): [Chemical formula 21] by the process in accordance with any of the above points (6) to (10). LfrRznn / zznz / E / YiAi (17) A process for producing a compound represented by the formula (VI): [Chemical formula 22] where R1 is methyl, or one of its salts, where the process comprises producing 1 / 2 salt of acid represented by Formula (V): [Chemical Formula 23] O h2n o3( V ) H CH3 by the process according to point (12): the stage of: sulfuric acid of a compound (18) A process for producing a compound represented by the formula (VI): [Chemical formula 24] where R1 is methyl, or one of its salts, where the process comprises the steps of: produce a p-toluenesulfonic acid salt from a compound represented by formula (IV-B): [Chemical formula 25]; H CH3O .X. χ-χ Xk -CH3fHx fí 'O- 3 ( |VB ) is H sj cu H Urh by the process in accordance with any of the preceding points (6) to (10); and produce 1 / 2 sulfuric acid salt of a compound represented by Formula (V): [Chemical Formula 26] or A .0¾t, H2N O'3(V ) Ηρο w by the process according to item (12). (19) A process for producing a compound represented by Formula (I): [Chemical formula 27]. or one of its salts, characterized in that: a compound is obtained represented by the formula (VI): [Chemical formula 28] wherein R1 is methyl, or one of its salts, by the process according to any of points (16) to (18) above; and the compound represented by formula (VI) or a salt thereof thus obtained is subjected to a hydrolysis reaction in the presence of one or more solvents selected from the group consisting of isopropyl alcohol, tetrahydrofuran and butanol. (20) The pharmaceutical composition in accordance with point (4) above, the pharmaceutical composition being a P2X3 and / or P2X2 / 3 antagonist. (21) The pharmaceutical composition in accordance with point (4) above, the pharmaceutical composition being used to treat and / or prevent chronic cough. (22) The pharmaceutical composition in accordance with point (4) above, the pharmaceutical composition being used to treat and / or prevent refractory chronic cough. (23) An antagonist of P2Xs and / or P2X2 / 3, characterized by containing a crystal according to any of the above points (1) to (3). (24) A therapeutic and / or preventive agent for chronic cough, characterized by containing the crystal in accordance with any of the points (1) to (3) above. (25) A therapeutic and / or preventive agent for refractory chronic cough, characterized by containing the crystal in accordance with any of the above points (1) to (3). (26) A method for the treatment and / or prevention of chronic cough, the method being characterized by administering a pharmaceutical composition containing the crystal in accordance with any of the above points (1) to (3). (27) A method for the treatment and / or prevention of refractory chronic cough, the method being characterized by administering a pharmaceutical composition containing the crystal in accordance with any of the above points (1) to (3). (28) Use of the crystal in accordance with any of the above points (1) to (3) to produce a drug for the treatment and / or prevention of chronic cough. (29) Use of the crystal in accordance with any of the above points (1) to (3) to produce a medicament for the treatment and / or prevention of chronic cough LfrRznn / zznz / E / YiAi refractory . (30) The crystal in accordance with any of the above points (1) to (3) for the treatment and / or prevention of chronic cough. (31) The crystal in accordance with any of the above points (1) to (3) for the treatment and / or prevention of refractory chronic cough. (32) The crystal according to the above point (1), characterized by a powder X-ray diffraction spectrum substantially identical to that shown in Figure 1. (33) The crystal according to the previous point (2), characterized by a powder X-ray diffraction spectrum substantially identical to that shown in Figure 1. (34) The crystal according to the above point (3), characterized by a powder X-ray diffraction spectrum substantially identical to that shown in Figure 1. (35) The crystal according to the previous point (1), characterized by a Raman spectrum substantially identical to that shown in Figure 2. (36) The crystal according to the previous point (2), characterized by a Raman spectrum substantially identical to that shown in Figure 2. (37) The crystal according to the previous point (3), characterized by a Raman spectrum substantially identical to that shown in Figure 2. LfrRznn / zznz / E / viaA EFFECT OF THE INVENTION A crystal of the present invention is useful as an active pharmaceutical ingredient of a compound represented by Formula (I). That is, the pharmaceutical composition containing a crystal of the present invention is very useful as a therapeutic or prophylactic agent for chronic cough or refractory chronic cough. Among the crystals of the present invention, an anhydrous crystal form I and a dihydrate crystal are useful as active pharmaceutical ingredients. Furthermore, the anhydrous crystal form I has the following characteristics: (i) have a low compressibility index (%) of the crystal and have a favorable crystal fluidity; (ii) have a crystalline form that does not contain any of the residual solvents listed in ICH guideline Q3C; and (iii) have high solid stability and generate few types of analogous substances during storage of the active pharmaceutical ingredient. In addition, the dihydrate crystal has the characteristics of (ii) and (iii) above. Furthermore, a process method of the present invention can produce useful compounds as process intermediates, represented by formula (IV) and formula (V), and LfrRznn / zznz / E / YiAi a compound represented by the formula (I) and a crystal thereof. The present process method is an industrially excellent process method, and the characteristics of the process method of the present invention may include the following points: (a) In the step of producing the compound represented by Formula (IV), the aza-Michael addition reaction can be accelerated by adding LiCl or similar; (b) In the step of producing the compound represented by Formula (V), by obtaining a product such as 1 / 2 sulfate, the product can be obtained in high yield; and (c) In the step of producing the compound represented by Formula (I), racemization can be suppressed by using isopropyl alcohol or similar as the reaction solvent. Brief Description of the Figures Figure 1. Figure 1 shows a powder X-ray diffraction pattern of an anhydrous crystalline Form I of a compound represented by Formula (I). The horizontal axis represents 2Θ (°), and the vertical axis represents intensity (Count). Figure 2. Figure 2 shows a Raman spectrum of the anhydrous crystalline Form I of the compound represented by Formula (I). The horizontal axis represents a Raman shift (cnr!), and the vertical axis represents a maximum intensity. Lfrfiznn / zznz / B / YiAi Figure 3. Figure 3 shows the results of the DSC analysis of the anhydrous crystalline Form I of the compound represented by Formula (I). Figure 4. Figure 4 shows a powder X-ray diffraction pattern of a dihydrate crystal of the compound represented by Formula (I). The horizontal axis represents 2Θ (°), and the vertical axis represents intensity (Count). Figure 5. Figure 5 shows the results of the TG / DTA analysis of the dihydrate crystal of the compound represented by Formula (I). The vertical axis represents a calorie (pV) or a weight change (%), and the horizontal axis represents temperature (°C). Cel in the figure means one degree Celsius (°C). Figure 6. Figure 6 shows a Raman spectrum of the dihydrate crystal of the compound represented by Formula (I). The horizontal axis represents a Raman change (cm-1), and the vertical axis represents a maximum intensity. Figure 7. Figure 7 shows a molecular structural diagram of the anhydrous crystalline Form I of the compound represented by Formula (I) (showing a molecule containing N3). Figure 8. Figure 8 shows a molecular structural diagram of the anhydrous crystalline Form I of the compound represented by Formula (I) (showing a molecule containing N8). LfrRznn / zznz / E / YiAi Figure 9. Figure 9 shows the NMR of an ethyl acetate / hexane solvate crystal of the compound represented by Formula (I). The horizontal axis represents a chemical shift (δ) value, and the vertical axis represents a relative intensity of a proton signal. Figure 10. Figure 10 shows a powder X-ray diffraction pattern of the ethyl acetate / hexane solvate crystal of the compound represented by Formula (I). The horizontal axis represents 2Θ (°), and the vertical axis represents an intensity (Count). Figure 11. Figure 11 shows a Raman spectrum of the ethyl acetate / hexane solvate crystal of the compound represented by formula (I). The horizontal axis represents a Raman change (cm-1), and the vertical axis represents a maximum intensity. Figure 12. Figure 12 shows a powder X-ray diffraction pattern of an anhydrous crystalline Form II of a compound represented by Formula (I). The horizontal axis represents 2Θ (°), and the vertical axis represents intensity (Count). Figure 13. Figure 13 shows the TG / DTA analysis results of the ethyl acetate / hexane solvate crystal of the compound represented by formula (I). The vertical axis represents a calorie (pV) or a weight change (%), and the horizontal axis represents temperature (°C). LfrRznn / zznz / E / YiAi the figure means one degree Celsius (°C). Detailed Description of the Invention The selection and control of the solid dosage form is important, especially for a compound such as a drug. Careful selection and control of the solid dosage form can reduce production, formulation, or administration problems related to the compound. Unless otherwise specified, a numerical value in this specification and claims is an approximate value. Numerical variation may result from device calibration, device error, substance purity, crystal size, sample size, temperature, and other factors. The term "crystal" as used in this specification means a solid in which the atoms, ions, molecules, and the like that constitute the crystal are three-dimensionally and regularly ordered, and is distinguished from an amorphous solid that does not have such a regular internal structure. The crystal of the present invention may be a single crystal, a twin crystal, a polycrystal, or the like. Furthermore, crystal polymorphs may be present in crystals. These are collectively called crystalline forms and are intended to be included in the present invention. Furthermore, the compound represented by Formula (1) LfrRznn / zznz / E / YiAi can form a solvate with water (i.e., a hydrate) or a solvate with a general organic solvent, and such a solvate is also intended to be included within the scope of the present invention. Crystalline form and crystallinity can be measured using many techniques which include, for example, powder X-ray diffractometry, Raman spectroscopy, infrared absorption spectroscopy, moisture adsorption / desorption measurement, differential scanning calorimetry, and dissolution characteristics. The term "salt" as used in this specification means, for example, that the compound represented by Formula (1) and the countermolecules are regularly arranged in the same crystal lattice, and any number of countermolecules may be included. The term refers to one in which an ionic bond is mediated by the transfer of protons between a compound and a countermolecule in a crystal lattice. Studies on salt formation provide a means to alter the physicochemical characteristics of an agent and the resulting biological characteristics without altering its chemical structure. Salt formation can have a dramatic impact on the agent's properties. Hygroscopicity, stability, solubility, and other factors are also important aspects when selecting a suitable salt. Salt processing properties. The solubility of a salt can affect its suitability for use as an agent. If aqueous solubility is low, the dissolution rate during in vivo administration is limited by the absorption process and may result in low bioavailability. Furthermore, low aqueous solubility can hinder administration by injection, thus limiting the selection of an appropriate route of administration. The compound represented by formula (1) can be converted into a solvate, a pharmaceutically acceptable salt, or a solvate of a salt. In one aspect of the present invention, the compound is in the form of a base addition salt. Examples of base addition salts include salts prepared from pharmaceutically acceptable, non-toxic bases, including inorganic and organic bases. Examples of salts derived from inorganic bases include, but are not limited to, salts of aluminum, calcium, lithium, potassium, magnesium, sodium, zinc, and other metal salts.Examples of a pharmaceutically acceptable salt based on a non-toxic base include salts of primary, secondary, or tertiary amines and substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, benzathine, caffeine, choline, chloroprocaine, cycloprocaine, N'N'-dibenzylethylenediamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2. LfrRznn / zznz / E / YiAi dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, Usina, meglumine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, tertiary butylamine (2-methylpropan-2-amine), theobromine, triethylamine, trimethylamine, tripropylamine and tromethamine; as well as non-toxic ammonium and quaternary ammonium, and salts of cations including, but not limited to, ammonium, tetramethylammonium and tetraethylammonium. Examples of acid addition salts of the compound represented by Formula (I), the compound represented by Formula (II), the compound represented by Formula (IV), the compound represented by Formula (IV-A), the compound represented by Formula (IV-B), and the compound represented by Formula (V) include a compound that has: an inorganic acid, such as hydrochloric acid, hydrobromic acid, orthophosphoric acid, nitric acid, phosphoric acid, or sulfuric acid; or an organic acid, such as formic acid, methanesulfonic acid, ethanesulfonic acid, p-toluensulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid, tartaric acid, benzoic acid, glutamic acid, LfrRznn / zznz / E / YiAi aspartic acid, benzenesulfonic acid, naphthalenesulfonic acid, such as 2-naphthalenesulfonic acid, hexanoic acid and acetylsalicylic acid. The term solvate used in this specification refers, for example, to one that is regularly arranged with an arbitrary number of solvent molecules with respect to the compound represented by Formula (I). Examples of solvent molecules include acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethene, xylene, acetic acid, anisole, 1-butanol, 2-butanol, t-butanol, n-butyl acetate, t-butyl methyl ether, eumene, dimethyl sulfoxide, ethyl acetate, diethyl ether, and formate. ethyl, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-l-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-l-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, water (i.e., hydrate), ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether,methyl isopropyl ketone, methyl tetrahydrofuran, LfrRznn / zznz / E / YiAi petroleum ether, trichloroacetic acid and trifluoroacetic acid. Preferred examples include acetic acid, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, eumene, dimethyl sulfoxide, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, tetrahydrofuran, water (i.e., hydrate), ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone. methyl tetrahydrofuran, petroleum ether, trichloroacetic