Crystalline forms of urea compounds that antagonize LPA1 receptors and methods for producing them

Abstract

To provide stable crystalline forms in use environment of a urea compound which antagonizes an LPA1 receptor as a medicine, and a production method thereof.SOLUTION: The problem is solved by a crystal of a N-methyl-D-glucamine salt hydrate of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid (a) having peaks at 2θ=3.5°, 8.1°, 10.1°, and 14.6°in powder X-ray diffractometry (Cu-Kα), (b) having characteristic absorption bands of 1610 cm-1, 1556 cm-1, 1412 cm-1, and 1075 cm-1 in infrared absorption spectroscopy (ATR method), and (c) having endothermic peaks of 45°C-55°C, and 70°C-79°C in differential thermal analysis / thermal mass measurement (TG / DTA).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to crystalline forms of urea compounds that antagonize LPA1 receptors and methods for preparing them. [Background technology]

[0002] Lysophosphatidic acid (sometimes referred to as "LPA" herein) is a physiologically active phospholipid in which a fatty acid is bound to the 1st or 2nd position of a glycerol backbone and a phosphate group is bound to the 3rd position, and includes 1-acyl LPA, 1-alkyl LPA, 2-acyl LPA, etc. Furthermore, there is diversity depending on the type of fatty acid bound to it, and there are many LPA subtypes that exhibit various chemical and physiological properties depending on the carbon chain length and degree of unsaturation of the fatty acid.

[0003] LPA is produced in vivo by various enzymes and binds to G protein-coupled receptors on the cell surface to transmit signals intracellularly, exerting various physiological effects. Six subtypes of LPA receptors, LPA1 receptor to LPA6 receptor, are known. Three receptors, LPA1 receptor (LPAR1), LPA2 receptor (LPAR2), and LPA3 receptor (LPAR3), belong to the EDG (Endotherial Differentiation Gene) family and are called EDG2, EDG4, and EDG7, respectively. LPA4 receptor to LPA6 receptor are non-EDG family members and have low homology with the aforementioned EDG family. LPA receptor subtypes are distributed throughout the body, but their localization differs depending on the subtype, and each subtype is thought to contribute to the physiological functions of each tissue.

[0004] LPA has been shown to be involved in various fibrotic diseases, and the EDG receptor family in particular has been implicated as a receptor. Regarding pulmonary fibrosis, elevated LPA concentrations have been reported in the alveolar lavage fluid of patients with idiopathic pulmonary fibrosis and mice with a bleomycin-induced pulmonary fibrosis model. Furthermore, it has been reported that the progression of fibrosis is significantly suppressed in Lpar1-deficient mice and mice treated with an LPA1 receptor antagonist (see Non-Patent Document 1). Similarly, elevated serum LPA concentrations have been reported in patients with systemic sclerosis, and LPA1 receptor antagonists and LPA1 / 3 receptor antagonists have been shown to suppress fibrosis in mice with bleomycin-induced skin fibrosis (see Non-Patent Documents 2-4). Regarding renal fibrosis, elevated LPA production has been reported in unilateral ureteral ligation model mice, and fibrosis formation has been suppressed in Lpar1-deficient mice and with an LPA1 receptor antagonist (see Non-Patent Documents 4 and 5). In relation to liver fibrosis, it has been reported that blood LPA levels are elevated in patients with chronic hepatitis C, and that the level correlates with the histological stage of fibrosis (see Non-Patent Document 6). Furthermore, autotaxin, an LPA-producing enzyme, is upregulated in the blood of patients with non-alcoholic fatty liver disease (NAFLD), and autotaxin inhibitors have been shown to have inhibitory effects in various mouse liver injury models (see Non-Patent Documents 7 and 8). Furthermore, high concentrations of LPA accumulate within atherosclerotic plaques, resulting in increased inflammation and apoptosis induction. It has been reported that administration of an LPA1 / 3 receptor antagonist improves lesions in model mice, suggesting the involvement of LPA in cardiovascular disease (see Non-Patent Document 9). Furthermore, LPA is known to induce the migration and proliferation of cancer cells, and elevated LPA concentrations and LPA1 receptor expression have been observed in tissues of various cancer patients (see Non-Patent Documents 10 to 12). In addition, LPA has been reported to contract bladder smooth muscle cells, promote the proliferation of prostate cells, and be involved in the regulation of intraurethral pressure in vivo, suggesting its involvement in lower urinary tract diseases (see Patent Document 1, Non-Patent Documents 13 and 14). Additionally, it has been shown that LPA and LPA receptors are expressed in the nervous system, and that LPA induces neuropathic pain via the LPA1 receptor. It has been reported that Lpar1 knockout mice do not show pain symptoms in a mouse nerve ligation pain model (see Non-Patent Document 15).

[0005] As substances that antagonize the LPA1 receptor, alkanoic acid compounds having a ring (Patent Documents 2 to 4), cyclohexylcarboxylic acid compounds having a triazole ring (Patent Document 5), and carboxylic acid compounds having an amide structure (Patent Documents 6 to 7) have been reported, but the urea compound of the present invention has not been disclosed.

[0006] From the viewpoint of pharmaceuticals, it is also important to have a substance that is easy to handle on an industrial scale and has excellent storage stability. Compounds with these physiological properties are desired. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] WO02 / 062389 [Patent Document 2] WO03 / 099765 [Patent Document 3] WO2004 / 031118 [Patent Document 4] WO2005 / 058790 [Patent Document 5] WO2017 / 223016 [Patent Document 6] WO2015 / 025164 [Patent Document 7] WO2017 / 177004 [Non-patent literature]

[0008] [Non-Patent Document 1] Nat Med. 2008 Jan;14(1):45-54. [Non-patent document 2] Int J Med Sci. 2009 Jun 5;6(4):168-76. [Non-licensed document 3] Exp Dermatol. 2015 Sep;24(9):698-702.

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[0009] The object of the present invention is to provide a crystalline form of a novel compound that has excellent LPA1 receptor antagonistic activity, can be reproducibly obtained as a single crystal of consistent quality, can be stably supplied as a crystalline drug substance used in the production of pharmaceuticals and pharmaceutical raw materials, and has physicochemical properties with excellent storage stability, and a method for producing the same. [Means for solving the problem]

[0010] As a result of extensive research to achieve the above object, the present inventors have discovered a novel compound represented by the following formulas [I-1] to [I-5], which is a compound selected from the group consisting of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid, 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid, -3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid, trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid, trans-1-[([ The present inventors have discovered that (1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid and trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid (hereinafter referred to as compounds [I-1] to [I-5], respectively, or collectively as the compounds of the present invention or compound [I]) have excellent LPA1 receptor antagonistic activity, and that compound [I] or a pharmaceutically acceptable salt thereof, or a hydrate crystal thereof, which have excellent physicochemical properties, and a method for producing the same, can be provided, leading to the completion of the present invention.

[0011] [ka]

[0012] The present invention will be described in detail below.

[0013] (1) One aspect of the present invention is The present invention provides a crystalline hydrate of the N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid, which has the following physical properties (a) and (b): (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=3.5 degrees, 8.1 degrees, 10.1 degrees, and 14.6 degrees; and (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1610 cm -1 , 1556cm -1 , 1412cm -1 , and 1075 cm -1 is located.

[0014] (2) Another aspect of the present invention is The object of the present invention is to provide a crystal according to (1), which further has the following physical property (c): (c) In differential thermal analysis / thermogravimetry (TG / DTA), endothermic peaks are observed at 45°C to 55°C and 70°C to 79°C.

[0015] (3) Another aspect of the present invention is a solution of N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid in a mixed solvent of water and one or more solvents selected from the group consisting of tert-butyl methyl ether and ethyl acetate, (i) n-heptane, or (ii) a mixed solvent of n-heptane and one or more solvents selected from the group consisting of tert-butyl methyl ether and ethyl acetate and then crystallizing the mixture to provide a method for producing a crystal having the following physical properties (a) to (b): (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=3.5 degrees, 8.1 degrees, 10.1 degrees, and 14.6 degrees; and (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1610 cm -1 , 1556cm -1 , 1412cm -1 , and 1075 cm -1 is located.

[0016] (4) Another aspect of the present invention is The present invention provides a crystalline anhydrous N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid, which has the following physical properties (a) to (c): (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 3.6 degrees, 10.2 degrees, 15.1 degrees, and 20.6 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1643 cm -1 , 1591cm -1 , 1242cm -1 , and 1075 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 72°C to 82°C.

[0017] (5) Another aspect of the present invention is The present invention provides a method for producing crystals of anhydrous N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid, which has the following physical properties (a) to (c): (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 3.6 degrees, 10.2 degrees, 15.1 degrees, and 20.6 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1643 cm -1 , 1591cm -1 , 1242cm -1 , and 1075 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 72°C to 82°C.

[0018] (6) Another aspect of the present invention is The object of the present invention is to provide a crystal of the potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid (hereinafter sometimes referred to as type A crystal) having the following physical properties (a) to (b): (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 3.7 degrees, 7.3 degrees, 8.2 degrees, and 18.3 degrees; and (b) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 89°C to 99°C.

[0019] (7) Another aspect of the present invention is The object of the present invention is to provide a method for producing a crystal (type A crystal) having the following physical properties (a) to (b): (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 3.7 degrees, 7.3 degrees, 8.2 degrees, and 18.3 degrees; and (b) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 89°C to 99°C.

[0020] (8) Another aspect of the present invention is The object of the present invention is to provide a crystal of the potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid (hereinafter sometimes referred to as type B crystal) having the following physical properties (a) to (c): (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 3.5 degrees, 9.1 degrees, 10.3 degrees, and 15.0 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1707 cm -1 , 1636cm -1 , 1407cm -1 , and 1101 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 49°C to 59°C.