acid and trifluoroacetic acid. The most preferred examples of these include water (i.e., hydrate), ethanol, acetone, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, and trifluoroacetic acid. When the compound represented by Formula (1) is left to stand in the atmosphere, moisture is absorbed and the adsorbed water can adhere to it, or a hydrate can be formed. Furthermore, for the compound represented by the Formula LfrRznn / zznz / E / YiAi (II), the compound represented by Formula (III), the compound represented by Formula (IV), the compound represented by Formula (IV-A), the compound represented by Formula (IV-B), the compound represented by Formula (V) and the compound represented by Formula (VI), can form solvates. The hydrate of the present invention or the crystal thereof contains, for example, approximately 2 molar equivalents of water molecules with respect to the compound represented by Formula (I). Preferred examples of the hydrate crystal of the present invention include a dihydrate. The hydrate of the present invention or the crystal thereof has a water content of, for example, 4.7 to 9.7% by weight. Preferably, the water content is approximately 5.6 to 7.6% by weight (the theoretical value of the dihydrate is 6.6%, but the moisture content may increase due to the influence of water adhering to the crystal, or some of the water in the crystal may be desorbed before measurement, so the moisture content may decrease). The crystal of the present invention may be a deuterium conversion product. The crystal of the present invention may be labeled with an isotope (examples: 3H, 14C, 35S, 125I). The term anhydride used in this specification is synonymous with ansolvate, non-solvate, anhydrate, and non- Lfrfiznn / zznz / B / YiAi hydrate. The compound represented by the P2X3 and / or P2X2 / 3 antagonist described Formula (I) is a in the Document of Patent 9: [Chemical formula 29] It is very useful as a therapeutic or prophylactic agent for chronic cough. The compound represented by Formula (I) can be prepared with reference to the Examples in this application. A tautomer of the compound represented by Formula (I) is a compound (amino form) represented by Formula (1'): [Chemical formula 30] This compound has an antagonistic action on the receptor P2X3 and / or P2X2 / 3, as the compound represented by Formula (I) · Furthermore, the compound represented by formula (VI) can also take tautomers in the same way as described above. [Chemical formula 31] The compound represented by Formula (I) may also include a mixture of the compound represented by Formula (I) (imino form) and the compound represented by Formula (I') (amino form), and these may be mixed in any arbitrary proportion. The same applies to the compound represented by Formula (VI). As a result of the analysis of the single-crystal structure, it was confirmed that the anhydrous crystalline Form I of the compound represented by Formula (I) had the following molecular structure (imino form) (details are described in Example 3). [Chemical formula 32] LfrRznn / zznz / E / YiAi For the dihydrate crystal of the compound represented by Formula (I) and Form II of the anhydrous crystal of the compound represented by Formula (I), the molecular structure (amino form / imino form) has not been identified. Powder X-ray Diffraction (XRPD) In general, a crystalline organic compound is composed of a large number of molecules arranged periodically in three-dimensional space. Structural periodicity typically leads to physical properties that are clearly distinguishable by most spectroscopic probes (e.g., X-ray diffraction, infrared spectroscopy, Raman spectroscopy, and solid-state NMR). Among these, powder X-ray diffraction (XRPD) is one of the most sensitive analytical methods for measuring the crystallinity of a solid. When the crystal is irradiated with X-rays, the X-rays are reflected off the crystal lattice planes and interfere with each other. Only the diffraction rays in the direction that satisfies the condition predicted by Bragg's law increase in intensity, resulting in ordered diffraction patterns that correspond to the period of the structure. In contrast, for an amorphous solid, no ordered diffraction pattern is observed.An amorphous solid generally does not have an ordered repeating period in its structure, so no diffraction phenomenon occurs and it shows a broad featureless XRPD pattern (also known as a halo pattern). The crystalline form of the anhydride of the compound represented by formula (I) can be characterized by a powder X-ray diffraction pattern and characteristic peaks. The crystalline form of the anhydride of the compound represented by formula (I) can be distinguished from other crystalline forms (e.g., a hydrate crystal) by the presence of characteristic diffraction peaks. The characteristic diffraction peaks used in this specification are those selected from the observed diffraction patterns. When distinguishing a plurality of crystals, a peak observed in one crystal and not in the others, rather than the peak size, is the preferred characteristic peak for specifying the crystal. With such a characteristic peak, even one or two peaks can characterize the crystal. When comparing the graphs obtained by measurement with these characteristic peaks LfrRznn / zznz / E / YiAi coincide with each other, it can be said that the powder X-ray diffraction spectra coincide substantially with each other. In general, since the diffraction angle (2Θ) in powder X-ray diffraction can have an error within a range of ±0.2°, the value of the diffraction angle in powder X-ray diffraction should be understood as including a numerical value within a range of approximately ±0.2°. Therefore, the present invention encompasses not only crystals in which the diffraction angles of the peaks in powder X-ray diffraction coincide completely with each other, but also crystals in which the diffraction angles of the peaks coincide with each other with an error of approximately ±0.2°. In general, it is known that the peak intensities shown in the following tables and figures can vary depending on many factors, such as the effect of selective crystal orientation in the X-ray beam, the effect of coarse particles, the purity of the material being analyzed, or the crystallinity of a sample. The peak position can also change depending on variations in the sample height. Furthermore, different displacements, according to Bragg's equation (ηλ = 2dsin0), are obtained when the measurement is performed using a different wavelength, resulting in a different XRPD pattern. Lfrfiznn / zznz / B / YiAi using a different wavelength is also within the scope of the present invention. Single-crystal structure analysis (see Toshio Sakurai, X-sen Kozo Kaiseki no Tebiki (Guide to X-ray Structural Analysis), published by Shokabo Co., Ltd. (1983), and Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), etc.) is one of the methods for determining a crystal, and it is possible to obtain crystallographic parameters of the crystal, atomic coordinates (values ​​that indicate a spatial position relationship of each atom), and a three-dimensional structure model. Single-crystal structure analysis is useful for identifying the crystal structure of the compound as in the present invention. Raman Spectroscopy A Raman spectrum reveals the vibrational characteristics of molecules or a complex system. Its origin lies in the inelastic collisions between molecules and photons, which are particles of light, including light rays. The collision of molecules with photons leads to an exchange of energy, resulting in a change in energy, which in turn changes the wavelength of the photons. That is, since Raman spectra consist of spectral lines emitted when photons strike a target molecule and have extremely narrow wavelengths, a laser or similar device is used to generate them. LfrRznn / zznz / E / YiAi light source. The wavelength of each Raman line is represented by a change in the wavenumber of incident light, which is the difference between the inverse of the wavelength of the Raman line and that of the incident light. The Raman spectrum is used to measure the vibrational state of a molecule, which is determined by its molecular structure. In general, since an absorption band (cm²) in a Raman spectrum may have an error within a range of ±2 cm⁻¹, the value of the absorption peak should be understood as including a numerical value within a range of approximately ±2 cm⁻¹. Therefore, the present invention encompasses not only crystals in which the peaks of the absorption bands in the Raman spectra coincide completely with each other, but also crystals in which the peaks of the absorption bands coincide with each other with an error of approximately ±2 cm⁻¹. Infrared absorption spectroscopy (IR method) Infrared absorption spectroscopy is a method for measuring, for each wavenumber, the degree of absorption of infrared rays as they pass through a sample. The infrared absorption spectrum is typically represented by a graph where the horizontal axis represents a wavenumber and the vertical axis represents either transmittance or absorbance. The wavenumber and transmittance (or absorbance) of the absorption peak can be The infrared absorption spectrum can be read from a graph, and the values ​​calculated by a data processing device can be used. The infrared absorption spectrum is determined by the chemical structure of the substance. Therefore, absorption can be measured at various wavenumbers to confirm or quantify a substance. The discrimination of a crystalline polymorph can be performed by comparing the absorption bands of the functional groups characteristic of crystalline polymorphs, that is, a functional group primarily involved in hydrogen bonding in the crystal structure, such as a C=O bond, an OH bond, and an NH bond, as well as other characteristic functional groups, such as a CX (halogen) bond, a C=C bond, and a C=C bond.The absorption bands for the characteristic functional group are selected from approximately 20 absorption peaks, more preferably approximately 10 absorption peaks, and most preferably approximately 5 absorption peaks corresponding to the characteristic functional groups. Typically, the absorption spectrum of a sample is measured over a wavenumber range of 4,000 cm⁻¹ to 400 cm⁻¹. The absorption spectrum is measured under the same operating conditions as when the resolution, wavenumber scale, and wavenumber accuracy of the instrument were confirmed. In general, given that an absorption band (cm-1) in infrared absorption spectroscopy can have an error LfrRznn / zznz / E / YiAi within a range of ±2 cm1, the absorption peak value should be understood as including a numerical value within a range of approximately ±2 cm-1. Therefore, the present invention encompasses not only crystals in which the absorption band peaks in infrared absorption spectroscopy coincide completely with each other, but also crystals in which the absorption band peaks coincide with each other with an error of approximately ±2 cm-1. Examples of methods for measuring an infrared absorption spectrum include the potassium bromide tablet method, the solution method, the paste method, the liquid film method, the thin film method, the gas sample measurement method, the ATR method, and the diffuse reflection method. Among these, the attenuated total reflection (ATR) method is called the total reflection measurement method and is one of the reflection methods. In this method, a sample is placed in close contact with the surface of a prism made of a substance with a high refractive index, such as KRS-5. Light strikes the prism at an angle equal to or greater than a critical angle, and the light totally reflected at the boundary between the prism and the sample is measured to obtain an absorption spectrum. One of the conditions that allows measurement by the ATR method is that the refractive index of the prism is The LfrRznn / zznz / E / YiAi value is greater than that of the sample, so it is necessary to change the prism material depending on the sample. Furthermore, as another condition, the prism and the sample must be in close contact. Therefore, it is suitable for measuring liquids, powders, plastics, soft rubber, and similar materials, and has the advantage that the measurement can be performed without chemically or physically treating the sample. On the other hand, the diffuse reflection method is a method for measuring a powder sample without forming a potassium bromide tablet. When light is applied to a sample, some light is specularly reflected off the surface of the powder and exits, while diffusely reflected light (scattered light) enters the sample, repeats the transmission and scattering process, and then exits at the surface. In the diffuse reflection method, this latter light is used to obtain an absorption spectrum. Solid-state 13C NMR (nuclear magnetic resonance) Solid-state 13C NMR is useful for specifying a crystal form because (i) the number of spectra corresponds to the number of carbon atoms in a target compound, (ii) the chemical shift range is wider than that of 3H NMR, (iii) the signal is sharper than that of solid-state 3H NMR, and (iv) even if it contains an additive, the chemical shift remains unchanged when there is no interaction. Note that the observed chemical shift is expected to vary slightly depending on the specific spectrometer used and the LfrRznn / zznz / E / YiAi Analyst's sample preparation technique. The error range in the 13C NMR solid spectrum is approximately ±0.5 ppm. Differential scanning calorimetry (DSC) DSC is one of the main measurement methods of thermal analysis and is a method for measuring the thermal properties of a substance as an aggregate of atoms and molecules. A differential scanning calorimetry (DSC) curve is obtained by measuring the change in heat content with respect to temperature or time for the active pharmaceutical ingredient and plotting the data against temperature or time. From the DSC curve, it is possible to obtain information about the initial melting temperature of the active pharmaceutical ingredient, the maximum value of the endothermic peak associated with melting, and the enthalpy. For DSC, it is known that the observed temperature can depend on the rate of temperature change, as well as the sample preparation technique and the specific equipment used. Therefore, the melting point in DSC refers to the starting temperature, which is least susceptible to sample preparation techniques. An error interval at the starting temperature obtained from the curve of The Lfrfiznn / zznz / B / YiAi differential scanning calorimetry is approximately ±2°C. In the recognition of the identity of crystals, not only is the melting point important, but also the general pattern, and the general pattern may vary slightly according to the measurement conditions and the measuring instrument. Thermogravimetry / Differential Thermal Analysis (TG / DTA) TG / DTA is one of the main measurement methods of thermal analysis and is a method for measuring the weight and thermal properties of a substance as an aggregate of atoms and molecules. TG / DTA is a method for measuring changes in the weight and heat content of a pharmaceutically active ingredient with respect to temperature or time. TG (thermogravimetric analysis) and DTA (differential thermal analysis) curves are obtained by plotting the data against temperature or time. From the TG / DTA curves, it is possible to obtain information about the change in weight and heat