[0021] (9) Another aspect of the present invention is A solution of potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid in a mixed solvent of tert-butyl methyl ether and water, (i) n-heptane, or (ii) A mixed solvent of tert-butyl methyl ether and n-heptane and then crystallizing the mixture to obtain a crystal (type B crystal) having the following physical properties (a) to (c): (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 3.5 degrees, 9.1 degrees, 10.3 degrees, and 15.0 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1707 cm -1 , 1636cm -1 , 1407cm -1 , and 1101 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 49°C to 59°C.

[0022] (10) Another aspect of the present invention is The present invention provides a crystal of the potassium salt of trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid, which has the following physical properties (a) to (c): (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 4.0 degrees, 4.9 degrees, 7.9 degrees, and 15.0 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1625 cm -1 , 1572cm -1 , 1255cm -1 , and 1124 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 69°C to 79°C.

[0023] (11) Another aspect of the present invention is A solution of the potassium salt of trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid in a mixed solvent of tert-butyl methyl ether and water, (i) n-heptane, or (ii) A mixed solvent of tert-butyl methyl ether and n-heptane and then crystallizing the mixture to provide a method for producing crystals having the following physical properties (a) to (c): (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 4.0 degrees, 4.9 degrees, 7.9 degrees, and 15.0 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1625 cm -1 , 1572cm-1 , 1255cm -1 , and 1124 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 69°C to 79°C.

[0024] (12) Another aspect of the present invention is The present invention provides a crystal of trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid, which has the following physical properties (a) to (c): (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 13.9 degrees, 14.9 degrees, 15.8 degrees, and 20.1 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1746 cm -1 , 1695cm -1 , 1121cm -1 , and 1082 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), the endothermic peak is between 90°C and 100°C.

[0025] (13) Another aspect of the present invention is The present invention provides a method for producing a crystal having the following physical properties (a) to (c), which comprises adding water to trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid to crystallize it: (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 13.9 degrees, 14.9 degrees, 15.8 degrees, and 20.1 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1746 cm -1 , 1695cm -1 , 1121cm -1 , and 1082 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), the endothermic peak is between 90°C and 100°C.

[0026] (14) Another aspect of the present invention is The present invention provides a crystal of trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid, which has the following physical properties (a) to (c): (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 4.6 degrees, 13.9 degrees, 19.9 degrees, and 22.2 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1745 cm -1 , 1424cm -1 , 1146cm -1 , and 1068 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 81°C to 91°C.

[0027] (15) Another aspect of the present invention is The present invention provides a method for producing a crystal having the following physical properties (a) to (c), which comprises adding water to trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid to form a solution, followed by crystallization: (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 4.6 degrees, 13.9 degrees, 19.9 degrees, and 22.2 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1745 cm -1 , 1424cm -1 , 1146cm -1 , and 1068 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 81°C to 91°C.

[0028] (16) Another aspect of the present invention is The object of the present invention is to provide a pharmaceutical containing, as an active ingredient, a urea compound or a salt thereof, or a crystalline hydrate thereof, which antagonizes the LPA1 receptor, as set forth in any one of (1), (2), (4), (6), (8), (10), (12), and (14).

[0029] (17) Another aspect of the present invention is The present invention provides the pharmaceutical agent according to (16), which is an LPA1 receptor antagonist.

[0030] (18) Another aspect of the present invention is The present invention also provides the pharmaceutical composition according to (16), which is a preventive or therapeutic drug for systemic sclerosis. [Effects of the Invention]

[0031] The present invention provides crystals of a urea compound or its salt, or a hydrate thereof, having LPA1 receptor antagonistic activity. The crystals are stable at temperatures around room temperature and have excellent storage stability. Furthermore, the present invention provides a novel production method for stably obtaining the crystals with consistent quality. [Brief explanation of the drawings]

[0032] [Figure 1] 1 shows the powder X-ray diffraction pattern of a crystal of N-methyl-D-glucamine salt hydrate of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. [Figure 2]This shows the infrared absorption spectrum (ATR method, crystal: diamond) of a crystal of N-methyl-D-glucamine salt hydrate of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. [Figure 3] 1 shows a differential thermal analysis / thermogravimetric measurement curve for a crystal of N-methyl-D-glucamine salt hydrate of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. [Figure 4] 1 shows the powder X-ray diffraction pattern of a crystal of anhydrous N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. [Figure 5] This shows the infrared absorption spectrum (ATR method, crystal: diamond) of a crystal of the anhydrous N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. [Figure 6] 1 shows a differential thermal analysis / thermogravimetric measurement curve for a crystal of anhydrous N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. [Figure 7]The powder X-ray diffraction pattern of the crystal (crystal form A) of the potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid is shown. [Figure 8] 1 shows a differential thermal analysis / thermogravimetric measurement curve for the crystal (A-type crystal) of the potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid. [Figure 9] The powder X-ray diffraction pattern of the crystals (type B crystals) of the potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid is shown. [Figure 10] The infrared absorption spectrum (ATR method, crystal: diamond) of the crystal (B-type crystal) of the potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid is shown. [Figure 11] 1 shows a differential thermal analysis / thermogravimetric measurement curve for the crystals (B-type crystals) of the potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid. [Figure 12] 1 shows the powder X-ray diffraction pattern of a crystal of the potassium salt of trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. [Figure 13]The infrared absorption spectrum (ATR method, crystal: diamond) of the crystal of the potassium salt of trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid is shown. [Figure 14] 1 shows a differential thermal analysis / thermogravimetric measurement curve for a crystal of the potassium salt of trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. [Figure 15] 1 shows the powder X-ray diffraction pattern of a crystal of trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. [Figure 16] The infrared absorption spectrum (ATR method, crystal: diamond) of a crystal of trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid is shown. [Figure 17] 1 shows a differential thermal analysis / thermogravimetric measurement curve for a crystal of trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. [Figure 18] 1 shows the powder X-ray diffraction pattern of a crystal of trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. [Figure 19]The infrared absorption spectrum (ATR method, crystal: diamond) of a crystal of trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid is shown. [Figure 20] 1 shows a differential thermal analysis / thermogravimetric measurement curve of a crystal of trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. DETAILED DESCRIPTION OF THE INVENTION

[0033] Hereinafter, embodiments for carrying out the present invention will be specifically described.

[0034] The compounds of the present invention have the chemical structures shown in the above formulas [I-1] to [I-5].

[0035] The crystals of the compound of the present invention (hereinafter, sometimes referred to as "the crystals of the present invention") can be obtained reproducibly as single crystals having a certain quality as described above, can be stably supplied as crystals of drug substances used in the production of pharmaceuticals, and have excellent storage stability.

[0036] The crystals of the compound of the present invention can be prepared, for example, by the following method.

[0037] The compound of the present invention or a salt thereof is dissolved in a predetermined good solvent (first solvent), if necessary by heating, and then slowly cooled or a predetermined poor solvent (second solvent) is added to precipitate crystals. The precipitated crystals are separated from the solvent by filtration, centrifugation, etc., and then dried as necessary to obtain the crystals of the present invention. Note that recrystallization may be repeated once or twice or more times, but usually only one recrystallization is performed. The recrystallization can be carried out using only a good solvent (first solvent), or can be carried out using a mixed solvent of a good solvent (first solvent) and a poor solvent (second solvent).

[0038] The cooling time is not particularly limited as long as it is 10 seconds or more, but is usually 10 minutes to 24 hours, preferably 30 minutes to 5 hours.

[0039] Seed crystals can be used for crystallization, and can be obtained in advance by methods well known to those skilled in the art, such as scraping the wall of a vessel containing a solution for crystallization with a spatula, or by a solvent evaporation method in which crystals are obtained by concentrating a compound solution by slowly evaporating a solvent.

[0040] The crystals of the N-methyl-D-glucamine salt hydrate of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid (compound [I-1]), a compound of the present invention, are described below.

[0041] The crystals of the N-methyl-D-glucamine salt hydrate of compound [I-1] have the following physical properties (a) to (c). (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 3.5 degrees, 8.1 degrees, 10.1 degrees, and 14.6 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1610 cm -1 , 1556cm -1 , 1412cm -1 , and 1075 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), endothermic peaks are observed at 45°C to 55°C and 70°C to 79°C.

[0042] The powder X-ray diffraction pattern of the crystalline N-methyl-D-glucamine salt hydrate of compound [I-1] is shown in Figure 1, the infrared absorption spectrum (ATR method, crystal: diamond) is shown in Figure 2, and the differential thermal analysis / thermogravimetric measurement curve is shown in Figure 3.

[0043] Note that characteristic peaks in powder X-ray crystal diffraction, infrared absorption spectrum, and differential thermal analysis / thermogravimetry (TG / DTA) may vary depending on the measurement conditions, and therefore, these peaks of the compound of the present invention may be inaccurate or unclear.

[0044] As can be seen from Figures 1 to 3, the crystals of N-methyl-D-glucamine salt hydrate of compound [I-1] produced by the production method of the present invention are essentially crystals of high purity. High crystal purity is desirable, and preferably, the crystals are substantially free of other crystalline forms. Furthermore, as will be shown in the Examples below, the crystals of N-methyl-D-glucamine salt hydrate of compound [I-1] produced by the production method of the present invention can be obtained reproducibly as single crystals of consistent quality, and can be stably supplied as crystals of active pharmaceutical ingredients used in the production of pharmaceuticals and pharmaceutical raw materials, and have excellent physicochemical properties with excellent storage stability.

[0045] Next, a method for producing the crystals of N-methyl-D-glucamine salt hydrate of compound [I-1] will be described. The crystals of the N-methyl-D-glucamine salt hydrate of compound [I-1] can be prepared, for example, by the following method.

[0046] The N-methyl-D-glucamine salt of compound [I-1] is dissolved in a predetermined good solvent (first solvent), if necessary with heating, and then slowly cooled or a predetermined poor solvent (second solvent) is added to precipitate crystals. A miscible amount of water is added to this predetermined good solvent (first solvent). The precipitated crystals are separated from the solvent by filtration, centrifugation, or the like, and then the humidity is adjusted appropriately to obtain crystals of the N-methyl-D-glucamine salt hydrate of compound [I-1].

[0047] In the above recrystallization, the solution of the N-methyl-D-glucamine salt of compound [I-1] may be prepared by adding a solvent to the N-methyl-D-glucamine salt of compound [I-1], or by adding N-methyl-D-glucamine to a solution of compound [I-1] to prepare a salt solution.

[0048] In the above recrystallization, there are also cases where recrystallization can be performed using only a predetermined good solvent (first solvent) without adding a predetermined poor solvent (second solvent).

[0049] Before being dissolved in a solvent, the starting compound [I-1], N-methyl-D-glucamine salt, is amorphous or crystalline.

[0050] Specific examples of the predetermined good solvent (first solvent) include: ether solvents such as tert-butyl methyl ether (MTBE), 2-methyltetrahydrofuran (2Me-THF), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), and diisopropyl ether (IPE); Ester solvents such as ethyl acetate, isopropyl acetate, methyl acetate, butyl acetate, and propyl acetate; alcoholic solvents such as 2-propanol (IPA), ethanol (EtOH), methanol (MeOH), 1-propanol (1-PrOH), and 1-butanol (1-BuOH); benzene-based solvents such as toluene and xylene; ketone solvents such as acetone, 2-butanone, and methyl isobutyl ketone (MIBK); acetonitrile (MeCN); or water Examples include: Specific examples of the predetermined poor solvent (second solvent) include: Hydrocarbon solvents such as n-heptane, n-hexane, cyclohexane, methylcyclohexane (MCH), and isooctane; Diisopropyl ether (IPE) Examples include:

[0051] The mixing ratio of the good solvent (first solvent) and the poor solvent (second solvent) can be changed as appropriate. A preferred mixing ratio of tert-butyl methyl ether and n-heptane is 10:1. The preferred mixture ratio of ethyl acetate and n-heptane is 3:2.

[0052] The mixing ratio of water to the good solvent (first solvent) can also be changed as appropriate. In the recrystallization, a miscible amount of water can be added to tert-butyl methyl ether, preferably a saturation amount of water or 1 / 100 of the amount of water to tert-butyl methyl ether. Furthermore, a miscible amount of water can be added to ethyl acetate, preferably in an amount of 1 / 100 of the ethyl acetate.

[0053] Crystallization of the N-methyl-D-glucamine salt hydrate of compound [I-1] is usually carried out at 0°C to 45°C, preferably 20°C to 30°C.

[0054] The precipitated crystals of N-methyl-D-glucamine salt hydrate of compound [I-1] can be separated from the solvent by filtering the suspension, centrifuging, or the like.

[0055] The crystals of the anhydrous N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid (compound [I-1]), a compound of the present invention, are described below.

[0056] The crystals of the anhydrous N-methyl-D-glucamine salt of compound [I-1] have the following physical properties (a) to (c). (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 3.6 degrees, 10.2 degrees, 15.1 degrees, and 20.6 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1643 cm -1 , 1591cm -1 , 1242cm -1 , and 1075 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 72°C to 82°C.

[0057] The powder X-ray diffraction pattern of the crystals of the anhydrous N-methyl-D-glucamine salt of compound [I-1] is shown in Figure 4, the infrared absorption spectrum (ATR method, crystal: diamond) is shown in Figure 5, and the differential thermal analysis / thermogravimetric measurement curve is shown in Figure 6.

[0058] Note that characteristic peaks in powder X-ray crystal diffraction, infrared absorption spectrum, and differential thermal analysis / thermogravimetry (TG / DTA) may vary depending on the measurement conditions, and therefore, these peaks of the compound of the present invention may be inaccurate or unclear.

[0059] 4 to 6, the crystals of the anhydrous N-methyl-D-glucamine salt of compound [I-1] produced by the production method of the present invention are essentially highly pure crystals. High purity crystals are desirable, and preferably they are substantially free of other crystalline forms. Furthermore, as will be shown in the Examples below, the crystals of the anhydrous N-methyl-D-glucamine salt of compound [I-1] produced by the production method of the present invention can be obtained with good reproducibility as single crystals of consistent quality, and can be stably supplied as crystals of a drug substance used in the production of pharmaceuticals and pharmaceutical raw materials, and have excellent physicochemical properties with excellent storage stability.

[0060] Next, a method for producing crystals of the anhydrous N-methyl-D-glucamine salt of compound [I-1] will be described. Crystals of the anhydrous N-methyl-D-glucamine salt of compound [I-1] can be prepared, for example, by the following method.

[0061] Crystals of the N-methyl-D-glucamine salt hydrate of compound [I-1] can be dried using a desiccant to obtain crystals of the N-methyl-D-glucamine salt anhydrate of compound [I-1].

[0062] Examples of the desiccant include synthetic zeolite desiccant, silica gel desiccant, and calcium chloride desiccant, with the synthetic zeolite desiccant being preferred.

[0063] The crystals of the anhydrous N-methyl-D-glucamine salt of compound [I-1] are usually dried at 45°C or lower, preferably 20°C to 30°C.

[0064] The crystal (crystal form A) of the potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid (compound [I-2]), a compound of the present invention, is described below.

[0065] The crystals of the potassium salt of the compound [I-2] (crystal form A) have the following physical properties (a) and (b). (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ = 3.7 degrees, 7.3 degrees, 8.2 degrees, and 18.3 degrees; and (b) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 89°C to 99°C.

[0066] The powder X-ray diffraction pattern of the crystals (A-form crystals) of the potassium salt of compound [I-2] is shown in FIG. 7, and the differential thermal analysis / thermogravimetric measurement curve is shown in FIG.

[0067] Note that characteristic peaks in powder X-ray crystal diffraction and differential thermal analysis / thermogravimetry (TG / DTA) may vary depending on the measurement conditions, and therefore, these peaks of the compound of the present invention may be inaccurate or unclear.

[0068] As can be seen from Figures 7 and 8, the crystals of the potassium salt of compound [I-2] (crystals of type A) produced by the production method of the present invention are essentially crystals of high purity. The crystals desirably have high purity, and preferably are substantially free of other crystalline forms. Furthermore, as will be shown in the Examples below, the crystals of the potassium salt of compound [I-2] (crystals of type A) produced by the production method of the present invention can be reproducibly obtained as single crystals of consistent quality, and can be stably supplied as crystals of active pharmaceutical ingredients used in the production of pharmaceuticals and pharmaceutical raw materials, and have physicochemical properties with excellent storage stability.

[0069] Next, a method for producing the crystals (A-type crystals) of the potassium salt of compound [I-2] will be described. The crystals of the potassium salt of compound [I-2] (crystals A) can be prepared, for example, by the following method.

[0070] A predetermined solvent is added to the potassium salt of compound [I-2], the resulting suspension is stirred, and then the solid in the suspension is filtered, separated from the solvent by centrifugation or the like, and dried to obtain crystals of the potassium salt of compound [I-2] (type A crystals).

[0071] Before being dissolved in a solvent, the potassium salt of the starting compound [I-2] is amorphous or crystalline.

[0072] Specific examples of the predetermined solvent include a mixed solvent of tert-butyl methyl ether, ethyl acetate, and acetonitrile.

[0073] The mixing ratio of tert-butyl methyl ether, ethyl acetate, and acetonitrile in the mixed solvent can be changed as appropriate. A preferred mixing ratio of tert-butyl methyl ether, ethyl acetate, and acetonitrile in the mixed solvent is 20:2:1.

[0074] Crystallization of the potassium salt of compound [I-2] (crystal type A) is usually carried out at 0°C to 60°C, preferably 20°C to 30°C.

[0075] The crystals of the potassium salt of compound [I-2] (crystals of type A) in the suspension can be separated from the solvent by filtering, centrifuging, or the like.

[0076] The crystals of the potassium salt of compound [I-2] (crystals of type A) are usually dried at 60°C or lower, preferably 20°C to 30°C.

[0077] The crystals (type B crystals) of the potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid (compound [I-2]), a compound of the present invention, are described below.

[0078] The crystals (type B crystals) of the potassium salt of the compound [I-2] have the following physical properties (a) to (c). (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 3.5 degrees, 9.1 degrees, 10.3 degrees, and 15.0 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1707 cm -1 , 1636cm -1 , 1407cm -1 , and 1101 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 49°C to 59°C.

[0079] The powder X-ray diffraction pattern of the potassium salt crystal (B-type crystal) of compound [I-2] is shown in Figure 9, the infrared absorption spectrum (ATR method, crystal: diamond) is shown in Figure 10, and the differential thermal analysis / thermal mass measurement curve is shown in Figure 11.

[0080] Note that characteristic peaks in powder X-ray crystal diffraction, infrared absorption spectrum, and differential thermal analysis / thermogravimetry (TG / DTA) may vary depending on the measurement conditions, and therefore, these peaks of the compound of the present invention may be inaccurate or unclear.

[0081] 9 to 11, the crystals of the potassium salt of compound [I-2] (type B crystals) produced by the production method of the present invention are essentially highly pure crystals. High crystal purity is desirable, and preferably, the crystals are substantially free of other crystal forms. Furthermore, as will be shown in the Examples below, the crystals of the potassium salt of compound [I-2] (type B crystals) produced by the production method of the present invention can be reproducibly obtained as single crystals of consistent quality, and can be stably supplied as crystals of active pharmaceutical ingredients used in the production of pharmaceuticals and pharmaceutical raw materials, and have physicochemical properties with excellent storage stability.

[0082] Next, a method for producing crystals of the potassium salt of compound [I-2] (crystals of type B) will be described. The crystals of the potassium salt of compound [I-2] (crystals B) can be prepared, for example, by the following method.