content related to the decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of the pharmaceutically active ingredient. For TG / DTA, it is known that the observed temperature and weight change can depend on the rate of temperature change, as well as the sample preparation technique and the specific equipment used. Therefore, the point The melting point in TG / DTA refers to the starting temperature that is least susceptible to sample preparation techniques. In crystal identification, not only is the melting point important, but also the overall pattern, and this pattern can vary slightly depending on the measurement conditions and the measuring instrument. Method for measuring moisture sorption / desorption isotherms (DVS) The moisture adsorption / desorption isotherm measurement is a measurement method to measure the adsorption and desorption behavior of moisture by measuring a weight change in a solid as the measurement target under each relative humidity condition. As a basic measurement method, based on dry weight at 0% RH (0% relative humidity), the relative humidity is increased every 5% or 10%. After the weight stabilizes at each relative humidity, the amount of water adsorbed can be determined from the weight increase relative to the reference value. Similarly, the amount of water desorption can be measured by decreasing the relative humidity every 5% or 10% from 100% RH. By plotting the weight change at each relative humidity, an adsorption / desorption isotherm can be obtained. From this result, it is possible to consider a phenomenon LfrRznn / zznz / E / YiAi of adsorption and desorption of adherent moisture at each humidity. Furthermore, when an anhydride crystal and a hydrate crystal undergo a crystal transition due to humidity, it is possible to calculate the humidity at which the crystal transition occurs and the amount of crystalline water. The sorption and desorption of adhering water and crystalline water are affected by particle size, crystallinity, crystal habit, and the like, so the measurement results may change slightly. The pharmaceutical composition containing a crystal of the present invention is very useful as a therapeutic or prophylactic agent for chronic cough. The crystal of the present invention can be administered to a human patient on its own or as a pharmaceutical composition in which the crystal is mixed with a suitable vehicle or excipient. Techniques for drug formulation and administration can be appropriately selected and used in combination with pharmaceutical formulations and techniques known to those skilled in the art. Examples of the route of administration of the crystal of the present invention or of the pharmaceutical composition containing the crystal may include, but are not limited to, oral, rectal, transmucosal or intestinal administration, LfrRznn / zznz / E / YiAi can be administered intramuscularly, subcutaneously, intraspinally, intrathecally, directly intraventricularly, intravenously, intravitreally, intraperitoneally, intranasally, and intraocularly. A preferred route of administration is oral administration. The pharmaceutical composition of the present invention can be produced by a method well known in the art, for example, a conventional process of mixing, dissolving, granulating, sugar coating, spraying, emulsifying, encapsulating, sealing, or lyophilizing. The crystal of the present invention or the pharmaceutical composition containing the crystal can be administered by injection using an aqueous solution, preferably a physiologically compatible buffer, such as Ringer's solution or physiological saline solution. The crystal of the present invention or the pharmaceutical composition containing the crystal can be administered transmucosally using a suitable penetrant to permeate a barrier. A penetrant generally known in the art may be used. The crystal of the present invention or the pharmaceutical composition containing the crystal can be combined with a pharmaceutically acceptable vehicle well known in the art for oral administration. The vehicle allows the crystal of the invention to be administered in the form of tablets, pills, lozenges, sugar-coated tablets, LfrRznn / zznz / E / YiAi capsules, solution, gel, syrups or suspensions. Pharmaceutical compositions for oral administration may be prepared by adding solid excipients and, if desired, other suitable auxiliaries, followed by grinding the resulting mixture and processing the granule mixture to obtain tablets or sugar-coated tablet cores. Useful excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, and potato starch; gelatin; tragacanth gum; methylcellulose; hydroxypropyl methylcellulose; and / or sodium carboxymethylcellulose. If necessary, a disintegrant such as agar or alginic acid may be added. A salt such as sodium alginate may also be used. Examples of pharmaceutical compositions that can be used for oral administration include snap-fit ​​capsules made of gelatin and sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The snap-fit ​​capsule may contain an active ingredient mixed with a filler, such as lactose, a binder, such as starch, and / or a lubricant, such as talc or magnesium stearate. The pharmaceutical composition may also contain a LfrRznn / zznz / E / YiAi suitable solid or gel-phase vehicle or excipient. Examples of such a vehicle or excipient include calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. For the crystals of the invention or pharmaceutical compositions thereof, a therapeutically effective amount can first be estimated from cell culture testing. A dosage of a larger quantity can then be formulated for use in animal models to achieve a circulating concentration range that covers the IC50 (i.e., a concentration of the crystal of the present invention or pharmaceutical composition thereof at which half of the maximum inhibition of PK activity is achieved), as determined in cell culture. This information can then be used to more precisely determine a useful amount for humans. The therapeutic effects of the crystal of the present invention or its pharmaceutical composition can be measured using a standard pharmaceutical method in cell culture or experimental animals. For example, the evaluation can be performed according to a biological testing method described in patent document 9. The data obtained from these cell culture tests and animal experiments can be used to formulate a range of dosages for human use. The dosage may vary according to LfrRznn / zznz / E / YiAi with the form of administration used and the route of administration used. The individual physician may select the exact route of administration of the formulation and dosage from the standpoint of the patient's condition. It is also an aspect of the present invention that the crystals of the present invention or pharmaceutical compositions thereof can be combined with other agents for the treatment of diseases and disorders. The present invention provides an anhydride crystal or a hydrate crystal of the compound represented by Formula (I). The crystalline solid has at least one of the following characteristics: (1) It has good stability against heat, humidity, solvents, light and the like, and high storage stability; (2) has good color stability; (3) has good solubility in water or organic solvents; (4) has a high dissolution rate with respect to water or organic solvents; (5) has high purity; (6) has a low rate of residual organic solvent; (7) has excellent operability in filtration, centrifugation and formulation; (8) has a small specific volume; (9) barely loaded; LfrRznn / zznz / E / YiAi (10) is produced with high performance under conditions with reduced environmental loads, and can be mass-produced; (11) is useful as a pharmaceutically active ingredient for an injection, or as an active material for the production thereof; (12) is controllable to a pH range suitable for intravenous injection without vascular pain, thus being advantageous for controlling the amount of fluid, reducing excipients, etc., at the time of formulation; (13) has good flowability; and (14) has a low Compressibility Index (%). In particular, the crystalline solid of the present invention has high stability even in a wide humidity range (e.g., 25 to 99% RH or similar) and a severe environment (e.g., under high humidity). The meaning of each term used in this specification is described below. Unless otherwise specified, each term is used with the same meaning when used alone or in combination with another term. The term consisting of means that it has only the components. The term "includes" means not limited to the components, but does not exclude elements that are not described. Lfrfiznn / zznz / B / YiAi The present invention will now be described with reference to its embodiments. It should be understood throughout this specification that singular forms of expression also include the concept of their plural forms, unless otherwise indicated. Thus, the singular article (e.g., in English, a, an, the, and the like) should also be understood to include its plural form, unless otherwise indicated. It should also be understood that the terms used in this specification are used in the sense commonly used in the art, unless otherwise indicated. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meanings as those commonly understood by those skilled in the art to which this invention belongs. In case of conflict, this specification (including the definitions) shall prevail. The term halogen encompasses a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In particular, a fluorine atom and a chlorine atom are preferred. The term alkyl encompasses a linear or branched hydrocarbon group having from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, and even more preferably from 1 to 4 carbon atoms. LfrRznn / zznz / E / YiAi carbon. Examples of these include methyl, ethyl, n64 propyl, isopropyl, n-butyl, isobutyl, seso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, nnonyl and n-decyl. Preferred alkyl forms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. The most preferred forms include methyl, ethyl, n-propyl, isopropyl, and tert-butyl. Examples of C1-C4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. The present invention includes a step for producing a compound represented by formula (IV): [Chemical formula 33] where R1 is a C1-C4 alkyl, or one of its salts, characterized by causing a reaction between a compound represented by formula (II): [Chemical formula 34] or one of its salts, and a compound represented by Formula (III): [Chemical Formula 35] Lfrfiznn / zznz / B / YiAi where R1 is C1-C4 alkyl, or one of its salts, in the presence of one or more additives selected from the group consisting of lithium chloride, calcium chloride, magnesium chloride, lithium bromide, p-toluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid. The compound represented by Formula (II) or a salt thereof and the compound represented by Formula (III) or a salt thereof may be produced according to a known method from commercially available reagents, or a commercially available product such as these compounds and salts may be used. The solvent is not particularly limited as long as it does not inhibit the reaction, but methanol, ethanol, isopropyl alcohol, tert-butanol, or a mixture thereof can be used. For example, methanol can be used. Regarding the reaction temperature, the reaction is typically carried out within a temperature range of room temperature to a temperature at which the solvent is refluxed. For example, the reaction can be performed within a range of -10°C to a temperature at which the solvent is refluxed. For example, it can be carried out at 80°C. The reaction time is from 1 to 20 hours, for example, from 5 to 7 hours. The amount of use of the compound represented by Formula (III) with respect to the compound represented by Formula (II) can normally be from 1.0 to 10.0 equivalents, for example, from 2.0 to 4.0 equivalents, for example, from 3.0 equivalents. Lithium chloride, calcium chloride, magnesium chloride, lithium bromide, ptoluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, or similar additives may be used. A plurality of these additives may be selected and used simultaneously. The amount of use of the additive with respect to the compound represented by Formula (II) can normally be from 0.1 to 5.0 equivalents, for example, from 1.0 to 2.0 equivalents, for example, from 1.0 to 1.5 equivalents. The present invention includes a step for producing a p-toluenesulfonic acid salt from a compound represented by Formula (IV-A): [Chemical Formula 36] LfrRznn / zznz / E / YiAi where R1 is a C1-C4 alkyl, characterized by: Lfrfiznn / zznz / B / YiAi add p-toluenesulfonic acid to a compound represented by Formula (IV): [Chemical Formula 37] where R1 is C1-C4 alkyl, or a salt thereof. The amount of use of p-toluenesulfonic acid monohydrate (or aqueous solution of p-toluenesulfonic acid) with respect to the compound represented by Formula (II) can normally be from 0.5 to 2.0 equivalents, for example, from 0.8 to 1.0 equivalents. The present invention includes a step of producing a 1 / 2 sulfuric acid salt from a compound represented by Formula (V): [Chemical Formula 38] characterized by: subject a p-toluenesulfonic acid salt of a compound represented by Formula (IV-B): [Chemical formula 39] Lfrfiznn / zznz / B / YiAi to a hydrogenolysis reaction; and add sulfuric acid. The compound represented by the formula (IV-B) can be produced according to the step described above. The solvent is not particularly limited as long as it does not inhibit the reaction, but methanol, ethanol, 1-propanol, isopropyl alcohol, tert-butanol, tetrahydrofuran, or a mixture of these solvents can be used. For example, methanol can be used. Regarding the reaction temperature, the reaction is typically carried out within a temperature range of room temperature to a temperature at which the solvent is refluxed. For example, the reaction can be performed between 30 and 50°C. The reaction time is from 30 minutes to 20 hours, for example, from 1 to 3 hours. Palladium on carbon, palladium hydroxide, palladium black, or similar materials can be used as a catalyst for the hydrolysis reaction. The amount of catalyst used in the hydrolysis reaction with respect to the compound represented by formula (IV-B) can normally be from 0.01 to 1 w / w, for example, from 0.1 to 0.3 w / w. The amount of concentrated sulfuric acid used with respect to the compound represented by Formula (IV-B) can normally be from 0.01 to 5.0 equivalents, for example, from 0.3 to 0.4 equivalents. The present method includes a step to produce a compound represented by Formula (I): [Chemical Formula 40] or one of its salts, characterized by: subject the compound represented by formula (VI): [Chemical formula 41] where R1 is C1-C4 alkyl, or its salt, to a hydrolysis reaction in the presence of one or more solvents selected from the group consisting of isopropyl alcohol, tetrahydrofuran, and t-butanol. The compound represented by Formula (VI) can be produced according to the steps mentioned above and the methods described in Patent Documents 6, 7, 8 and 9. The solvent is not particularly limited as long as it does not inhibit the reaction, but isopropyl alcohol (2-propanol), tetrahydrofuran, and tert-butanol, or a mixture of these solvents, can be used. For example, isopropyl alcohol (2-propanol) can be used. Regarding the reaction temperature, the reaction is normally carried out within a range of -10°C to a temperature at which the solvent is refluxed. For example, it can be performed at a temperature of 30°C to 40°C. The reaction time is from 0.1 to 20 hours, for example, from 1 to 5 hours. Sodium hydroxide, potassium hydroxide, lithium hydroxide, or similar substances can be used as a base. For example, sodium hydroxide can be used. The amount of use of a base with respect to the compound represented by Formula (VI) can normally be from 2.0 to 5.0 equivalents, for example, from 2.0 to 3.0 equivalents. LfrRznn / zznz / E / viaA EXAMPLES The present invention will be described in more detail by means of the following examples. These do not limit the present invention. For numerical values ​​(e.g., quantity, temperature, and the like), some error and deviation should be considered. Unless otherwise stated, means % by weight of the component and % by weight of the total composition weight, and pressure means a pressure at or near atmospheric pressure. Measurement of the powder X-ray diffraction pattern The powder X-ray diffraction measurement of a crystal obtained in each Example was performed according to the powder X-ray diffraction measurement method described in the General Tests, Processes, and Apparatus of the Japanese Pharmacopoeia. The measurement conditions are shown below. Method 1 Apparatus SmartLab manufactured by Rigaku Corporation Operating Method Measurement Method: Reflection method Wavelength used: CuKa beam Tube current: 200 mA Tube voltage: 45 kV LfrRznn / zznz / E / YiAi Sample plate: glass X-ray incidence angle: 2.5° Sampling width: 0.02° Detector: HyPix-3000 (two-dimensional detection mode) Method 2 Apparatus D-8 Discover manufactured by Bruker Corporation Method of operation Measurement method: reflection method Wavelength used: CuKa beam Tube current: 40 mA Tube voltage: 40 kV Sample plate: aluminum X-ray incidence angle: 3oy 12° Method 3 D-8 Discover manufactured by Bruker Corporation Method of operation Measurement method: reflection method Wavelength used: CuKa beam Tube current: 40 mA Tube voltage: 40 kV Sample plate: aluminum X-ray incidence angle: 3° Raman spectrum measurement LfrRznn / zznz / E / YiAi A Raman spectrum of a crystal obtained in each was measured Example. The measurement conditions are shown below. Method 1 Measuring device: LabRAM ARAMIS (manufactured by HORIBA Jobin Yvon SAS) Measurement method: Raman microlaser spectroscopy Laser wavelength: 633 nm (He-Ne laser) Diffraction grating: 600 slots / mm. Detector: CCD detector Objective lens: 20x (NA 0.25) Number of integrations: 5 times Exposure time: 5 seconds Method 2 Measuring instrument: RAMANTouch Vis2-NIR-SNU (manufactured by Nanophoton Corporation) Measurement method: Raman microlaser spectroscopy Laser wavelength: 532 nm Diffraction grating: 1200 slots / mm Detector: CCD detector Objective lens: 20x (NA 0.45) Number of integrations: 1 time Exposure time: 3 seconds Differential scanning calorimetry (DSC) measurement The DSC of a crystal obtained in each Example was measured. Approximately 4,199 mg of a sample were weighed in a LfrRznn / zznz / E / YiAi aluminum tray and weight was measured by simple sealing. The measurement conditions are shown below. Incidentally, an error within a range of ±2°C may occur in the differential scanning calorimetry (DSC) measurement. Apparatus: TA Instruments Discovery; Measurement temperature range: 0°C to 220°C; Heating rate: 10°C / min; Atmosphere: N2 50 mL / min; NMR measurement When NMR data are displayed, not all measured peaks may be described. HPLC Measurement Method A Column: XBridqe C18, φ 4.6 x 150 mm, 3.5 pm (Waters) Column oven: 40°C Flow rate: 1.0 mL per minute UV detection wavelength: 254 nm Mobile phase A: 0.1% aqueous trifluoroacetic acid solution Mobile phase B: acetonitrile for liquid chromatography The gradient program is shown in Table 1. LfrRznn / zznz / E / YiAi Table 1 Time after injection (min) Mobile phase A (% vol) Mobile phase B (% vol) 0-4 85 15 4-10 85^60 15^4 0 10-13 60^10 4 0^90 13-17 10 90 17-17.01 10^8 5 90^15 17.01-27 85 15 LfrRznn / zznz / E / viaA Method B Column: CHIRALPACK AS-RH, φ 4.6 x 150 mm, 5 pm (Daicel Chemical Industries, Ltd.) Column oven: 35°C Flow rate: 1.0 mL per minute UV detection wavelength: 254 nm Mobile phase A: purified water for liquid chromatography Mobile phase B: Acetonitrile for liquid chromatography The gradient program is shown in Table 2. Table 2 Time after injection (min) Mobile phase A (% vol) Mobile phase B (% vol) 0-14 80 20 14-18 8 0^10 20^90 Time after injection (min) Mobile phase A (% vol) Mobile phase B (% vol) 18-24 10 90 24-24.01 10^8 0 90^2 0 24.01-30 80 20 0-14 80 20 LfrRznn / zznz / E / viaA Method C Column: CHIRALPACK IC, φ 4.6 x 250 mm, 5 pm (Daicel Chemical Industries, Ltd. ) Column oven: 35°C Flow rate: 1.0 mL per minute UV detection wavelength: 262 nm Mobile phase: 0.1% aqueous formic acid solution / acetonitrile mixed solution for liquid chromatography (3:2) Method D Column: Cadenza CD-C18, φ 3.0 x 150 mm, 3 pm Column oven: 50°C Flow rate: 0.55 mL per minute UV detection wavelength: 262 nm Mobile phase A: 0.1% aqueous TFA solution Mobile phase B: Acetonitrile The gradient program is shown in Table 3. Table 3 Time (min) Mobile Phase A (%) Mobile Phase B (%) 0 80 20 1 80 20 10 45 55 15 45 55 20 10 90 25 10 90 25.01 80 20 30 80 20 LfrRznn / zznz / E / viaA HPLC retention time should be understood to include some errors. TG / DTA measurement Approximately 4.4 mg of the crystal obtained in Example 7 were weighed, placed on an aluminum tray, and measured in an open system. The measurement conditions are as follows: Apparatus: Hitachi High-Technologies TG / DTA STA7200RV; Measurement temperature range: ambient temperature to 300°C; Heating rate: 10°C / min Method of measurement and analysis of single crystal structure analysis The following are the measurement conditions and analysis methods for single-crystal structure analysis. XtaLAB P 200 MM007 apparatus manufactured by Rigaku Corporation Measurement conditions Measurement temperature: 25°C Used wavelength: CuKa ray (λ=1.5418 Á) Programming elements (Software): CrysAlisPro 1.171.39.46e (Rigaku Oxford diffraction, 2018) Data processing Programming elements: CrysAlisPro 1.171.39.46e (Rigaku Oxford diffraction, 2018) The data were subjected to Lorentz and polarization correction and absorption correction. Crystal structure analysis Phase determination was performed using the ShelXT direct method program (Sheldrick, GM, 2015) and refined using the full-array least squares method with ShelXL (Sheldrick, GM, 2015). All temperature factors for non-hydrogen atoms were refined for anisotropy. A hydrogen atom (H5) in an oxygen atom (O5) was derived from a Fourier difference map and refined. The remaining hydrogen atoms were introduced by calculation using predefined ShelXL parameters and treated as assembled atoms. All hydrogen atoms were refined for isotropic parameters. R1 (I>2.00s(I)) was 0.0470, and this was confirmed from the final Fourier difference, which indicates no missing or erroneous electron density. PLUTON (Spek, 1991) / ORTEP (Johnson, 1976) was used to Lfrfiznn / zznz / B / YiAi draw Figures 7 and 8 (50% PROBABILITY level). LfrRznn / zznz / E / YiAi Example 1 Synthesis of compound (3) [Chemical formula 42] (1) (2) (3) [1] Synthesis of compound (3) Methanol (20 mL) and methyl methacrylate (2) (49.64 g, 495.8 mmol) were added to (R)-(+)-1-phenylethylamine (1) (20.01 g, 165.1 mmol) at room temperature. After cooling to 10°C, lithium chloride (7.07 g, 167 mmol) was added. The reaction solution was heated to 80°C and stirred for 6 hours. The reaction solution was cooled to 25°C, a 9.1% aqueous sodium chloride solution (77.03 g) was added, and the aqueous layer was removed by liquid separation. Toluene (61.04 g) was added to the aqueous layer obtained at room temperature, and another aqueous layer was removed by liquid separation. The two organic layers obtained were combined, toluene (16.99 g) was added and the mixture was concentrated under reduced pressure at 50°C. Ethanol (16.00 g) and p-toluenesulfonic acid monohydrate (28.91 g, 152.0 mmol) were mixed to give a solution in ethanol (44.91 g) of p-toluenesulfonic acid. Toluene (155.91 g) was added to the previously prepared concentrate. The previously prepared ethanolic solution (5.88 g) of p-toluenesulfonic acid and a seed crystal suspension (19.95 mg, 0.05070 mmol) in toluene (63 mL) were added to the mixture at room temperature to give a suspension of compound (3). The remaining ethanolic solution (39.93 g) of the previously prepared p-toluenesulfonic acid was added to the resulting suspension, and ethanol (10 mL) was added. The resulting mixture was stirred for 2 hours and allowed to stand overnight. The mixture was cooled to 0°C and stirred for 2 hours, and a solid was collected by filtration to give compound (3) (20.75 g, 31.9%) as the crude product. Toluene (1.92 g), ethyl acetate (21.70 g), and methanol (2.90 g) were added to a portion (5.00 g) of the crude product of compound (3), and the mixture was stirred at 50°C for 3 hours. The mixture was cooled to 0°C, and a solid was collected by filtration, yielding compound (3) (4.65 g). Elemental analysis: C 61.22%, H 7.09%, N 3.56%, S 8.12% NMR (DMSO-d6) δ ppm: 1.12 (d, J=7.0 Hz, 3H), 1.55 (br d, J=6.7 Hz, 3H), 2.29 (s, 3H), 2.50 (s, 2H), 2.83 (br dd, J=13.2 Hz, 6.9 Hz, 1H), 2.90 (m, 2H), 3.62 (s, 3H), 7.13 (m, 2H), 7.47 (m, 7H). [2] Synthesis of the seed crystal of compound (3) (R) — ( + )—1 phenylethylamine (1) (2.00 g, 16.5 mmol), methanol (1.59 g) , methyl methacrylate (2) (4.97 g, 49.6 mmol) and Lithium chloride (0.70 g, 17 mmol) was mixed at room temperature, and the mixture was heated to 80°C and stirred for 4 hours. The reaction solution was cooled to 25°C, a 9.1% aqueous sodium chloride solution (7.70 g) was added, and the aqueous layer was removed by liquid separation. After adding toluene (5.21 g) to the resulting organic layer, a methanol solution (4.46 g) of p-toluenesulfonic acid, prepared by dissolving p-toluenesulfonic acid monohydrate (2.88 g, 15.1 mmol) in methanol (1.58 g), was added. This reaction solution was added to toluene (6.94 g) cooled to 0°C, and the mixture was stirred at 0°C for 30 minutes. The precipitated solid was collected by filtration to obtain a seed crystal (1.60 g, 24.6%) of compound (3). Example 1-1 Synthesis of compound (3) [Chemical formula 43] LfrRznn / zznz / E / YiAi At room temperature, ptoluenesulfonic acid monohydrate (1.57 g, 8.25 mmol) and methyl methacrylate (2, 49.57 g, 495.1 mmol) were added to (R)-(+)-1 phenylethylamine (1) (20.00 g, 165.0 mmol), and the mixture was heated to 99°C and stirred at 99°C for 16 hours. After cooling the mixture to At 25°C, methanol (8 mL) was added and mixed with a p-toluenesulfonic acid solution prepared by dissolving p-toluenesulfonic acid monohydrate (27.31 g, 143.6 mmol) in ethyl acetate (40 mL) and methanol (4 mL). Ethyl acetate (100 mL) was added to this reaction solution at 25°C and the precipitated solid was collected by filtration to obtain compound (3) (28.14 g) as a crude product. Ethyl acetate (15 mL) and methanol (30 mL) were added to the crude product (28.14 g) of compound (3), and the mixture was heated to 60°C and then cooled to 40°C. A seed crystal suspension (20.0 mg, 0.308 mmol) of compound (3) in ethyl acetate (60 mL) at 40°C was added to the mixture. After the resulting suspension was stirred at 40°C for 30 minutes and then cooled to 22°C, ethyl acetate (218 mL) was added, the mixture was cooled to 0°C, and stirred for 1 hour. The precipitated solid was collected by filtration to obtain compound (3) (22.29 g, 34.32%). Example 2 Synthesis of compound (4) [Chemical formula 44] (4) Lfrfiznn / zznz / B / YiAi Toluene (95.26 g) and water (44.00 g) were added to compound (3) (22.00 g, 55.91 mmol) to suspend compound (3). An aqueous solution of 8% sodium hydroxide (27.54 g) and water (4.40 g) were added, and an aqueous layer was removed by liquid separation. Water (11.00 g) was added to the resulting organic layer, and the aqueous layer was removed by liquid separation. The resulting organic layer was then concentrated under reduced pressure at 50°C with the addition of methanol to replace the solvent. Concentrated sulfuric acid (2.04 g, 19.8 mmol), 10% palladium on carbon (2.20 g, approximately 40% wet), and methanol (17.41 g) were added to the resulting concentrated solution. The reaction solution was It was heated to 40°C and stirred for 90 minutes in a hydrogen atmosphere. The palladium was removed over carbon by filtration, and methanol (52.24 g) and concentrated sulfuric acid (0.67 g, 6.5 mmol) were added to the resulting filtrate.The operation of adding acetonitrile to the obtained reaction solution was repeated and the concentration was reduced under reduced pressure so that the solvent was replaced with acetonitrile and the reaction solution was cooled to 0°C. The precipitated solid was collected by filtration to obtain compound (4) (8.58 g, 92.3%). Elemental analysis: C 35.72%, H 7.18%, N 8.55%, S 9.63% NMR iHYDMSO-de) δ ppm: 1.10 (d, J=7.1 Hz, 3H), 2.62 (m, 1H), 2.75 (dd, J=12.7H, 5.9 Hz, 1H), 2.89 (dd, J= 12.7 Hz, 7.3 Hz, 1H), 3.63 (s, 3H). LfrRznn / zznz / E / YiAi Reference example 1. Synthesis of compound (5) [Chemical formula 45] Lfrfiznn / zznz / B / YiAi OO Compound (4) (19.00 g, 114.3 mmol) was suspended in acetonitrile (45.00 g). At 2°C, 1,8-diazabicyclo[5.4.0]-7-undecene (19.10 g, 125.5 mmol) and acetonitrile (3.00 g) were added, and the mixture was stirred at 2°C for 30 minutes. The reaction solution was added, at 2°C, to a suspension obtained by suspending N,N-carbonyldiimidazole (21.30 g, 131.4 mmol) in acetonitrile (75.00 g). Acetonitrile (15.00 g) was added to the reaction solution, and the mixture was stirred at 2°C for 1 hour and 22 minutes. At 2°C, 1,8-diazabicyclo[5.4.0]-7-undecene (17.40 g, 114.3 mmol) and acetonitrile (3.00 g) were added to the reaction solution, and the mixture was cooled to 1°C. 1H-Pyrazol-L-carboxamidine hydrochloride (16.80 g, 114.6 mmol) and acetonitrile (3.00 g) were added to the reaction solution. The reaction solution was heated to 60°C and stirred for 2 hours and 10 minutes. The reaction solution was cooled to 20°C. At 2°C, 1,8-diazabicyclo[5.4.0]-7-undecene (17.40 g, 114.3 mmol) and acetonitrile (3.00 g) were added to the reaction solution.0]-7-undecene (27.80 g, 182.6 mmol) and acetonitrile (3.00 g), and the mixture was cooled to -10°C. The reaction solution was added. N,N-Carbonyldiimidazole (29.70 g, 183.2 mmol) and acetonitrile (3.00 g) were added to the reaction solution. The reaction solution was stirred at 2°C for 1 hour and 20 minutes. Methanol (7.50 g), acetic acid (4.80 g, 79.9 mmol), and acetonitrile (3.00 g) were added to the reaction solution at 2°C. The reaction solution was concentrated under reduced pressure at 50°C. N,N-Dimethylacetamide (27.00 g) was added to the resulting concentrated solution, the mixture was cooled to 10°C, and 17% aqueous sulfuric acid (204.1 g) and water (19.00 g) were added. Aqueous sulfuric acid (17%) (31.30 g) and water (2.50 g) were added to the reaction solution at 25°C, and the mixture was stirred for 1 hour and 48 minutes. The reaction solution was concentrated under reduced pressure at 50°C. Water (190 mL) was added to the resulting concentrated solution, and it was cooled to 2°C. Then, aqueous sulfuric acid (3.30 g) and water (1.30 g) were added.The reaction solution was stirred at 2°C for 1 hour and 15 minutes and the precipitated solid was collected by filtration to obtain compound (5) (27.13 g, 85.0%). NMR (CDCla) δ ppm: 1.24 (d, J=7.1 Hz, 3H), 3.02 (m, 1H), 3.68 (s, 3H), 4.02 (dd, J=13.4 Hz, 6.3 Hz, 1H), 4.24 (dd, J=13.3 Hz, 8.4 Hz, 1H), 6.60 (dd, J=2.8 Hz, 1.6 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H) , 8.48 (dd, J=2.9 Hz, 0.6 Hz, 1H) , 9.70 (brs, 1H) . Reference example 2. Synthesis of compound (8) [Chemical formula 46] Lfrfiznn / zznz / B / YiAi (6) (7) (8) [1] Synthesis of compound (8) Sodium tert-butoxide (12.50 g, 130.1 mol) was suspended in N-methyl-2-pyrrolidone (64.00 g), and 4-aminophenol (7) (14.10 g, 129.2 mmol) and N-methyl-2-pyrrolidone (16.00 g) were added. The reaction solution was heated to 100°C, and 2-bromopyridine (6) (19.50 g, 123.4 mmol) and N-methyl-2-pyrrolidone (4.00 g) were added. The reaction solution was stirred at 115°C for 8 hours and 20 minutes and then cooled to 50°C. Water (29.00 g) was added to the reaction solution at 50°C. The reaction solution was cooled to 25°C, and water (107.00 g) was added. Seed crystals (8, 20 mg) of compound (8) and water (195 mg) were added to the reaction solution, and the mixture was stirred at 20°C for 50 minutes. Water (156.00 g) was added to the reaction solution at 25°C, the reaction solution was cooled to 5°C, and it was stirred for 1 hour and 30 minutes. The precipitated solid was collected by filtration to obtain compound (8) (17.81 g, 77.5%). NMR (CDCla) δ ppm: 3.60 (s, 2H) , 6.69-6.73 (m, 2H) , 6.83 (ddd, J=8.4 Hz, 0.8 Hz, 0.8 Hz, 1H), 6.92-6.96 (m, 3H) , 7.63 (ddd, J=8.0 Hz, 7.2 Hz, 2.0 Hz, 1H), 8.18 (ddd, J=5.2 Hz, 2.0 Ηζ, 0.8 Ηζ, 1Η) . [2] Síntesis del cristal semilla del compuesto (8) Sodium tert-butoxide (3.20 g, 33.3 mmol) was suspended in N-methyl-2-pyrrolidone (16.42 g), and 4-aminophenol (7) (3.64 g, 33.4 mmol) and N-methyl-2-pyrrolidone (4.12 g) were added. The reaction solution was heated to 100°C, and 2-bromopyridine (6) (5.01 g, 31.7 mmol) and N-methyl-2-pyrrolidone (1.10 g) were added. The reaction solution was stirred at 115°C for 6 hours, and sodium tert-butoxide (1.07 g, 11.1 mmol) was added. The mixture was stirred at 115°C for 2 hours and 35 minutes and then cooled to 50°C. Water (7.50 g) was added to the reaction solution at 50°C, and the reaction solution was then cooled to 25°C. Water (67.54 g) was added, and the solution was cooled to 1°C for crystallization. After stirring the resulting suspension at 5°C for 30 minutes, the precipitated solid was collected by filtration to obtain a seed crystal (3.84 g, 65.2%) of compound (8). Reference Example 3. Synthesis of compound (9) [Chemical formula 47] LfrRznn / zznz / E / viaA [1] Synthesis of compound (9) Sodium bromide (4.1 g, 39.9 mmol) and N,N-dimethylacetamide (27.70 g) were added to compound (5) (10.13 g, 36.27 mmol). N,N-Diisopropylethylamine (5.16 g, 39.9 mmol) and N,N-dimethylacetamide (0.96 g) were added to the reaction solution and the mixture was heated to 75°C. A solution of 4-chlorobenzyl chloride in N,N-dimethylacetamide, prepared by dissolving 4-chlorobenzyl chloride (6.43 g, 39.9 mmol) in N,N-dimethylacetamide (9.56 g), was added to the reaction solution at 75°C. The reaction solution was stirred at 75°C for 5 hours and 15 minutes. The reaction solution was cooled to 25°C, acetic acid (0.65 g, 11 mmol) was added, and the mixture was heated to 40°C. A solution of compound (8) in N,N-dimethylacetamide was added to the reaction solution. This solution was prepared by dissolving compound (8) (7.43 g, 39.9 mmol) in N,N-dimethylacetamide (9.55 g).The reaction solution was stirred at 40°C for 3 hours and cooled to room temperature. Acetone (27.94 g) and water (35.46 g) were added to the reaction solution. A seed crystal (10.13 mg) of compound (9), water (0.40 g), and acetone (0.08 g) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours and 25 minutes and then left overnight. After stirring the reaction solution at room temperature for 1 hour, water (30.39 g) was added, and the mixture was stirred for another 3 hours and 25 minutes. The precipitated solid was collected by filtration. LfrRznn / zznz / E / YiAi obtain compound (9) (16.72 g, 88.3%). NMR (CDCla) δ ppm: 1.19 (d, J=7.1 Hz, 3H), 2.91(m, 1H), 3.61 (s, 3H), 3.90 (dd, J=13.6 Hz, 6.2 Hz, 1H), 4.12(dd, J=13.6 Hz, 8.4 Hz, 1H), 5.18 (d, J=14.2 Hz, 1H), 5.22(d, J=14.2 Hz, 1H), 6.85 (m, 2H), 6.96 (m, 1H), 7.00 (m, 1H),7.14 (m, 2H), 7.31 (m, 2H), 7.50 (m, 2H), 7.70 (m, 1H), 7.89 (brs, 1H) , 8.14 (m, 1H) . [2] Síntesis del cristal semilla del compuesto (9) Sodium bromide (2.00 g, 19.4 mmol) and N,N-dimethylacetamide (13.67 g) were added to compound (5) (5.01 g, 17.9 mmol). N,N-Diisopropylethylamine (2.55 g, 19.7 mmol) and N,N-dimethylacetamide (0.47 g) were added to the reaction solution and the mixture was heated to 75°C. A solution of 4-chlorobenzyl chloride in N,N-dimethylacetamide, prepared by dissolving 4-chlorobenzyl chloride (3.16 g, 19.6 mmol) in N,N-dimethylacetamide (4.71 g), was added to the reaction solution at 75°C. The reaction solution was stirred at 75°C for 4 hours and 30 minutes. The reaction solution was cooled to 25°C, acetic acid (0.32 g, 5.3 mmol) was added, and the mixture was heated to 40°C. A solution of compound (8) in N,N-dimethylacetamide was prepared by dissolving compound (8) (3.66 g, 19.7 mmol) in N,N-dimethylacetamide (4.71 g), and N,N-dimethylacetamide (4.71 g) was added to the reaction solution. The reaction solution was stirred at 40°C for 3 The reaction solution was heated to 25°C and stirred for 5 hours and 25 minutes and cooled to room temperature. Acetone (13.79 g) and water (17.54 g) were added to the reaction solution. The reaction solution was allowed to stand overnight at room temperature. After the reaction solution was heated to 25°C and stirred for 5 hours, water (15.00 g) was added and the mixture was stirred at 25°C for 2 hours. The precipitated solid was collected by filtration to obtain a seed crystal of compound (9) (8.17 g, 87.2%). Example 3 Synthesis of the compound represented by Formula (I) [Chemical Formula 48] (9) (I) Lfrfiznn / zznz / B / YiAi [1] Synthesis of the compound represented by Formula (I) To compound (9) (70.00 g, 134.1 mmol), 2-propanol (109.91 g), water (63.00 g), and a 48% aqueous sodium hydroxide solution (27.94 g, 335.3 mmol) were added. The reaction solution was heated to 35°C and stirred for 4 hours and 10 minutes. 2-propanol (32.97 g), methanol (177.30 g), and water (63.00 g) were added to the reaction solution, and the mixture was heated to 50°C. Formic acid (18.52 g, 402.3 mmol) and the seed crystal of the compound represented by formula (I) (70.00 mg) were added to the reaction solution, and the mixture was stirred at 50°C for 1 hour and 10 minutes. Then, water (280.00 g) was added, and the mixture was cooled to 25°C. The precipitated solid was collected by filtration to obtain anhydrous crystalline Form I of the compound represented by Formula (I) (62.86 g, 92.3%). NMR2Η (CDC13) δ ppm: 1.13 (d, J=7.0 Hz, 3H) , 2.76 (m, 1H) , 3.83 (dd, J=13.5 Hz, 6.1 Hz, 1H) , 4.03 (dd, J=13.5 Hz, 13.5 Hz, 1H) . 5.14 (m, 1H), 5.25 (d, J=14.4 Hz, 1H), 6.82 (d, J=8.6 Hz, 2H), 7.00 (m, 2H), 7.08 (m, 2H), 7.25 (m, 2H), 7.43 (d, J, 8.3 Hz, 7.7 Hz) (m, 1H) , 8.06 (dd, J=5.4 Hz, 1.8 Hz, 1H), 8.67 (brs, 1H). [2] Synthesis of the crystal seed of the compound represented by Formula (I) Methanol (5.95 g), water (3.00 g), and a 48% aqueous sodium hydroxide solution (0.60 g, 7.20 mmol) were added to compound (9) (1.50 g, 2.87 mmol). The reaction solution was heated to 40°C and stirred for 1 hour and 30 minutes. The reaction solution was cooled to room temperature, and formic acid (0.40 g, 8.62 mmol), ethyl acetate (10.5 mL), and water (9 mL) were added at room temperature. An aqueous layer was removed by liquid separation. Water (3 mL) was added to the resulting organic layer, another aqueous layer was removed by liquid separation, and 2 LfrRznn / zznz / E / YiAi propanol (90 mL) was added to the organic layer, and the mixture was concentrated under reduced pressure at 40°C. Water (7.5 mL) and 2-propanol (7.5 mL) were added to the resulting concentrated residue, and the mixture was stirred at 25°C for 1 hour and 30 minutes. Water (7.5 mL) and methanol (7.5 mL) were then added, and the mixture was heated to 60°C, stirred for 2 hours, and cooled to 25°C. The precipitated solid was collected by filtration to obtain a seed crystal (10, 1.25 g, 85.6%) of an anhydrous form I crystal of the compound represented by formula (I). The results of powder X-ray diffraction of the anhydrous crystalline Form I of the compound represented by Formula (I) are shown in Figure 1 (Method 1). In the X-ray diffraction spectrum of powder, the peaks are recognized at: diffraction angles (29) of: 12.6°±0.2°, 12.9°±0.2°, 15.8°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2°, 25.4°±0.2°, 26.6°±0.2°, 27.8°±0.2° and 32.8°±0.2°; or diffraction angles (29) of 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2°, 17.2°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9° ±0.2°, 25.4°±0.2° and 27.8°±0.2°. In the powder X-ray diffraction spectrum, the peaks at the following diffraction angles (29) are particularly characteristic of the anhydrous crystalline Form I of the compound represented by Formula (I): 15.8°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2°; and LfrRznn / zznz / E / YiAi 25.4°±0.2°; or 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2° and 19.4°±0.2°. The Raman spectrum results of the anhydrous crystalline Form I of the compound represented by Formula (I) are shown in Figure 2 (Method 1). The main absorption peaks are recognized at 829 cm ^cm-1, 989 cm-1±2 cm-1, 1013 cm-1±2 cm-1, 1093 cm-1±2 cm-1, 1128 cm-1±2 cm-1, 1243 cm-1±2 cm-1, 137 0 cm-1!! cm-1, 1599 cm-1!! cm-1, 1659 cm-1±2 cm-1, 1735 cm-1!! cm-1, 2938 cm-1!! cm-1 and 3067 cm-1!! cm-1. In one modality, Form I of the anhydrous crystal of the compound represented by Formula (I) has absorption peaks at 829 cm-1!! cm-1, 989 cm-1±2 cm-1, 1013 cm-1!! cm-1, 1128 cm-1± 2 cm-1 and 1370 cm-1!! cm-1. In one modality, the anhydrous crystalline Form I of the compound represented by Formula (I) has an absorption peak of 829 cm-1± 2 cm-1. In one modality, the anhydrous crystalline Form I of the compound represented by Formula (I) has an absorption peak of 989 cnu1± 2 cm-1. In one modality, the anhydrous crystalline Form I of the compound represented by Formula (I) has an absorption peak of 1013 cnu1± 2 cm-1. In one modality, the anhydrous crystalline Form I of The compound LfrRznn / zznz / E / viA represented by Formula (I) has an absorption peak of 112 8 cnu1± 2 cm-1. In one modality, the anhydrous crystalline Form I of the compound represented by Formula (I) has an absorption peak of 137 0 cm-1± 2 cm-1. In one embodiment, the anhydrous crystalline Form I of the compound represented by Formula (I) has one or more absorption peaks selected from the group consisting of an absorption peak at 829 cm-1+2 crr1, an absorption peak at 989 cmT± 2 cm-1, an absorption peak at 1013 cnr^ cnu1, an absorption peak at 1128 cm-1±2 cnu1 and an absorption peak at 1370 cm1±2 cm-1. The results of the DSC analysis of the anhydrous crystalline Form I of the compound represented by Formula (I) are shown in Figure 3. The starting temperature was approximately 196°C. The results of the analysis of the single-crystal structure of the anhydrous crystalline Form I of the compound represented by Formula (I) are shown below. The crystallographic data are shown in Table 4. Table 4 Space group P1 a (A) 9.8720(5) b (Á) 10.9952(5) c (A) 12.2781(6) α (Ί 67.712 (4) β (Ί 80.870 (4) y (Ί 86.935 (4) V (Á3) 1217.50 (11) z 2 Density (calculated value) (g / cm3) 1.386 Measured temperature (K) 298.15 LfrRznn / zznz / E / YiAi Here, V represents the volume of a unit lattice and Z represents the number of molecules in the unit lattice. The atomic coordinates of atoms other than hydrogen are shown in Tables 5 to 7. Here, U (eq) means an equivalent isotropic temperature factor. Table 5 The atom X yz U (eq) C12 2485 (2) 7006(2) -759.2(19) 104.9(7) CU 7426.0(16) 2947.5(18) 10766.8(15) 88.4 28(5) N 7834 (3) 46.5(9) Atom xyz U (eq) N9 7630(4) 7464(4) 4017 (4) 50.4(9) N2 1056 (4) 4687(4) 8118 (4) 51.9(5)35 9435 (4) 44.5(10) 05 5867 (3) 1451 (3) 5338 (3) 63.8(8) N8 8842 (4) 5752 (4) 3669 (4) 50.7(10) C9 394 (5) 5906(5) 7725 (5) 48.6(11) 02 1151 (4) 4145(4) 4553 (3) 65.3(10) 06 11217(6) 534 (5) 3496 (4) 86.5(15) 012 1387(5) 4061 (5) 7442 (4) 44.9(10) C21 4123 (5) 1390 (5) 10288 (4) 48.7(11) 03 3152 (4) 1150 (4) 7525 (4) 69.7 (11) 07 8862 (4) 6055(4) 5375 (4) 73.6(12) 08 6672(5) 8973 (4) 2517 (4) 76.4 (12) N3 1081 (4) 4424 (4) 6293 (3) 47.9(9) 06 -895(6) 8306(6) 7034(5) 61.0(14) 04 5488 (6) 3422(5) 5303 (6) 122 (2) 01 -1611(5) 9501 (4) 6620 (4) 72.8(12) N4 2263 (4) 2677 (4) 5979 (3) 46.6(9) NI -2337(5) 11398 (4) 6748 (4) 61.2(11) CU -1514(6) 7271(6) 7984 (5) 62.9(14) C39 7334 (5) 7962(5) 2859 (5) 53.8(12) C26 11309(6) -350(6) 2949 (6) 61.7(14) N10 7785 (4) 7278 (4) 2156 (4) 54(1) Átomo X yz U (eq) C13 1468 (4) 3771(5) 5546(4) 46.8(11) 027 10625(6) -195(6) 2050(5) 62.2(14) N7 8777(5) 5455(4) 1869(4) 56.6(11) LfrRznn / zznz / E / YiAi C19 5944 (5) 2756(5) 10236(5) 56.2(12) C15 2220(5) 2247(5) 9106 (4) 50.8(12) C35 8767 (6) 3165(65(6) C3357) 5306(6) 1541(5) 10695(5) 58.4(14) C43 4464 (7) 6225(6) 638(6) 77.4(18) CIO -861 (6) 6078 (6) 8345. (85) . Retail / sales / E / YiAi Table 6 Atom X yz U (eq) C14 2559(5) 2162(5) 7135 (4) 47.9(11) C3 -797 (7) 11219(6) 8455(6) 71.5(16) C42 5746 286 (4.6) (16) C25 5201 (4) 2540 (5) 5041 (5) 59.2 (11) C33 10562(6) 3952(6) 1643 (5) 63.7 (14) C45 4543(6) 84-465.3 C 9349 (7) 1932(6) 3659 (6) 67.0 (14) C37 8488(5) 6084(5) 2556(4) 48.2(11) C22 2781 (6) 1991(5) 5161(1) 3587(5) 6986 (5) 6771(5) 57.1 (12) C38 8481 (5) 6386 (5) 4415(5) 51.8 (12) Atom X yz U (eq) C23 4057(6) 2625 C24(6) 4372 (6) 7882 (6) 887(5) 60.1(13) C17 4243(6) 3641(6) 8995(6) 67.1(16) C2 -706 (6) 10229(6) 8011(5) 61.3 (14) C48 5436(6) 7790(5) 5213(6) 75.3(15) C47 7008 (5) 8083(5) 4823(5) 57.3 (13) C7 357 (6) 8178(5) 6432(6) 62.8(14) C29 11615 (9) -2201(9) 1989 (10) 102 (3) C5 -2364 (7) 12341 (6) 7181 (7) 75.4(17) N6 12158 (7) -1341 (7) 3399 (7) 101 (2) C4 -1580 (7) 12266(7) 8041(6) 76.8(17) C44 3942(6) 7268 (6) -236(6) 67.4 (16) C34 9370(5) 4183(5) 2302 (4) 50.9 (12) C28 10776 (8) -1146(8) 1577 (7) 87 (2) C46 5696(6) 8637 (5) -274(5) 55.9(13) C18 5428(6) 3801 (6) 9379(6) 72.0(17) 01 -1548 (6) 10380(5) 7151(5) 55.8 (12) C32 11169 (7) 2719 (7) 2022 (6) 72.8(17) C31 10575 (7) 1732(6) 3028(5) 64.7(15) 041 6282(5) 7645(5) 579 (4) 50.7 (12) 024 4458(8) 1956(11) 3447 (7) 116(3) 030 12262 (10) -2294(9) 2895 (10) 108 (3) O10 4974 (11) 6061 (7) 4658 (8) 178(4) Átomo X yz U (eq) 050 5087 (8) 6417 (7) 5478 (7) 95(2) LfrRznn / zznz / E / YiAi Lfrfiznn / zznz / B / YiAi Tabla 7 Atom The atomic coordinates of the hydrogen atoms are shown in Tables 8 and 9. Here, U (iso) signifies an isotropic temperature factor. The numbers of hydrogen atoms in Tables 8 and 9 were assigned relative to the number of non-hydrogen atoms bonded to them. Table 8 Atom 8382.1 75 H27 10069.67 531.08 1757.55 75 H15A 2067.68 1310.62 9351.81 61 H15B 1497.97 2573.94 9556.73 61 H35 7956.48 3311.88 3730.76 72 H2 0 5667.21 833.82 11271.28 70 Atom 100 H3A -297.7 11150.91 9057.25 86 H42 6008.86 5728.15 1629.39 82 H33 10953.5 4619.29 949.33 76 H45 4185.23 9145.91 -1286.06 74 H36 8922.52 1244.53 4318.29 80 H22A 2066.94 1977.02 4712.78 70 H22B 2984.22 1087.66 5637.74 70 H8A 1852.43 6897.22 6360.72 69 H23 3869.03 3552.19 3869.51 85 H4 0A 8359.19 7555.79 439.33 72 H40B 7769.65 8823.57 624.36 72 H17 3883.02 4354.24 8424.64 81 