[0083] The potassium salt of compound [I-2] is added to a predetermined good solvent (first solvent), heated if necessary to dissolve, and then slowly cooled or a predetermined poor solvent (second solvent) is added to precipitate crystals. A miscible amount of water is added to this predetermined good solvent (first solvent). The precipitated crystals are separated from the solvent by filtration, centrifugation, or the like, and then the humidity is adjusted appropriately to obtain crystals of the potassium salt of compound [I-2] (type B crystals).

[0084] In the above recrystallization, there are cases where recrystallization can be performed using only a predetermined good solvent (first solvent) without adding a predetermined poor solvent (second solvent).

[0085] Before being dissolved in a solvent, the potassium salt of the starting compound [I-2] is amorphous or crystalline.

[0086] Specific examples of the predetermined good solvent (first solvent) include: ether solvents such as tert-butyl methyl ether (MTBE), 2-methyltetrahydrofuran (2Me-THF), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), and diisopropyl ether (IPE); Ester solvents such as ethyl acetate, isopropyl acetate, methyl acetate, butyl acetate, and propyl acetate; alcoholic solvents such as 2-propanol (IPA), ethanol (EtOH), methanol (MeOH), 1-propanol (1-PrOH), and 1-butanol (1-BuOH); benzene-based solvents such as toluene and xylene; ketone solvents such as acetone, 2-butanone, and methyl isobutyl ketone (MIBK); acetonitrile (MeCN); or water Specific examples of the predetermined poor solvent (second solvent) include: Hydrocarbon solvents such as n-heptane, n-hexane, cyclohexane, methylcyclohexane (MCH), and isooctane; Diisopropyl ether (IPE) Examples include:

[0087] The mixing ratio of the good solvent (first solvent) and the poor solvent (second solvent) can be changed as appropriate. A preferred mixing ratio of tert-butyl methyl ether and n-heptane is 10:3.

[0088] The mixing ratio of water to the good solvent (first solvent) can also be changed as appropriate. In the recrystallization, a miscible amount of water can be added to tert-butyl methyl ether, preferably a saturation amount of water or 1 / 100 of the amount of water to tert-butyl methyl ether.

[0089] Crystallization of the potassium salt of compound [I-2] (type B crystal) is usually carried out at 0°C to 50°C, preferably 20°C to 30°C.

[0090] The precipitated crystals of the potassium salt of compound [I-2] (type B crystals) can be separated from the solvent by filtering the suspension, centrifuging, or the like.

[0091] The crystals of the potassium salt of the compound of the present invention, trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid (compound [I-3]), are described below.

[0092] The crystals of the potassium salt of the compound [I-3] have the following physical properties (a) to (c). (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 4.0 degrees, 4.9 degrees, 7.9 degrees, and 15.0 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1625 cm -1 , 1572cm -1 , 1255cm -1 , and 1124 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 69°C to 79°C.

[0093] The powder X-ray diffraction pattern of the potassium salt crystal of compound [I-3] is shown in Figure 12, the infrared absorption spectrum (ATR method, crystal: diamond) is shown in Figure 13, and the differential thermal analysis / thermal gravimetric measurement curve is shown in Figure 14.

[0094] Note that characteristic peaks in powder X-ray crystal diffraction, infrared absorption spectrum, and differential thermal analysis / thermogravimetry (TG / DTA) may vary depending on the measurement conditions, and therefore, these peaks of the compound of the present invention may be inaccurate or unclear.

[0095] 12 to 14, the crystals of the potassium salt of compound [I-3] produced by the production method of the present invention are essentially highly pure crystals. High crystal purity is desirable, and preferably, the crystals are substantially free of other crystalline forms. Furthermore, as will be shown in the Examples below, the crystals of the potassium salt of compound [I-3] produced by the production method of the present invention can be reproducibly obtained as single crystals of consistent quality, and can be stably supplied as crystals of active pharmaceutical ingredients used in the production of pharmaceuticals and pharmaceutical raw materials, and have excellent physicochemical properties with excellent storage stability.

[0096] Next, a method for producing the crystals of the potassium salt of compound [I-3] will be described. The potassium salt crystals of compound [I-3] can be prepared, for example, by the following method.

[0097] The potassium salt of compound [I-3] is dissolved in a predetermined good solvent (first solvent) by heating if necessary, and then slowly cooled or a predetermined poor solvent (second solvent) is added to precipitate crystals. A miscible amount of water is added to this predetermined good solvent (first solvent). The precipitated crystals are separated from the solvent by filtration, centrifugation, or the like, and then the moisture content is adjusted appropriately to obtain crystals of the potassium salt of compound [I-3].

[0098] In the above recrystallization, there are also cases where recrystallization can be performed using only a predetermined good solvent (first solvent) without adding a predetermined poor solvent (second solvent).

[0099] Before being dissolved in a solvent, the potassium salt of the starting compound [I-3] is amorphous or crystalline.

[0100] Specific examples of the predetermined good solvent (first solvent) include: ether solvents such as tert-butyl methyl ether (MTBE), 2-methyltetrahydrofuran (2Me-THF), tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), and diisopropyl ether (IPE); Ester solvents such as ethyl acetate, isopropyl acetate, methyl acetate, butyl acetate, and propyl acetate; alcoholic solvents such as 2-propanol (IPA), ethanol (EtOH), methanol (MeOH), 1-propanol (1-PrOH), and 1-butanol (1-BuOH); benzene-based solvents such as toluene and xylene; ketone solvents such as acetone, 2-butanone, and methyl isobutyl ketone (MIBK); acetonitrile (MeCN); or water Examples include: Specific examples of the predetermined poor solvent (second solvent) include: Hydrocarbon solvents such as n-heptane, n-hexane, cyclohexane, methylcyclohexane (MCH), and isooctane; Diisopropyl ether (IPE) Examples include:

[0101] The mixing ratio of the good solvent (first solvent) and the poor solvent (second solvent) can be changed as appropriate. A preferred mixing ratio of tert-butyl methyl ether and n-heptane is 1:5.

[0102] The mixing ratio of water to the good solvent (first solvent) can also be changed as appropriate. In the recrystallization, a miscible amount of water can be added to tert-butyl methyl ether, preferably a saturation amount of water or 1 / 100 of the amount of water to tert-butyl methyl ether.

[0103] Crystallization of the potassium salt of compound [I-3] is usually carried out at 0°C to 60°C, preferably 20°C to 30°C.

[0104] The precipitated crystals of the potassium salt of compound [I-3] can be separated from the solvent by filtering the suspension, centrifuging, or the like.

[0105] The crystals of the compound of the present invention, trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid (compound [I-4]), are described below.

[0106] The crystals of the compound [I-4] have the following physical properties (a) to (c). (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 13.9 degrees, 14.9 degrees, 15.8 degrees, and 20.1 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1746 cm -1 , 1695cm -1 , 1121cm -1 , and 1082 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), the endothermic peak is between 90°C and 100°C.

[0107] The powder X-ray diffraction pattern of the crystals of compound [I-4] is shown in Figure 15, the infrared absorption spectrum (ATR method, crystal: diamond) is shown in Figure 16, and the differential thermal analysis / thermal gravimetric measurement curve is shown in Figure 17.

[0108] Note that characteristic peaks measured by powder X-ray crystal diffraction, infrared absorption spectrum, and differential thermal analysis / thermogravimetry (TG / DTA) may vary depending on the measurement conditions. Therefore, these peaks of the compound of the present invention may be inaccurate or unclear.

[0109] 15 to 17, the crystals of compound [I-4] produced by the production method of the present invention are essentially highly pure crystals. The crystals are desirably highly pure, and preferably substantially free of other crystalline forms. Furthermore, as will be shown in the Examples below, the crystals of compound [I-4] produced by the production method of the present invention can be reproducibly obtained as single crystals of consistent quality, and can be stably supplied as crystals of active pharmaceutical ingredients used in the production of pharmaceuticals and pharmaceutical raw materials, and have excellent physicochemical properties with excellent storage stability.

[0110] Next, a method for producing the crystals of compound [I-4] will be described. The crystals of compound [I-4] can be prepared, for example, by the following method.

[0111] A predetermined solvent is added to compound [I-4], the resulting suspension is stirred, and then the solid in the suspension is filtered, separated from the solvent by centrifugation or the like, and then dried to obtain crystals of compound [I-4].

[0112] Before being dissolved in a solvent, the raw material compound [I-4] is amorphous or crystalline.

[0113] A specific example of the predetermined solvent is water.

[0114] The crystallization of the compound [I-4] is usually carried out at 0°C to 60°C, preferably 20°C to 30°C.

[0115] The crystals of compound [I-4] in the suspension can be separated from the solvent by filtering, centrifuging, or the like.

[0116] The crystals of compound [I-4] are usually dried at 60°C or lower, preferably 20°C to 30°C.

[0117] The crystals of the compound of the present invention, trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid (compound [I-5]), are described below.

[0118] The crystals of the compound [I-5] have the following physical properties (a) to (c). (a) Powder X-ray diffraction (Cu-Kα) shows peaks at 2θ = 4.6 degrees, 13.9 degrees, 19.9 degrees, and 22.2 degrees; (b) Infrared absorption spectrum (ATR method) shows a characteristic absorption band at 1745 cm -1 , 1424cm -1 , 1146cm -1 , and 1068 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 81°C to 91°C.

[0119] The powder X-ray diffraction pattern of the crystals of compound [I-5] is shown in Figure 18, the infrared absorption spectrum (ATR method, crystal: diamond) is shown in Figure 19, and the differential thermal analysis / thermal gravimetric measurement curve is shown in Figure 20.

[0120] Note that characteristic peaks in powder X-ray crystal diffraction, infrared absorption spectrum, and differential thermal analysis / thermogravimetry (TG / DTA) may vary depending on the measurement conditions, and therefore, these peaks of the compound of the present invention may be inaccurate or unclear.

[0121] 18 to 20, the crystals of compound [I-5] produced by the production method of the present invention are essentially highly pure crystals. The crystals preferably have a high purity, and are preferably substantially free of other crystalline forms. Furthermore, as will be shown in the Examples below, the crystals of compound [I-5] produced by the production method of the present invention can be reproducibly obtained as single crystals of consistent quality, and can be stably supplied as crystals of active pharmaceutical ingredients used in the production of pharmaceuticals and pharmaceutical raw materials, and have excellent physicochemical properties with excellent storage stability.

[0122] Next, a method for producing the crystals of compound [I-5] will be described. The crystals of compound [I-5] can be prepared, for example, by the following method.

[0123] A predetermined solvent is added to compound [I-5], the resulting suspension is stirred, and then the solid in the suspension is filtered, separated from the solvent by centrifugation, etc., and dried to obtain crystals of compound [I-5].

[0124] Before being dissolved in a solvent, the raw material compound [I-5] is amorphous or crystalline.

[0125] A specific example of the predetermined solvent is water.

[0126] The crystallization of the compound [I-5] is usually carried out at 0 to 60°C, preferably 20 to 30°C.

[0127] The crystals of compound [I-5] in the suspension can be separated from the solvent by filtering, centrifuging, or the like.

[0128] The crystals of compound [I-5] are usually dried at 60°C or lower, preferably 20 to 30°C.

[0129] The compound of the present invention has tautomerism and exists in various tautomeric forms. The compound of the present invention includes these isomers and mixtures containing these isomers in any ratio.

[0130] In the present invention, "n" indicates normal, "i" indicates iso, "s" and "sec" indicate secondary, "tert" indicates tertiary, "c" indicates cyclo, "o" indicates ortho, "m" indicates meta, and "p" indicates para.

[0131] In this specification, examples of pharmaceutically acceptable salts include mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate; acid addition salts such as organic acid salts such as oxalate, tartrate, citrate, maleate, fumarate, succinate, acetate, trifluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, and malate; amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate; inorganic salts or ammonium salts such as lithium salt, sodium salt, potassium salt, calcium salt, and magnesium salt; and salts with organic bases such as triethylamine salt, diisopropylamine salt, cyclohexylamine salt, N-methyl-D-glucamine salt, and ethanolamine salt. The salts also include hydrated salts. Furthermore, when the compound of the present invention or a salt thereof forms a hydrate or solvate, it is also included within the scope of the compound of the present invention or a salt thereof.

[0132] The compound of the present invention or a salt thereof may absorb moisture upon exposure to the atmosphere, recrystallization, etc., and may become adsorbed water or become a hydrate. The compound of the present invention also includes such hydrates.

[0133] As mentioned above, LPA1 receptors, LPA3 receptors, and others have a variety of functions in the body. Diseases caused by LPA receptors include, for example, diseases accompanied by fibrosis (idiopathic pulmonary fibrosis, systemic sclerosis, chronic kidney disease, chronic hepatitis, chronic rejection after organ transplantation, etc.), inflammatory diseases (rheumatoid arthritis, osteoarthritis of the knee, etc.), cardiovascular diseases (arteriosclerosis, etc.), cancer-related diseases (prostate cancer, breast cancer, ovarian cancer, etc.), urinary system diseases (benign prostatic hyperplasia, overactive bladder, etc.), and neurological diseases (neuropathic pain, diabetic neuropathy, etc.).

[0134] Drugs that suppress the physiological activity of LPA receptors, particularly antagonists of the EDG family such as LPA1 receptors and LPA3 receptors, are thought to be useful as preventive or therapeutic agents for diseases accompanied by organ fibrosis such as idiopathic pulmonary fibrosis, systemic sclerosis, chronic kidney disease, and chronic hepatitis, cardiovascular diseases such as arteriosclerosis, proliferative diseases including various cancers, urinary system diseases such as benign prostatic hyperplasia, and central and peripheral nervous system diseases.

[0135] The LPA receptor antagonism of the compound of the present invention can be evaluated according to known techniques, such as the methods described in the test examples of this specification below.

[0136] The pharmaceutical composition according to the present invention contains the compound of the present invention that antagonizes the LPA1 receptor, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which can be administered alone or together with a pharmaceutically or pharmaceutical acceptable additive.

[0137] The additives may include commonly used excipients or diluents, and, if necessary, commonly used binders, disintegrants, lubricants, coating agents, sugar-coating agents, pH adjusters, solubilizers, or aqueous or non-aqueous solvents.Specific examples include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, corn starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzoate, talc, stearic acid, magnesium stearate, agar, pectin, gum arabic, glycerin, sesame oil, olive oil, soybean oil, cocoa butter, ethylene glycol, low-viscosity hydroxypropyl cellulose (HPC-L), microcrystalline cellulose, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), and other commonly used additives.

[0138] The medicament according to the present invention may be in any form of a solid composition, a liquid composition or other composition, and the most suitable one can be selected according to the need.

[0139] The pharmaceutical composition of the present invention can be prepared into tablets, pills, capsules, granules, powders, dispersing agents, liquids, emulsions, suspensions, injections, etc. by adding the above-mentioned additives to the compound of the present invention and using conventional formulation techniques.

[0140] Furthermore, the pharmaceutical agent according to the present invention can be formulated by forming an inclusion compound between the compound of the present invention and α-, β-, or γ-cyclodextrin, methylated cyclodextrin, or the like.

[0141] The pharmaceutical agent according to the present invention may be a single preparation (combined preparation) or two or more preparations (combined preparation) obtained by separately formulating the compound of the present invention and a compound that can be used in combination with the compound of the present invention. When these compounds are formulated separately to form two or more formulations, the individual formulations can be administered simultaneously or at a fixed time interval. In this case, it does not matter which formulation is administered first. The two or more formulations can also be administered at different times per day. Furthermore, the two or more formulations can also be administered by different routes.

[0142] When these compounds are formulated separately to form two different preparations, they may be administered simultaneously or at a very short interval. For example, it is preferable to state in documents such as package inserts and sales pamphlets of commercially available pharmaceuticals that they are to be used in combination. It is also preferable to formulate these active ingredients separately into a kit consisting of two different formulations.

[0143] When the compound of the present invention is used as an LPA1 receptor antagonist, the compound of the present invention may be orally administered as it is, or as a formulation containing the compound of the present invention as an active ingredient.

[0144] When the compound of the present invention is used as a prophylactic or therapeutic agent for systemic sclerosis, the compound of the present invention may be administered orally or parenterally as it is. Alternatively, the compound of the present invention may be administered orally or parenterally as a formulation containing the compound of the present invention as an active ingredient. Parenteral administration includes intravenous administration, nasal administration, transdermal administration, subcutaneous administration, intramuscular administration, and sublingual administration.

[0145] The dosage of the compound of the present invention varies depending on the subject, administration route, target disease, symptoms, etc., but for example, when orally administered to an adult patient, the single dose is usually 0.1 mg to 1000 mg, preferably 1 mg to 200 mg, and it is desirable to administer this amount once to three times a day, or once every two to three days.

[0146] Examples of preparations of the compounds of the present invention are given below. Formulation Example 1 Granules containing the following ingredients are prepared: Ingredients: Compound [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof, lactose, cornstarch, HPC-L. Compound [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and lactose are passed through a sieve. Cornstarch is passed through a sieve. These are mixed in a mixer. An aqueous solution of HPC-L is added to the mixed powder, kneaded, granulated (extrusion granulation), and then dried. The resulting dried granules are passed through a vibrating sieve to obtain granules.

[0147] Formulation Example 2 A capsule filling powder containing the following ingredients is prepared: Ingredients: Compound [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof, lactose, corn starch, magnesium stearate. Compound [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and lactose are passed through a sieve. Cornstarch is passed through a sieve. These and magnesium stearate are mixed in a mixer to obtain a powder. The obtained powder can be filled into capsules.

[0148] Formulation Example 3 Granules for capsule filling are prepared containing the following ingredients: Ingredients: Compound [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof, lactose, cornstarch, HPC-L. Compound [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and lactose are passed through a sieve. Cornstarch is passed through a sieve. These are mixed in a mixer. An aqueous solution of HPC-L is added to the mixed powder, kneaded, granulated, and then dried. The resulting dried granules are passed through a vibrating sieve and sized to obtain granules. The resulting granules can be filled into capsules.

[0149] Formulation Example 4 Tablets containing the following ingredients are prepared: Ingredients: Compound [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof, lactose, microcrystalline cellulose, magnesium stearate, CMC-Na. Compound [I] or a pharmaceutically acceptable salt thereof, or a hydrate thereof, lactose, microcrystalline cellulose, and CMC-Na are passed through a sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for formulation. This mixed powder is then directly compressed to obtain tablets. [Example]

[0150] Next, the present invention will be explained in more detail by the following Reference Examples, Examples, and Test Examples, but the present invention is not limited to these examples and may be modified within the scope of the present invention.

[0151] The abbreviations used in this specification have the following meanings:

[0152] s: singlet d: doublet t: triplet q: Quartet quin: quintet sxt: sextet spt: septet dd: doublet of doublets ddd: double doublet of doublets dt: doublet of triplets td: triplet of doublets tt: triple of triplets qd: quarter doublet m: multiplet br: broad J: Coupling constant Hz: Hertz CHLOROFORM-d: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide METHANOL-d4: deuterated methanol ACETONE-d6: deuterated acetone D2O: heavy water

[0153] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride CDI: 1,1'-carbonyldiimidazole DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride HOBt: N-hydroxybenzotriazole monohydrate DBU: 1,8-diazabicyclo[5.4.0]-7-undecene

[0154] Rf: retardation factor posi : positive(mode) nega : negative(mode)

[0155] 1 H-NMR (proton nuclear magnetic resonance spectrum) was measured by the following Fourier transform NMR using tetramethylsilane as an internal standard, and all δ values ​​were expressed in ppm. 400MHz: AVANCE III HD400 (Bruker) 600MHz: JNM-ECA600 (JEOL) After the measurement, heavy water (D2O) was added as necessary and the measurement was continued. Analysis was performed using ACD / Spectrus Processor 2017.1.3 ACD / Labs 2017.1.3 Release (File Version S70S41, Build 97027, 27 Sep 2017) and ACD / Spectrus Processor 2019.1.2 ACD / Labs 2019.1.2 Release (File Version S05S41, Build 112501, 07 Nov 2019) (trade name). Peaks with very gentle protons, such as hydroxy, amino, amide, and pyrazole, may not be recorded. In the analysis of a compound, there may be protons that overlap with the peak of water or solvent and cannot be identified.