H2 -128.04 9513.17 8265.23 74 H48 4971.94 8339.68 4545.7 90 H47A 7150.32 9026.02 4438.25 69 H47B 7459.01 7775.33 5525.24 69 H7 769.29 8894.74 5794.62 75 H2 9 11730.8 -2832.7 1649.99 122 H5A -2923.15 13066.86 6898.98 90 H4 -1599.17 12938.91 8326.23 92 H2 8 10297.82 -1073.81 960.63 105 Átomo 2566.14 1591.72 87 LfrRznn / zznz / E / Yi 101 Lfrfiznn / zznz / B / YiAi Tabla 9 Atom 12805.06 -3025.75 3202.32 130 H10 4972.25 5256.08 4903.89 267 H4 9A 5188.95 7556.53 6980.6 182 H49B 3912.1 8211.16 6373.01 182 H49C 5249.84 9039.79 6125.23 182 H5 6580 (60) 1560(80) 5680 (70) 140 (30) In addition, interatomic bond distances (unit: angstrom) are shown in Tables 10 to 11. Table 10 Atom Atom Length / A Atom Atom Length / A C12 C44 1,744 (6) C26 C27 1,336 (8) CU C19 1,746 (5) C26 N6 1,337 (8) N5 C12 1,387 (6) N10 C37 1,403 (6) Atom Atom Length / A Atom Atom Length / A N5 C15 1.474 (6) N10 C40 1.473 (7) N5 C14 1.390 (6) C27 C28 1.368(9) N9 C39 1.389(6) N7 C37 1.271 (7) N9 C38 1.390(6) N7 C34 1,423(6) 102 N9 C47 1.448 (7) C19 C20 1.381 (8) N2 C9 1.405 (6) C19 018 1.370 (8) N2 C12 1.262 (6) C35 C36 1.381 (8) C16 C21 1.388 (6) C35 C34 1.380 (8) C16 C15 1.513 (7) C43 042 1.396(9) C16 C17 1.370 (8) C43 C44 1.383 (8) 05 C25 1.288(5) C3 02 1.384 (8) N8 C37 1.371(6) C3 C4 1.329 (9) N8 C38 1.344(6) C42 C41 1.387 (8) C9 CIO 1.391 (7) C25 023 1.527 (7) C9 C8 1.392 (8) C33 C34 1.388 (7) 02 C13 1.216(6) C33 C32 1.392 (8) 06 C26 1.367 (7) C45 044 1.339 (9) 06 C31 1.386 (7) C45 C46 1.375 (8) 012 N3 1.391(6) C36 031 1.385(9) 021 C20 1.382 (7) C22 023 1.514 (8) 03 C14 1.194(5) C8 C7 1.369 (7) 07 C38 1.210(6) C23 C24 1.501 (9) 08 C39 1.222(6) C40 041 1.505 (8) Átomo Átomo Longitud / A Átomo Átomo Longitude / A N3 C13 1.364 (6) C17 C18 1.372 (8) 06 01 1.412(6) C2 Cl 1.401 (8) 06 CU 1.368(9) C48 C47 1.563 (8) 06 C7 1.365 (8) C48 C50 1.467 (8) LfrRznn / zznz / E / Yi 103 04 C25 1,191(6) C48 049 1,532(10) 01 C1 1,364 (6) C29 C28 1,368 (12) N4 C13 1,375 (5) C29 C30 1,337 (13) N4 C14 1,388 (6) C5 C4 1,381 (9) N4 C22 1,481 (6) N6 C30 1,398 (12) Table 11 Atom Atom Length / A Atom Atom Length / A NI C5 1,331 (7) C46 C41 1,371(7) NI C1 1,309 (7) C32 C31 1,366(10) CU CIO 1,376 (8) O10 C50 1,231 (10) C39 N10 1,359(7) C50 09 1,178(13) In the anhydrous crystalline Form I of the compound represented by Formula (I), two molecules of the compound represented by Formula (I) were present in an asymmetric unit. The molecular structural diagrams of the compound represented by Formula (I) are shown in Figures 7 and 8, respectively. The numbers of non-hydrogen atoms in Tables 5 to 7 and Tables 10 and 11 correspond to the numbers shown in Figures 7 and 8, respectively. As shown in Tables 10 to 11, the bond distance of C12-N2 was approximately 1.26 Å and the bond distance of C37-N7 was approximately 1.27 Å. 104 Since the bond distance of C12-N2 and the bond distance of C37-N7 are shorter than the bond distance of C12-N3 (approximately 1.39 Å) and the bond distance of C37-N8 (approximately 1.37 Å), the compounds represented by formula (I) in Form I of the anhydrous crystal were identified as having an imino structure: [Chemical Formula 49] Lfrfiznn / zznz / B / YiAi Example 4 Effect achieved by the additive for accelerating the aza-Michael addition reaction [Chemical Formula 50] í'h ib © A reaction similar to the above reaction scheme is described in Tetrahedron Asymmetry, vol. 7, No. 3, pages 699-708, 1996 (Patent Document No. 16). In this literature, a product of an azaMichael addition reaction is obtained by heating and refluxing for 9 days, using methanol as the reaction solvent (74% yield). 105 diastereomeric mixture 1:1). Methyl methacrylate (compound 2), which is a raw material, is a compound used as a raw material for polymer synthesis and can polymerize when subjected to a high-temperature reaction for a long time. Therefore, these reaction conditions are not suitable for an industrial process method. On the other hand, it was found that, in the aza-Michael addition reaction described above, when lithium chloride, calcium chloride, magnesium chloride, lithium bromide, p-toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid were used as an additive, the reaction was accelerated as shown in Table 12 below. LfrRznn / zznz / E / YiAi Table 12 Additive Equivalent number with respect to compound (1) (eq.) Reaction temperature (°C) Reaction time (h) Conv. (%) * Lithium chloride 1 80 1.3 76 Lithium chloride 1 80 6.5 96 Calcium chloride 1 80 1 68 Additive Equivalent number with respect to compound (1) (eq.) Reaction temperature (°C) Reaction time (h) Conv. (%) * Magnesium chloride 1 80 4 74 Lithium bromide 1 80 6 95 p-Toluenesulfonic acid 0.1 100 4 78 106 p-Toluenesulfonic acid 0.1 100 7 85 Methanesulfonic acid 0.05 100 4 7 5 Methanesulfonic acid 0.05 100 7 84 Trifluoromethanesulfonic acid 0.05 80 5 77 LfrRznn / zznz / E / YiAi As in Example 1, the reactions were carried out under the respective conditions in Table 12 above. Samples were taken from each reaction solution while stirring, approximately 100 mg of the reaction solution was weighed, liquid chromatography methanol was added to dilute the solution to 100 mL, 10 pL of the diluted solution was injected, and HPLC was measured (Method A). *Conv. (%) was calculated using the following formula. [Mathematical Formula 1] A 3'+AV ---------------------------............... >1Q0 AUArW' Here, Al, A3' and A3 represent peak areas in the HPLC measurement, respectively. Al: Compound (1) A3': Compound (3') A3: Composite (3) Compound (3) has the following chemical structural formula. 107 [Chemical formula 51] Lfrfiznn / zznz / B / YiAi So far, only the reaction conditions for heating and refluxing for 9 days as described in Patent Document No. 16 are known, but the reaction is accelerated in the presence of these additives and is completed in a short time of 1 hour to 7 hours, so it can be said that the present process method is an industrially excellent process method. In Patent No. 16, after completing the aza-Michael addition reaction of (S)-1-phenylethylamine ((S)-α-methylbenzylamine) and methyl methacrylate, p-toluensulfonic acid is added to obtain a salt of p-toluensulfonic acid. On the other hand, in the present application, after completing the aza-Michael addition reaction of (R)-1-phenylethylamine ((R)-(+)-1-phenylethylamine) and methyl methacrylate, p-toluensulfonic acid is added to obtain p-toluensulfonic acid. That is, in Patent No. 16, the salt of p-toluensulfonic acid is obtained from an enantiomer of Formula (IV-B) of the present application; therefore, the present invention is not described in Patent No. 16. 108 [Chemical formula 52] LfrRznn / zznz / E / YiAi Example 5 Comparison of sulfate and hydrochloride isolation yields of compound (4')) [Chemical formula 53] Methanol and a 4 mol / L solution of ethyl acetate and hydrochloric acid were added to the filtrate after removing the palladium on carbon in the same manner as in the process method described in Example 2. Ethyl acetate was added as the crystallization solvent, and the concentration operation was repeated under reduced pressure. The solvent was replaced with ethyl acetate, and the mixture was cooled to 0°C. The precipitated solid was collected by filtration to obtain a hydrochloride of compound (4'). The sulfate of compound (4') was synthesized according to Example 2 described above. In the present, with respect to the insulation performance of the hydrochloride of the compound (4' or the sulfate of the compound 109 (4') and the filtrates after collecting the solid precipitated by filtration, approximately 200 mg of each and 15 mL of acetonitrile were weighed and 45 pL of triethylamine for liquid chromatography were added, then 15 pL of benzoyl chloride was added and acetonitrile for liquid chromatography was added to dilute each mixture to 20 mL, then 10 pL of the mixture was injected and measured by HPLC (Method B).Separately, as a standard solution for concentration calculation, approximately 10 mg of an isolated solid of the hydrochloride of compound (4') or the isolated solid of the sulfate of compound (4') were weighed out, and 15 mL of acetonitrile were added and 45 pL of triethylamine for liquid chromatography was added, then 15 pL of benzoyl chloride was added and acetonitrile for liquid chromatography was added to dilute the mixture to 20 mL, then 10 pL of the mixture was injected, HPLC was measured (Method B), and the concentration of compound (4') contained in the filtrate was calculated using the following formula. [Mathematical formula 2] Filtration loss (%) MsÁL= — x—xFiltration weight (g) / Theoretical yield (g)xl00 Here, Ms, Ml, As, and Al represent peak areas in the HPLC measurement, respectively. Ms: weighted amount (mg) of an isolated solid of compound (4') hydrochloride or compound (4') sulfate in 110 HPLC measurement. Ml: amount weighed (mg) of filtrate in HPLC measurement. As: peak area of ​​an isolated solid of compound hydrochloride (4') or compound sulfate (4') in HPLC measurement. Al: area of ​​the filtrate peak in the HPLC measurement. LfrRznn / zznz / E / YiAi Table 13 Inlet Salt Insulation performance (%) Filtration loss (%) Crystallization solvent 1 Hydrochloride 88.0 - AcOEt 2 Hydrochloride 83.0 7.1 AcOEt 3 Hydrochloride 79.0 10.3 AcOEt 4 Hydrochloride 82.9 6.2 AcOEt 5 Hydrochloride 83.4 6.5 AcOEt 6 Hydrochloride 77.0 3.0 AcOEt 7 Sulfate 92.4 2.5 MeCN 8 Sulfate 94.0 3.0 MeCN 9 Sulfate 91.9 1.8 MeCN 10 Sulfate 93.4 3.0 MeCN As is evident from Table 13, when compound (4') was isolated as a hydrochloride (entries 1 to 6), the isolation yield ranged from approximately 77% to approximately 88%. Furthermore, it was confirmed that approximately 3% to approximately 10% of a free form (compound (4')) had eluted in the filtrate. 111 On the other hand, when compound (4') was isolated as a sulfate (entries 7 to 10), a high isolation yield of approximately 92% to approximately 94% was achieved. The proportion of the free form eluted in the filtrate was approximately 2% to approximately 3%. Based on the previous results, it can be said that the method for producing compound (4') as sulfate is an industrially excellent process method because the amount of free form eluded in the filtrate is small, meaning that the loss during the process is small. Example 6 Suppression effect of racemization [Chemical formula 54] LfrRznn / zznz / E / YiAi Patent Documents 6, 7, 8, and 9 describe a process method for obtaining a carboxylic acid by hydrolyzing an ester, using dioxane, THF, DMSO, a MeOH-THF mixed solution, a THF-EtOH-water mixed solution, a MeOH-water mixed solution, a MeOH-THF-water mixed solution, or similar solvents as solvents. On the other hand, when isopropyl alcohol, THF, or tBuOH was used as the reaction solvent in the hydrolysis reaction, it was found that the racemization of a product was suppressed. 112 is shown in Table 14 below. Table 14 Solvent Reaction time (h) Reaction temperature (°C) R form of compound o) m* R form of compound represented by Formula (I) (%)** MeOH 1 40 0.43 0.93 EtOH 1 40 0.43 0.70 EtOH 2 40 0.43 0.68 Isopropyl alcohol 1 40 0.43 0.54 Isopropyl alcohol 2 40 0.43 0.53 THE 1 40 0.43 0.52 t-BuOH 0.5 50 0.44 0.48 As in Example 3, the reactions were carried out under the respective conditions in the table above. Approximately 100 mq of each reaction solution were weighed, liquid chromatography methanol was added to dilute the solution to 20 mL, 10 pL of the diluted solution was injected, and HPLC (Method C) was used for measurement. *The amount of the R form of compound (9) was calculated using the following formula. The unit represents a peak area (%) . [Mathematical Formula 3] % area of ​​the R isomer of the compound (9í --------------------------:---- XWO Area % of the compound (9) + % Area of ​​the R isomer of the compound (9) **The amount of R isomer of the compound represented by 113 Formula (I) was calculated using the following formula. The unit represents a peak area (%). [Mathematical Formula 4] Lfrfiznn / zznz / B / YiAi Area % of the R isomer of the compound represented by ia Formula (I) Area % of the compound represented by ia Formula (i) + Area % of the R isomer of the compound represented by Formula (I) x TOO The structural formulas of the R isomer of compound (9) and the R isomer of the compound represented by formula (I) are as follows. The molecular structures (amino form / imino form) of the R isomer of compound (9) and the R isomer of the compound represented by formula (I) have not been determined. [Chemical formula 55] R isomer of compound (9) R isomer of the compound represented by Formula (1) As described in Table 14 above, it was found that when methanol was used as the reaction solvent, racemization occurred and the amount of optical isomers increased from 0.43% to 0.93%. Similarly, with ethanol, the amount of optical isomers increased from 0.43% to approximately 0.7%. On the other hand, when alcohol was used 114 isopropyl, tetrahydrofuran and t-butanol, increased to approximately 0.5%. From the previous results, it was clear that when isopropyl alcohol, tetrahydrofuran, and tert-butanol were used, the proportion increased slightly with respect to the proportion of the R isomer initially contained in compound (9) as the starting material, and racemization was suppressed, compared to the case where methanol and ethanol were used as reaction solvents. Therefore, it can be said that the present process method is an industrially excellent method. Example 7 [1] Synthesis of the dihydrate crystal of the compound represented by Formula (I) To an anhydrous crystal form I (50.00 g, 98.43 mmol) of the compound represented by Formula (I), 2-propanol (314.02 g), water (150.00 g), and 48% sodium hydroxide (20.51 g, 246.1 mmol) were added and dissolved. To the resulting solution, 35% hydrochloric acid (25.64 g, 246.1 mmol) and a seed crystal of a dihydrate of the compound represented by Formula (I) (50.00 mg) were added. The mixture was then stirred at room temperature for 1 hour, followed by the addition of water (250.00 g) and stirring for another 2 hours. The resulting suspension was cooled to 5°C and filtered to obtain a dihydrate crystal (49.23 g) of the compound represented by Formula (I). LfrRznn / zznz / E / YiAi 115 The dihydrate crystal was confirmed by thermogravimetry / differential thermal analysis (TG / DTA), moisture absorption and desorption (DVS) measurement, and powder X-ray diffraction measurement. Figure 4 (Method 1) shows a powder X-ray diffraction pattern of the dihydrate crystal of the compound represented by Formula (I). Peaks at diffraction angles of 5.7°±0.2°, 7.7°±0.2°, 11.8°±0.1°, 15.1°±0.1°, 17.7°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 6.5°±0.2°, 27.1°±0.2° and 29.1°±0.2° are particularly characteristic of the dihydrate crystal of the compound represented by formula (I). The Raman spectrum results of the dihydrate crystal of the compound represented by Formula (I) are shown in Figure 6 (Method 2). The main absorption peaks are recognized at 871 cm-1±2 cm-1, 996 cm-1±2 cm-1, 1093 cm-1±2 cm-1, 1114 cm-1±2 cm-1, 1234 cm-1!2 cm-1, 1248 cm-1!2 cm-1, 1340 cm-1±2 cm-1, 1577 cm-1!2 cm-1, 1603 cm-1!2 cm-1, 1662 cm-1!2 cm-1, 1738 cm-1!2 cm-1, 2971 cm-1!2 cm-1 and 3073 cm-1! In one modality, the dihydrate crystal of the compound represented by Formula (I) has absorption peaks at 871 cm-1!! cm-1, 996 cm-1!! cm-1, 1114 am1!! crr1, 1!34 am1!! cm1, 134 0 am1!! am1y 157 7 cnu1!! cm-1. In one form, the dihydrate crystal of the compound LfrRznn / zznz / E / YiAi 116 represented by formula (I) has an absorption