[0156] MS (mass spectrum) was measured using the following equipment. PlatformLC (Waters Corporation) LCMS-2010EV (Shimadzu Corporation) LCMS-IT-TOF (Shimadzu Corporation) Agilent6130 (Agilent technologies Inc.) Agilent6150 (Agilent technologies Inc.) The ionization methods used were electrospray ionization (ESI), electron ionization (EI), or dual ionization using ESI and atmospheric pressure chemical ionization (APCI). The data presented are actual measurements. Molecular ion peaks are usually observed, but in the case of compounds containing tert-butoxycarbonyl (-Boc), fragment ion peaks resulting from the elimination of tert-butoxycarbonyl or tert-butyl may also be observed. In the case of compounds containing tetrahydropyranyl (THP), fragment ion peaks resulting from the elimination of tetrahydropyranyl may also be observed. In the case of compounds containing hydroxyl (-OH), fragment peaks resulting from the elimination of HO or OH radicals may also be observed. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.

[0157] In the examples and reference examples, LC-MS was measured under the following conditions. HPLC: Agilent 1290 Infinity MS: Agilent 6130 or 6150 [HPLC conditions] Column: Acquity UPLC CSH C18, 1.7 μm, 2.1 x 50 mm (WATERS) Solvent: Solution A: Water containing 0.1% formic acid, Solution B: Acetonitrile containing 0.1% formic acid

[0158] (Normal mode) Gradient: 0.00 min (solution A / solution B = 80 / 20), 1.20 min (solution A / solution B = 1 / 99), 1.40 min (solution A / solution B = 1 / 99), 1.41 min (solution A / solution B = 80 / 20), 1.50 min (solution A / solution B = 80 / 20) (HP mode) Gradient: 0.00 min (A / B = 95 / 5), 0.80 min (A / B = 60 / 40), 1.08 min (A / B = 1 / 99), 1.38 min (A / B = 1 / 99), 1.41 min (A / B = 95 / 5), 1.50 min (A / B = 80 / 20) (LP mode) Gradient: 0.00 min (Solution A / Solution B = 70 / 30), 0.80 min (Solution A / Solution B = 1 / 99), 1.40 min (Solution A / Solution B = 1 / 99), 1.42 min (Solution A / Solution B = 70 / 30), 1.50 min (Solution A / Solution B = 70 / 30)

[0159] Injection volume: 0.5μL, flow rate: 0.8mL / min Detection method: UV 210nm, 254nm Evaporative Light Scattering Detector (ELSD) included: Agilent 385-ELSD [MS conditions] Ionization method: ESI or ESI / APCI dual mode The measurement conditions for analytical data are described below.

[0160] [Table 1]

[0161] In the Examples and Reference Examples, purification by preparative HPLC was carried out under the following conditions. Equipment: Gilson High-Throughput Purification System Column: Triart C18, 5 μm, 30 × 50 mm (YMC) or X-Bridge Prep C18 5 μm OBD, 30 × 50 (Waters) Solvent: Solution A: 0.1% formic acid in water, Solution B: 0.1% formic acid in acetonitrile, or Solution A: 0.1% trifluoroacetic acid in water, Solution B: 0.1% trifluoroacetic acid in acetonitrile

[0162] (Method A) Gradient: 0.00 min (A / B = 90 / 10), 2.00 min (A / B = 90 / 10), 11.0 min (A / B = 20 / 80), 12.0 min (A / B = 5 / 95), 13.52 min (A / B = 5 / 95), 15.0 min (A / B = 90 / 10) (Method B) Gradient: 0.00 minutes (Liquid A / B = 95 / 5), 3.00 minutes (Liquid A / B = 95 / 5), 8.53 minutes (Liquid A / B = 80 / 20), 10.0 minutes (Liquid A / B = 80 / 20), 11.0 minutes (Liquid A / Liquid B = 50 / 50), 12.02 minutes (Liquid A / Liquid B = 5 / 95), 13.5 minutes (Liquid A / Liquid B = 5 / 95), 13.65 minutes (Liquid A / Liquid B = 95 / 5), 15.0 minutes (Liquid A / Liquid B = 95 / 5) (Method C) Gradient: 0.00 min (Liquid A / B = 80 / 20), 2.00 min (Liquid A / B = 80 / 20), 10.0 min (Liquid A / B = 5 / 95), 11.0 min (Liquid A / Liquid B = 1 / 99), 13.5 minutes (Liquid A / Liquid B = 1 / 99), 13.55 minutes (Liquid A / Liquid B = 80 / 20), 15.0 minutes (Liquid A / Liquid B = 80 / 20)

[0163] Flow rate: 40mL / min Detection method: UV210nm, UV254nm When ELSD is attached SofTA MODEL 300S ELSD

[0164] X-ray crystal structure analysis was performed using an R-AXIS RAPIDII (Rigaku) ​​instrument.

[0165] The microwave reactor used was an Initiator manufactured by Biotage or a MONOWAVE300 manufactured by Anton-Paar.

[0166] Differential thermal analysis / thermogravimetry (TG / DTA) was performed using the Thermo Plus Evo TG8 Measurements were taken using 120 (Rigaku). The melting point was measured using a melting point measuring instrument B-545, BUCHI.

[0167] Infrared absorption spectra (ATR method) were measured using a TENSOR II (Bruker).

[0168] The phase separator used was an ISOLUTE (registered trademark) Phase Separator manufactured by Biotage.

[0169] The synthetic zeolite desiccant used was MS-Ceram-W manufactured by Tokai Chemical Industry Co., Ltd.

[0170] Compound names were generated using ACD / Name (ACD / Name 2017.1.3 and ACD / Name 2019.1.2, Advanced Chemistry Development, Inc.) and LexiChem (version 0.96), a component of PipelinePilot 9.2 manufactured by OpenEye.

[0171] Regarding the asymmetric carbons in the compounds of the Reference Examples and Examples, the stereostructures shown in this specification indicate the absolute configurations, while for meso isomers, the relative configurations are shown. A compound in which the absolute configuration of an asymmetric carbon is indicated is an optically active compound.

[0172] In this specification, "room temperature" refers to 20 to 30°C unless otherwise specified. Additionally, "ice-cold temperature" and "ice-water-cold temperature" refer to 0 to 5°C unless otherwise specified. Furthermore, "ice-cold temperature" with added salt (sodium chloride) refers to -20 to 0°C unless otherwise specified. Unless otherwise specified, "water-cooled temperature" refers to 10 to 20°C.

[0173] Reference example 1-1 1-{4-[(1R)-1-aminoethyl]-3-chloro-2,6-diethoxyphenyl}ethan-1-one

[0174] [ka] (1) To a solution of 4-bromo-3,5-dihydroxybenzoic acid (4 g) in N,N-dimethylformamide (29 mL), potassium carbonate (14.2 g) and iodoethane (6.87 mL) were added and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with a 2:1 mixture of n-hexane and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated. The resulting residue was dissolved in a 4:3 mixture of n-hexane and ethyl acetate (7 mL), and n-hexane (12 mL) was added. The precipitated solid was collected by filtration, and the filtrate was concentrated. The resulting residue was dissolved in 3 mL of ethyl acetate, and n-hexane (16 mL) was added. The precipitated solid was collected by filtration. The resulting solids were combined to give ethyl 4-bromo-3,5-diethoxybenzoate (5.11 g) as a colorless solid. (2) Under a nitrogen atmosphere, a solution of the compound (10 g) obtained in (1) above in acetonitrile (105 mL) was cooled in an ice bath containing sodium chloride. Sulfuryl chloride (2.55 mL) was added (internal temperature: -18°C to -16°C) and the mixture was stirred for 1 hour (internal temperature: -17°C to -12°C). Saturated aqueous sodium bicarbonate solution (75 mL) was added at the same temperature (internal temperature: -17°C to -10°C, pH: 7), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated to obtain ethyl 4-bromo-2-chloro-3,5-diethoxybenzoate (10.4 g) as a colorless oil. (3) A solution of the compound (12.5 g) obtained in (2) above in tetrahydrofuran (59 mL) was ice-cooled, and lithium borohydride (1.93 g) and ethanol (3.0 mL) were slowly added, followed by stirring at the same temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at the same temperature, and the mixture was extracted with chloroform. The organic layer was filtered through a phase separator and concentrated to obtain (4-bromo-2-chloro-3,5-diethoxyphenyl)methanol (10.5 g) as a colorless oil. (4) To a solution of the compound (9 g) obtained in (3) above in toluene (97 mL), manganese dioxide (50.5 g) was added and stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated to give 4-bromo-2-chloro-3,5-diethoxybenzaldehyde (8.1 g) as a yellow powder. MS ESI posi: m / z 307[M+H] + . Retention time: 0.974 min (method A) (5) To a solution of the compound (6.00 g) obtained in (4) above in toluene (39 mL) were added (S)-(-)-tert-butylsulfinamide (2.48 g) and tetraethyl orthotitanate (containing 35% or less of tetraisopropyl orthotitanate) (6.43 mL), and the mixture was stirred at 100°C for 3 hours and then allowed to stand at room temperature overnight. A 10% aqueous solution of disodium citrate 1.5-hydrate was added to the reaction solution, and after stirring for 30 minutes, the mixture was filtered through Celite®, and the filtrate was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous solution of disodium citrate 1.5-hydrate and saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=90:10) to obtain (S 2 S)-N-[(E)-(4-bromo-2-chloro-3,5-diethoxyphenyl)methylidene]-2-methylpropane-2-sulfinamide (7.06 g) was obtained as a colorless powder. (6) This reaction was carried out with reference to the method described in the literature (Chemical Reviews, Vol. 110, p. 3600, 2010). Under a nitrogen atmosphere, a solution of the compound (7.06 g) obtained in (5) above in 1,2-dichloroethane (57 mL) was ice-cooled, and methylmagnesium bromide (3 mol / L diethyl ether solution, 11.5 mL) was added dropwise and stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution at the same temperature, and the mixture was extracted with chloroform. The organic layer was filtered and concentrated using a phase separator. The resulting residue was purified by silica gel column chromatography (n-hexane only, then ethyl acetate only) to obtain (S 2S)-N-[(1R)-1-(4-bromo-2-chloro-3,5-diethoxyphenyl)ethyl]-2-methylpropane-2-sulfinamide (3.94 g) was obtained as a colorless amorphous substance. (7) This reaction was carried out with reference to the method described in the literature (The Journal of Organic Chemistry, Vol. 66, p. 4340, 2001). Under a nitrogen atmosphere, butyl vinyl ether (1.51 mL), palladium(II) acetate (26.3 mg), 1,3-bis(diphenylphosphino)propane (121 mg), and potassium carbonate (486 mg) were added to a mixed solution (5.9 mL-0.59 mL) of the compound (500 mg) obtained in (6) above in N,N-dimethylformamide and water, and the mixture was stirred at 120°C for 3 hours under microwave irradiation. 1 mol / L hydrochloric acid (8 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 13 hours. A saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with chloroform. The organic layer was filtered through a phase separator and concentrated. Saturated saline was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was filtered through a phase separator, concentrated, and then purified by (S 2 S)-N-[(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]-2-methylpropane-2-sulfinamide (457 mg) was obtained as a brown oil. (8) To a solution of the compound obtained in (7) (457 mg) in methanol (3.9 mL), 4 mol / L hydrogen chloride-1,4-dioxane solution (0.88 mL) was added and stirred at room temperature for 45 minutes. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform only to chloroform:methanol = 95:5) to obtain the title compound (320 mg) as a brown amorphous solid. 1 H NMR (400 MHz, CHLOROFORM-d) : δ ppm 1.23 - 1.41 (m, 6 H) 1.63 - 1.72 (m, 3 H) 2.48 (s, 3 H) 3.89 - 4.10 (m, 4 H) 4.92 - 5.01 (m, 1 H) 7.20 (s, 1 H) 8.99 (br s, 2 H). MS ESI posi: m / z 286[M+H] + , 288[(M+2)+H] + . Retention time: 0.813 min (method C) Reference example 1-2 (1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethan-1-amine

[0175] [ka] (1) Methyl 3,5-dihydroxy-4-methylbenzoate (5 g) and potassium carbonate (3.79 g) were mixed with N,N-dimethylformamide (55 mL) and iodoethane (2.66 mL) and stirred at room temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with a 2:1 mixture of n-hexane and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate = 70:30) to give 2.16 g of methyl 3,5-diethoxy-4-methylbenzoate as a colorless powder. (2) Under a nitrogen atmosphere, a solution of the compound (0.5 g) obtained in (1) above in chloroform (0.8 mL) was ice-cooled, and titanium(IV) chloride (506 μL) was added dropwise. The mixture was stirred at the same temperature for 30 minutes. Dichloromethyl methyl ether (187 μL) and chloroform (0.8 mL) were added to the reaction solution, and the mixture was stirred for 30 minutes while returning to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed successively with 0.1 mol / L hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=85:15) to obtain methyl 3,5-diethoxy-2-formyl-4-methylbenzoate (527 mg) as a yellow oil. (3) Methyl 3,5-diethoxy-2,4-dimethylbenzoate

[0176] [ka] Triethylsilane (0.72 mL) was added to a solution of the compound (0.1 g) obtained in (2) above in trifluoroacetic acid (0.3 mL) and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate = 80:20) to obtain the title compound, methyl 3,5-diethoxy-2,4-dimethylbenzoate (62 mg), as a colorless oil. MS ESI positron: m / z 253[M+H] + . Retention time: 1.057 min (method A) (4) Under a nitrogen atmosphere, a solution of the compound obtained in (3) (7.14 g) in tetrahydrofuran (47 mL) was ice-cooled, and lithium borohydride (1.54 g) and ethanol (2.36 mL) were slowly added. The mixture was stirred at the same temperature for 10 minutes, then returned to room temperature for 14 hours. The reaction mixture was ice-cooled, and 18% aqueous ammonium chloride solution was slowly added, followed by extraction with chloroform. The organic layer was filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=70:30) to obtain (3,5-diethoxy-2,4-dimethylphenyl)methanol (4.74 g) as a colorless oil. (5) 3,5-diethoxy-2,4-dimethylbenzaldehyde

[0177] [ka] To a solution of the compound (4.74 g) obtained in (4) above in toluene (106 mL) was added manganese dioxide (18.4 g), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated to obtain the title compound, 3,5-diethoxy-2,4-dimethylbenzaldehyde (4.31 g), as a colorless solid. MS ESI posi: m / z 223[M+H] + . Retention time: 0.926 min (method A) (6) To a solution of the compound obtained in (5) above (474 ​​mg) in toluene (4.3 mL), (S)-(-)-tert-butylsulfinamide (271 mg) and tetraethyl orthotitanate (containing 35% or less of tetraisopropyl orthotitanate) (703 μL) were added, and the mixture was stirred at 100°C for 1 hour. A 10% aqueous solution of disodium citrate 1.5 hydrate was added to the reaction solution, followed by stirring. The mixture was filtered through Celite (registered trademark), and the filtrate was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous solution of disodium citrate 1.5 hydrate and saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=90:10) to give (S 2 S)-N-[(E)-(3,5-diethoxy-2,4-dimethylphenyl)methylidene]-2-methylpropane-2-sulfinamide (618 mg) was obtained as a colorless oil. (7) This reaction was carried out with reference to the method described in the literature (Chemical Reviews, Vol. 110, p. 3600, 2010). A solution of the compound (618 mg) obtained in (6) above in 1,2-dichloroethane (6.3 mL) was ice-cooled, and methylmagnesium bromide (3 mol / L diethyl ether solution, 1.52 mL) was slowly added. The mixture was stirred for 15 hours while returning to room temperature. The reaction solution was ice-cooled, and a saturated aqueous solution of ammonium chloride was added, followed by extraction with chloroform. The organic layer was filtered and concentrated using a phase separator. The resulting residue was purified by silica gel column chromatography (n-hexane only, then ethyl acetate only) to obtain (S 2S)-N-[(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]-2-methylpropane-2-sulfinamide (504 mg) was obtained as a colorless solid. (8) To a solution of the compound obtained in (7) (504 mg) in methanol (4.9 mL), 4 mol / L hydrogen chloride-1,4-dioxane solution (1.11 mL) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated. The resulting residue was purified by silica gel column chromatography (chloroform only to chloroform:methanol = 95:5) to give the title compound, (1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethan-1-amine (321 mg) as a dark green amorphous solid. 1 H NMR (400 MHz, METHANOL-d4) : δ ppm 1.36 - 1.46 (m, 6 H) 1.51 - 1.62 (m, 3 H) 2.12 (s, 3 H) 2.24 (s, 3 H) 3.72 - 3.85 (m, 2 H) 3.99 - 4.14 (m, 2 H) 4.64 - 4.74 (m, 1 H) 6.79 (s, 1 H). Reference example 1-3 1-{4-[(1R)-1-aminoethyl]-2,6-diethoxyphenyl}ethan-1-one hydrochloride

[0178] [ka] (1) Under a nitrogen atmosphere, a solution of lithium borohydride (10.1 g) in tetrahydrofuran (300 mL) was ice-cooled, and ethanol (15.5 mL) and a solution of the compound (58.9 g) obtained in Reference Example 1-1(1) in tetrahydrofuran (100 mL) were added. The mixture was stirred for 23 hours while returning to room temperature. Water (60 mL) was added to the reaction solution over 1 hour, and the mixture was stirred for 2 hours. The reaction solution was ice-cooled, and saturated aqueous ammonium chloride solution (300 mL) was slowly added. The mixture was stirred for 1 hour while returning to room temperature, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated to obtain a mixture (64 g) containing (4-bromo-3,5-diethoxyphenyl)methanol. (2) 4-Bromo-3,5-diethoxybenzaldehyde