peak of 871 cm-1± 2 cm-1. In one modality, the dihydrate crystal of the compound represented by formula (I) has an absorption peak of 99 6 cm-1± 2 cm-1. In one modality, the dihydrate crystal of the compound represented by formula (I) has an absorption peak of 1114 cm-1± 2 cm-1. In one modality, the dihydrate crystal of the compound represented by formula (I) has an absorption peak of 1234 cm-1± 2 cm-1. In one modality, the dihydrate crystal of the compound represented by formula (I) has an absorption peak of 1340 cm-1± 2 cm-1. In one modality, the dihydrate crystal of the compound represented by formula (I) has an absorption peak of 157 7 cm-1± 2 cm-1. In one embodiment, the dihydrate crystal of the compound represented by Formula (I) has one or more absorption peaks selected from the group consisting of an absorption peak at 871 cm-1± 2 cm-1, an absorption peak at 996 cm-1± 2 cm-1, an absorption peak at 1114 cm-1!! cm-1, an absorption peak at 1234 cm-1!! crr1, an absorption peak at 1340 cm-1!! cm-1 and an absorption peak at 1577 cm-1!! cm-1. The results of the thermal analysis LfrRznn / zznz / E / YiAi 117 Differential / thermogravimetric (TG / DTA) results of the dihydrate crystals of the compound represented by Formula (I) are shown in Figure 5. As a result, from approximately 55°C to approximately 85°C, a weight loss of 6.4% was confirmed with an endothermic peak. Since the theoretical value of the moisture content of the dihydrate crystal of the compound represented by Formula (I) was 6.6%, it was confirmed that it was a dihydrate crystal of the compound represented by Formula (I). [2] Synthesis of the dihydrate seed crystal of the compound represented by Formula (I) To compound (9) (70.00 g, 134.1 mmol), 2-propanol (109.91 g), water (63.02 g) and 48% sodium hydroxide (27.95 g, 335.4 mmol) were added, and the mixture was stirred at 25°C for 4 hours. To the resulting reaction solution, 2-propanol (16.49 g), methanol (127.43 g) and water (217.00 g) were added, then formic acid (9.88 g, 215 mmol) was added at 25°C, and the mixture was stirred at 25°C for 35 minutes. To the resulting suspension, an aqueous solution of formic acid prepared by mixing formic acid (8.64 g, 188 mmol) and water (70.00 g) was added dropwise at 25°C, and then water (7.00 g) and methanol (27.70 g) were added. The resulting suspension was filtered to obtain a seed crystal of a dihydrate (64.04 g) of the compound represented by formula (I). Lfrfiznn / zznz / B / YiAi 118 Reference example 4 Synthesis of Compound 1-127 described in Patent Document 9 As described above, each step in producing compound 1-127 is not specifically described in Patent Document 9. Compound 1-127 was synthesized in the same manner as the similar compound 1-127 (Example Reference 3 of Patent Document 9). Only the final step is shown below. Lfrfiznn / zznz / B / YiAi [Chemical formula 56] Methyl (S,E)-3-(3-(4-chlorobenzyl)-2,6-dioxo-4-((4-(pyridin-2-yloxy)phenyl)imino)-1,3,5-triazinan-l-yl)-2-methylpropanoate (0.365 g, 0.7 mmol), MeOH (1 mL), THF (1 mL), H2O (1 mL), and an aqueous solution of 4 mol / L LiOH (0.7 mL, 2.80 mmol) were mixed and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to semi-saturated brine (100 mL) and a 5% citric acid solution, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was then washed with semi-saturated brine (100 mL). The organic layer was dried over magnesium sulfate and then 119 was removed by distillation under reduced pressure. The residue obtained was purified by column chromatography (ethyl acetate / hexane = 50:50 to ethyl acetate / hexane = 80:20), then recrystallized with a solvent mixture of ethyl acetate / hexane, collected by filtration and then dried under reduced pressure at 80°C for 3 hours to obtain a white powder. NMR (DMSO-d6) δ: 0.86 (1.5H, t, J = 6.8 Hz, hexane), 1.03 (3H, d, J = 6.8 Hz), 1.18 (0.75H, t, J = 7.4 Hz, AcOEt), 1.25 (2H, brs, hexane), 1.99 (0.75H, s, AcOEt), 2.76 (1H, t, J = 7.2 Hz), 3.81 (1H, t, J = 10.5 Hz), 3.95 (1H, t, J = 10.2 Hz), 4.03 (0.5H, q, J = 7.4 Hz, AcOEt), 5.29 (2H, s), 7.027.12 (4H, m), 7.36-7.45 (6H, m), 7.85 (1H, t, J = 7.5 Hz), 8.16 (1H, s), 9.34 (1H, brs). LC / MS m / z 508 [M+] Retention time 2.02 minutes. Here, LC / MS was measured under the conditions of Method 1 of Patent Document 9. The results of 1H NMR are shown in Figure 9. In the NMR spectrum graph, peaks of ethyl acetate and hexane were identified. Since the obtained crystal was dried under reduced pressure at 80°C for 3 hours, it was assumed that the resulting crystal was not an adhesion solvent on the crystal surface, but rather ethyl acetate and hexane contained within the crystal lattice. In TG / DTA (Figure 13), weight loss accompanied by endothermy was confirmed, and therefore Lfrfiznn / zznz / B / YiAi 120 Therefore, it was suggested that the crystal obtained was a hexane ethyl acetate solvate crystal. LfrRznn / zznz / E / YiAi Furthermore, from the 1H NMR integration relation, the molar abundance ratio of the compound represented by the formula: [Chemical formula 57] The ratio of ethyl acetate to hexane was approximately 4:1:1. Therefore, with respect to compound 1-127 described in Patent Document 9, an ethyl acetate / hexane solvate crystal of the compound represented by the formula: [Chemical formula 58] EITHER And oo A x - < W' γ* X 'OH — a was supposed to have been obtained (however, the molecular structure (amino form / imino form) is unknown). 121 Next, the powder X-ray diffraction pattern of the white powder obtained is shown in Figure 10 (Method 2). In the powder X-ray diffraction spectrum, the peaks are recognized at diffraction angles (2Θ) of: 8.3°±0.2°, 10.8°±0.2°, 13.4°±0.2°, 17.9°±0.2°, 19.4°±0.2°, 21.7°±0.2° and 25.6°±0.2°. The Raman spectrum result of the obtained crystal is shown in Figure 11 (Method 2). The main absorption peaks are recognized at 821 cm1±2 cm-1, 856 cm-1±2 cm-1, 893 cm-1±2 cm-1, 1002 cm-1±2 cm-1, 1094 cm-1± 2CTT1, 1221 cm-1±2 cnr1, 1269 cm-1+2 crtr1, 1575 cm-1±2 citr1, 1604cm-1±2 cm-1, 1614 cm-1±2 cnr1, 1649 cm-1±2 cm-1, 1725 cm-1±2 cm-1 and 3073 cm-1±2 cm-1. The main absorption peaks are recognized at 821 cmτ±2 crr1, 1002 0^12 cnu1, 1269 cm-1±2 cnn1, 1575 cm-1±2 or1, 1614 cm-1±2 cm-1, 1649 cm-1±2 cm-1 and 1725 cm-1. The main absorption peaks are recognized at 1575 cm-1±2 cm-1, 1614 cm-1±2 cm-1 and 164 9 cm-1±2 cm-1. The main absorption peaks are recognized at 1614 cm-1±2 cnu1y 164 9 cnu1!! cm-1. Example 8 Synthesis of the anhydrous crystalline Form II of the compound represented by Formula (I) A crystalline Form I was weighed in an ampoule LfrRznn / zznz / E / YiAi 122 anhydrous (approximately 10 mg) of the compound represented by Formula (I) was mixed with 200 pL of CHCl3. The mixture was stirred with a magnetic stirrer at 400 rpm at 25°C (overnight operation). After 7 days, the mixture was filtered and the resulting powder was confirmed by powder X-ray diffraction measurement. The X-ray diffraction pattern of the anhydrous crystalline Form II powder of the compound represented by Formula (I) is shown in Figure 12 (Method 3). In the powder X-ray diffraction spectrum, peaks are recognized at diffraction angles (2Θ) of 8.5°±0.2°, 12.Γ10.20, 16.4°±0.2°, 17.1°±0.2°, 18.1°±0.2°, 18.50±0.20, 20.3°±0.2°, 23.0°±0.2° and 24.7°±0.2°. In the powder X-ray diffraction spectrum, peaks are recognized at diffraction angles (2Θ) of 8.5°±0.2°, 12.1°±0.2°, 16.4°±0.2°, 17.1°±0.2° and 18.1°±0.20. Example 9 Flow test (compressibility index and Hausner ratio) Measurement method 1) Approximately 10 g of a sample were gently placed into a 50 mL measuring cylinder and Lfrfiznn / zznz / B / Yii 123 measured the amount of sample. 2) The top surface of the powder layer was carefully leveled without compaction and the loose apparent volume (Vo) was read. 3) The measuring cylinder was mounted on a stand of a powder tester (type PT-X, Hosokawa Micron Corporation). 4) The powder sample was tapped 10 times, 500 times, 1250 times, 2500 times and the corresponding bulk volumes (VIO, V500, V1250, V2500) were read. 5) The process was terminated when the volume difference was equal to or less than the minimum scale (0.5 mL), and the final bulk volume was defined as the final tap volume (Vf). 6) Steps 1) to 5) were repeated three times and measured, and the average values ​​were adopted for calculating the Compressibility Index and the Hausner ratio. compressibility index and method for calculating the Hausner ratio compressibility index = (Vo - Vf) / Vo x 100 Hausner ratio = Vo / Vf Results LfrRznn / zznz / E / YiAi The results are shown in Table 15. 124 LfrRznn / zznz / E / YiAi Table 15 Specimen Form I of anhydrous crystal of the compound represented by Formula (I) Ethyl acetate / hexane solvate crystal of the compound represented by Formula (I) Dihydrate crystal of the compound represented by Formula (I) Vo (mL) 19.0 36.3 30.7 Vf (mL) 14.2 23.3 19.7 Compressibility index (%) 25.4 36.7 35.9 Hausner ratio 1.3 1.6 1.6 As is evident from Table 15, the anhydrous crystalline Form I of the compound represented by Formula (I) was found to have the lowest Compressibility Index (%) and better flowability compared to the other two crystalline forms (Reference: PMDA material; from powder; compression measurements and Hausner ratio, extracted from Table 16). Table 16 Compressibility Index of Flow Character Hausner Ratio <10 Excellent 1.00-1.11 11-15 Good 1.12-1.18 16-20 Very good 1.19-1.25 21-25 Passable 1.26-1.34 125 Flow Character Index Hausner Ratio Compressibility (%) 26-31 Worse 1.35-1.45 32-37 Much worse 1.46-1.59 >38 Much, much worse >1.60 LfrRznn / zznz / E / YiAi In general, it is known that stable production can be achieved when the flowability of a pharmaceutical powder is high in a solid formulation process. Low flowability of pharmaceutical powders can cause bridging in a hopper of a powder processing apparatus, such as a tablet press, and increase tablet weight deviation. To produce a stable pharmaceutical powder, a crystalline form with high flowability is required, and the anhydrous crystalline form I of the compound represented by formula (I) has been found to be a particularly preferable crystalline form in a pharmaceutical formulation process. Example 10 Amount of residual solvent as specified in ICH guideline Q3C Hexane is a solvent (class 2) whose residual amount in the active pharmaceutical ingredient must be regulated, and ethyl acetate is a solvent of low toxicity (class 3). Therefore, it is necessary to adjust the residual amount of 126 hexane in the active pharmaceutical ingredient to a specified value or less. Table 17 below shows the LfrRznn / zznz / E / YiAi class 2 solvents listed in ICH guideline Q3C. Table 17 PDE Solvent limit value (mg / day) concentration (ppm) Acetonitrile 4.1 410 Chlorobenzene 3.6 360 Chloroform 0.6 60 Cyclohexane 38.8 3880 1,2-dichloroethene 18.7 1870 Dichloromethane 6.0 600 1,2-dimethoxyethane 1.0 100 N,N-dimethylacetamide 10.9 1090 N,N-dimethylformamide 8.8 880 1,4-dioxane 3.8 380 2-ethoxyethanol 1.6 160 Ethylene glycol 6.2 620 Formamide 2.2 220 Hexane 2.9 290 Methanol 30.0 3000 2-methoxyethanol 0.5 50 Methyl butyl ketone 0.5 50 127 Solvent PDE (mg / day) Limit value concentration of (ppm) Methylcyclohexane 11.8 1180 N-methylpyrrolidone 48.4 4840 Nitromethane 0.5 50 Pyridine 2.0 200 Sulfolane 1.6 160 Tetralin 1.0 100 Toluene 8.9 890 1, 1,2-trichloroethene 0.8 80 Xylene 21.7 2170 LfrRznn / zznz / E / YiAi The permissible daily exposure (PDE) for hexane is 2.9 mg / day. When the ethyl acetate / hexane solvate crystal of the compound represented by Formula (I) is used as an active pharmaceutical ingredient, the PDE for hexane may be equal to or greater than the regulatory value, depending on the dose. Furthermore, the anhydrous crystal and the dihydrate crystal of the compound represented by Formula (I) did not contain hexane as a residual solvent and were found to be excellent crystalline forms used for an active pharmaceutical ingredient. Example 11 Solid stability test Measurement method A 5 mg sample (n = 4) was accurately weighed in a 128 ampoules of 2 mL each were capped and stored at a predetermined temperature (sealed storage). Each sample was then extracted after a predetermined storage period and its stability (contents) was assessed. Storage conditions: 80°C, hermetically sealed. Storage period: one week Conditions for preparing the test solution Each ampoule was washed in a 25 mL volumetric flask. Dilution medium: acetonitrile / water = 1 / 1 HPLC measurement conditions Method D Results The results are shown in Table 18. LfrRznn / zznz / E / YiAi Table 18 Retention Time (min) / Peak Area (%) of Analogous Substance Conditions Residual Ratio (%) Purity (%) 3 5.8 10.1 10.5 14 15.5 16.9 17.1 18.3 20.6 Anhydrous Crystal Form 1 of the compound represented by Formula (1) Initial - 99.76 0.16 0.05 0.03 80°C1W 99.79 99.77 0.16 0.04 0.03 Ethyl acetate / hexane solvate crystal of the compound represented by Formula (1) Initial - 99.71 0.06 0.01 0.15 0.04 0.04 80°C1W 99.03 99.71 0.06 0.01 0.14 0.04 0.03 129 Dihydrate crystal of the compound represented by Formula (1) Initial - 99.91 0.09 80°C1W 99.13 99.86 0.05 0.09 In any of the crystalline forms, the residual proportion was 99% or higher, and it was found to be a stable crystalline form. Five types of analogous substances were generated in the ethyl acetate / hexane solvate crystal of the compound represented by Formula (I). Three types of analogous substances were generated in Form I of the anhydrous crystal of the compound represented by Formula (I), and two types of analogous substances were generated in the dihydrate crystal of the compound represented by Formula (I). Based on this, it was found that few types of analogous substances can be generated in Form I of the anhydrous and dihydrate crystals of the compound represented by Formula (I). The following formulation examples are merely examples and are not intended to limit the scope of the invention in any way. The compound of the invention can be administered as a pharmaceutical composition by any conventional route, in particular by enteral route, for example, orally, for example, in tablet or capsule form, or by parenteral route, for example, in injectable or suspension form; or topically, for example, in lotion form, 130 gel, ointment, or cream; or in nasal or suppository form. A pharmaceutical composition containing the compound of the invention in free form or as a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable vehicle or diluent can be conventionally produced by mixing, granulating, or coating. For example, the oral composition can be a tablet, granule, or capsule containing an excipient, disintegrant, binder, lubricant, or the like, as well as an active ingredient or the like. The injectable composition can be a solution or suspension, can be sterilized, or can contain a preservative, stabilizer, buffer, or the like. INDUSTRIAL APPLICABILITY The crystal of the compound represented by formula (I) of the present invention is useful as an active pharmaceutical ingredient. The pharmaceutical composition containing the crystal of the compound represented by formula (I) is very useful as a therapeutic or prophylactic agent for chronic cough. Furthermore, the present invention is useful as a method for producing the compound represented by formula (I). It is hereby stated that, as of this date, the best method known to the applicant for putting the aforementioned invention into practice is the one that is clear from the present description of the invention. LfrRznn / zznz / E / YiAi

Claims

LfrRznn / zznz / E / YiAi Having described the invention as above, the contents of the following claims are claimed as property:

1. Crystal, characterized in that it is a compound represented by the formula (I): or a solvate thereof.

2. Anhydrous crystalline form I of the compound according to claim 1, characterized in that it has, in a powder X-ray diffraction spectrum, characteristic peaks at: diffraction angles (2Θ) of: 15.8°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2° and 25.4°±0.2°; or diffraction angles (2Θ) of 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2° and 19.4°±0.2°.

3. Anhydrous crystalline form I of the compound according to claim 1, characterized in that it has, in a powder X-ray diffraction spectrum, characteristic peaks at: 132 diffraction angles (2Θ) of 12.6°±0.2°, 12.9°±0.2°, 15.8°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9°±0.2°, 25.4°±0.2°, 26.6°±0.2°, 27.8°±0.2° and 32.8°±0.2°; or differential angles (2Θ) of 7.9°±0.2°, 9.3°±0.2°, 12.9°±0.2°, 15.8°±0.2°, 17.2°±0.2°, 19.4°±0.2°, 21.7°±0.2°, 23.9° ±0.2°, 25.4°±0.2° and 27.8°±0.2°.

4. Anhydrous crystalline form I of the compound according to claim 1, characterized in that it has absorption peaks at 829 cm-1±2 cnr1, 989 cm-1±2 cm-1, 1013 cm-1±2 cnr1, 1128 cm-1±2 cir1 and 1370 cm-1±2 cnr1 in Raman spectrum.

5. Dihydrate crystal of the compound according to claim 1, characterized in that it has characteristic peaks at diffraction angles (2Θ) of 5.7°±0.2°, 7.7°±0.2°, 11.8°±0.2°, 15.2°±0.2° and 17.7°±0.2° in a powder X-ray diffraction spectrum.

6. Dihydrate crystal of the compound according to claim 1, characterized in that it has characteristic peaks at diffraction angles (2Θ) of 5.7°±0.2°, 7.7°±0.2°, 11.8°±0.2°, 15.2°±0.2°, 17.7°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 26.5°±0.2°, 27.1°±0.2° and 29.1°±0.2° in a powder X-ray diffraction spectrum.

7. Dihydrate crystal of the compound according to claim 1, characterized in that it has absorption peaks at 871 cm-1±2 cnr1, 996 cm-1±2 cm-1, 1114 cm-1±2 cnr1, 1234 cm-1±2 cnr1, 1340 cm-1±2 cim1 and 1577 cm-1±2 cnr1 in the Lfrfiznn / zznz / B / YiAi 133 Raman spectrum.

8. Pharmaceutical composition, characterized in that it contains the crystal in accordance with any of claims 1 to 7.

9. Process, characterized in that it is for producing the crystal in accordance with any of claims 1 to 7.

10. Process for producing a compound represented by Formula (IV): [Chemical Formula 2] Lfrfiznn / zznz / B / YiAi where R1 is a C1-C4 alkyl, or a salt thereof, characterized in that it causes a reaction between a compound represented by Formula (II): [Chemical Formula 3] or one of its salts, and a compound represented by Formula (III): [Chemical Formula 4] 134 Lfrfiznn / zznz / B / YiA where R1 is a C1-C4 alkyl, or one of its salts, in the presence of one or more additives selected from the group consisting of lithium chloride, calcium chloride, magnesium chloride, lithium bromide, p-toluensulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid.

11. The process according to claim 10, characterized in that the additive is lithium chloride.

12. Process for producing a salt of p-toluenesulfonic acid from a compound represented by Formula (IV-A): [Chemical Formula 5] H CH3 OA! x '° ' IV'A ' HH OH; wherein R1 is C1-C4 alkyl, characterized in that: a compound represented by formula (IV) or a salt thereof is obtained by the process according to claim 10 or 11, and p-toluenesulfonic acid is added.

13. Process for producing a salt of p-toluenesulfonic acid from a compound represented by Formula 135 (IV-A): [Chemical Formula 6] LfrRznn / zznz / E / viA wherein R1 is C1-C4 alkyl, characterized in that the additive is p-toluenesulfonic acid in the process according to claim 10.

14. The process in accordance with any of claims 10 to 13, characterized in that R1 is methyl.

15. Salt of p-toluenesulfonic acid, characterized in that it is of a compound represented by Formula (IV-B): [Chemical formula 7] (IV-B) 16. Process for producing the 1 / 2 sulfuric acid salt of a compound represented by Formula (V): [Chemical Formula 8] O characterized in that: a salt of p-toluenesulfonic acid of a compound represented by Formula (IV-B): [Chemical Formula 9] H CH v π j ,ch3 LfrRznn / zznz / E / YiAi is subjected to a hydrogenolysis reaction; and sulfuric acid is added.

17. Salt of 1 / 2 sulfuric acid, characterized in that it is of a compound represented by Formula (V): [Chemical formula 10] 18. Process for producing a compound represented by Formula (I): [Chemical Formula 11] or one of its salts, characterized in that: a compound represented by Formula (VI): 137 [Chemical Formula 12] LfrRznn / zznz / E / YiAi where R1 is C1-C4 alkyl, or one of its salts, is subjected to a hydrolysis reaction in the presence of one or more solvents selected from the group consisting of isopropyl alcohol, tetrahydrofuran and t-butanol.

19. Process according to claim 18, characterized in that R1 is methyl.

20. Process for producing a compound represented by Formula (VI): [Chemical Formula 13] characterized in that R1 is methyl, or one of its salts, wherein the process comprises the step of: producing a salt of p-toluenesulfonic acid from a compound represented by formula (IV-B): Lfrfiznn / zznz / B / YiAi [Chemical Formula 14] by the process in accordance with any of claims 10 to 14.

21. A process for producing a compound represented by Formula (VI): [Chemical Formula 15] (VI) characterized in that R1 is methyl, or one of its salts, wherein the process comprises the step of: producing a 1 / 2 sulfuric acid salt of a compound represented by Formula (V): [Chemical Formula 16] H CH3 by the process according to claim 16. 139 22. A process for producing a compound represented by Formula (VI): [Chemical Formula 17] LfrRznn / zznz / E / YiAi, wherein R1 is methyl, or one of its salts, characterized in that the process comprises the steps of: producing a salt of p-toluenesulfonic acid from a compound represented by Formula (IV-B): [Chemical Formula 18] H CH3 O ( IV-B ) HH CH3 by the process according to any one of claims 10 to 14; and producing a salt of 1 / 2 sulfuric acid from a compound represented by Formula (V): [Chemical Formula 19] O (V ) H CH3 140 by the process according to claim 16. LfrRznn / zznz / E / YiAi 23. Process for producing a compound represented by Formula (I): [Chemical Formula 20] or one of its salts, characterized in that: a compound represented by [Chemical Formula 21] or formula (VI): (V!) wherein R1 is methyl, or one of its salts, is obtained by the process in accordance with any of claims 20 to 22; and the compound represented by formula (VI) or the salt thereof thus obtained is subjected to a hydrolysis reaction in the presence of one or more solvents selected from the group consisting of isopropyl alcohol, tetrahydrofuran, and butanol.