[0179] [ka] A solution of the mixture (64 g) obtained in (1) above in toluene (930 mL) was ice-cooled, and manganese dioxide (162 g) was slowly added. The mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered through Celite®. The filtrate was washed successively with a mixed solution of 10% aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate (5:3, 400 mL) and 5% brine (100 mL), and then concentrated. Ethyl acetate (20 mL), toluene (20 mL), and n-hexane (800 mL) were added to the resulting residue (53 g), and the mixture was stirred at 70°C for 30 minutes to dissolve the residue. The mixture was then stirred overnight while returning to room temperature. The reaction mixture was ice-cooled and stirred for 1 hour. The precipitated solid was collected by filtration to obtain the title compound, 4-bromo-3,5-diethoxybenzaldehyde (43.1 g), as a colorless powder. MS ESI posi: m / z 273[M+H] + . Retention time: 1.126min (method B) (3) To a solution of the compound (10 g) obtained in (2) above in toluene (73 mL) were added (S)-(-)-tert-butylsulfinamide (4.66 g) and tetraethyl orthotitanate (containing 35% or less of tetraisopropyl orthotitanate) (12.1 mL), and the mixture was stirred at 100°C for 2 hours. A 10% aqueous solution of disodium citrate 1.5 hydrate was added to the reaction solution, and after stirring for 2 hours, the mixture was filtered through Celite®, and the filtrate was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous solution of disodium citrate 1.5 hydrate and saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated. Ethyl acetate (10 mL) was added to the resulting residue, and the mixture was dissolved at 60°C. n-Hexane (90 mL) was slowly added, and the mixture was stirred for 1 hour while returning to room temperature. The reaction solution was ice-cooled and stirred for 20 minutes. The precipitated solid was collected by filtration, and (S 2 S)-N-[(E)-(4-bromo-3,5-diethoxyphenyl)methylidene]-2-methylpropane-2-sulfinamide (11.0 g) was obtained as a colorless powder. (4) This reaction was carried out with reference to the method described in the literature (Chemical Reviews, Vol. 110, p. 3600, 2010). Under a nitrogen atmosphere, a solution of the compound (10.0 g) obtained in (3) above in toluene (90 mL) was cooled to an internal temperature of -5 to -1°C, and methylmagnesium bromide (3 mol / L diethyl ether solution, 12.4 mL) was added dropwise and stirred at the same temperature for 3 hours. At the same temperature, a 10% aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was stirred overnight at room temperature. The reaction solution was partitioned into two layers, and the organic layer was washed with a 10% aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated and purified by filtration (S 2 A mixture (10.3 g) containing S)-N-[(1R)-1-(4-bromo-3,5-diethoxyphenyl)ethyl]-2-methylpropane-2-sulfinamide was obtained as a colorless solid. (5) (1R)-1-(4-bromo-3,5-diethoxyphenyl)ethan-1-amine hydrochloride

[0180] [ka] To a solution of the mixture (5.00 g) obtained in (4) above in a methanol-tert-butyl methyl ether mixture (10 mL-40 mL), 2 mol / L hydrogen chloride-methanol solution (12.7 mL) was added and stirred at room temperature for 2 hours. The reaction solution was cooled on ice and stirred for 1 hour. The precipitated solid was collected by filtration to obtain the title compound, (1R)-1-(4-bromo-3,5-diethoxyphenyl)ethan-1-amine hydrochloride (4.88 g), as a colorless powder. 1 H NMR (600 MHz, DMSO-d6) : δ ppm 1.34 - 1.39 (m, 6 H) 1.48 - 1.52 (m, 3 H) 4.08 - 4.15 (m, 4 H) 4.30 - 4.42 (m, 1 H) 6.88 - 6.97 (m, 2 H) 8.37 - 8.55 (m, 3 H). (6) To a solution of the compound obtained in (5) (500 mg) in chloroform (4.0 mL), N,N-diisopropylethylamine (537 μL) was added and the mixture was cooled on ice. A solution of di-tert-butyl dicarbonate (403 mg) in chloroform (2 mL) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was partitioned into two layers. The organic layer was filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate = 75:25) to obtain tert-butyl [(1R)-1-(4-bromo-3,5-diethoxyphenyl)ethyl]carbamate (584 mg) as a colorless solid. (7) Under a nitrogen atmosphere, butyl vinyl ether (829 μL), palladium(II) acetate (8.67 mg), 1,3-bis(diphenylphosphino)propane (31.9 mg), and potassium carbonate (534 mg) were added to a solution of the compound (500 mg) obtained in (6) above in N,N-dimethylformamide-water (6.4 mL-0.64 mL), and the mixture was stirred at 120°C for 2 hours under microwave irradiation. 1 mol / L hydrochloric acid (5.0 mL) and ethyl acetate were added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through Celite®, and 10% aqueous potassium carbonate solution was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, filtered through a phase separator, and concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=60:40) to obtain tert-butyl [(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]carbamate (375 mg) as a colorless amorphous substance. (8) To a solution of the compound obtained in (7) (375 mg) in ethyl acetate (2.7 mL), 4 mol / L hydrogen chloride-ethyl acetate solution (2.66 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and a chloroform-methanol mixed solvent (9:1) and saturated aqueous sodium bicarbonate solution were added, followed by extraction with chloroform. The organic layer was filtered through a phase separator and concentrated to obtain 1-{4-[(1R)-1-aminoethyl]-2,6-diethoxyphenyl}ethan-1-one (252 mg) as a pale yellow oil. (9) To a solution of the compound obtained in (8) (453 mg) in ethyl acetate (6.0 mL), 4 mol / L hydrogen chloride-ethyl acetate solution (1.80 mL) was added and stirred at room temperature for 4 hours. The reaction solution was concentrated, and a mixed solvent of n-hexane and ethyl acetate (1:1, 3 mL) was added. The precipitated solid was collected by filtration to obtain the title compound, 1-{4-[(1R)-1-aminoethyl]-2,6-diethoxyphenyl}ethan-1-one hydrochloride (378 mg), as a brown powder. 1H NMR (400 MHz, CHLOROFORM-d) : δ ppm 1.26 - 1.40 (m, 6 H) 1.60 - 1.67 (m, 3 H) 2.45 (s, 3 H) 3.97 - 4.12 (m, 4 H) 4.17 - 4.36 (m, 1 H) 6.72 (s, 2 H) 8.70 (br s, 3 H). Reference example 1-4 (1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethan-1-amine hydrochloride

[0181] [ka] (1) To a solution of the compound (598 mg) obtained in Reference Example 1-3(6) in toluene (15 mL), water (1.5 mL), potassium carbonate (639 mg), cyclopropylboronic acid (198 mg), palladium(II) acetate (69.2 mg), and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos, 287 mg) were added, and the mixture was stirred under reflux for 2 hours and then at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate:chloroform=90:0:10 to 72:18:10) to obtain tert-butyl [(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]carbamate (644 mg) as a yellow solid. (2) A solution of the compound obtained in (1) above (644 mg) in chloroform (2.5 mL) was ice-cooled, and 4 mol / L hydrogen chloride-1,4-dioxane solution (1.2 mL) was added and stirred at room temperature for 1 hour. To the reaction solution, chloroform (3 mL), methanol (2 mL), and 4 mol / L hydrogen chloride-1,4-dioxane solution (0.77 mL) were added, and the mixture was stirred at the same temperature for 6 hours. The reaction solution was then concentrated. Chloroform was added to the resulting residue, and the mixture was stirred at room temperature for 10 minutes. The precipitated solid was collected by filtration to obtain the title compound (380 mg) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) : δ ppm 0.65 - 0.81 (m, 2 H) 0.91 - 1.12 (m, 2 H) 1.33 (t, J = 6.90 Hz, 6 H) 1.41 - 1.54 (m, 3 H) 1.83 - 1.94 (m, 1 H) 4.00 (q, J = 6.90 Hz, 4 H) 4.19 - 4.36 (m, 1 H) 6.73 (s, 2 H) 8.32 (br s, 3 H). Reference example 2-1 2-[(1S)-1-Phenylethoxy]ethyl 4-methylbenzene-1-sulfonate

[0182] [ka] (1) A suspension of sodium hydride (60% dispersion in mineral oil, 1.96 g) in tetrahydrofuran (60 mL) was ice-cooled, and a solution of (S)-(-)-1-phenylethyl alcohol (2 g) in tetrahydrofuran (15 mL) was slowly added and stirred at room temperature for 1 hour. The reaction solution was ice-cooled, and a solution of bromoacetic acid (2.50 g) in tetrahydrofuran (15 mL) was added, and the mixture was stirred at room temperature for 2 days. Tetrahydrofuran (20 mL) was added to the reaction solution, and the mixture was ice-cooled, and water (60 mL) was slowly added. Diethyl ether (40 mL) was added to the reaction solution, and aqueous sodium hydroxide was added to adjust the pH to 12 or higher, and the mixture was extracted three times with water. The aqueous layers were combined, and concentrated hydrochloric acid (4 mL) was added to adjust the pH to 1 or lower, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered through a phase separator, and concentrated to give a mixture containing [(1S)-1-phenylethoxy]acetic acid (3.39 g) as an orange oil. (2) A solution of the mixture (3.39 g) obtained in (1) above in tetrahydrofuran (33 mL) was ice-cooled, and borane-tetrahydrofuran complex (1 mol / L tetrahydrofuran solution, 49.1 mL) was added, followed by stirring at room temperature for 2 hours. The reaction solution was ice-cooled, and isopropyl alcohol (10 mL) was slowly added. Methanol was then added at room temperature, and the mixture was stirred for 17 hours. The solvent was evaporated, and ethyl acetate was added, followed by washing with saturated brine. The organic layer was concentrated to obtain a mixture (2.92 g) containing 2-[(1S)-1-phenylethoxy]ethan-1-ol as a yellow oil. (3) A solution of the mixture (2.92 g) obtained in (2) above in tetrahydrofuran (20 mL) was ice-cooled, and a solution of triethylamine (6.85 mL), trimethylamine hydrochloride (157 mg), and p-toluenesulfonyl chloride (4.37 g) in tetrahydrofuran (8 mL) was added and stirred at room temperature for 17 hours. The reaction solution was ice-cooled, and saturated aqueous sodium bicarbonate solution was added, followed by stirring for 1 hour. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate = 70:30) to obtain the title compound (4.20 g) as a yellow oil. MS ESI positron: m / z 343[M+Na] + . Retention time: 1.141 min (method B) Reference example 3-1 1-{3-chloro-2,6-diethoxy-4-[(1R)-1-({2-[(1S)-1-phenylethoxy]ethyl}amino)ethyl]phenyl}ethan-1-one

[0183] [ka] To a solution of the compound obtained in Reference Example 1-1 (214 mg) in acetonitrile (3.7 mL), the compound obtained in Reference Example 2-1 (264 mg) and N,N-diisopropylethylamine (652 μL) were added, and the mixture was stirred at 85°C for 22 hours. The reaction solution was ice-cooled, and saturated aqueous sodium bicarbonate solution was added, followed by extraction with chloroform. The organic layer was filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only, then ethyl acetate only) to obtain the title compound (96 mg) as a pale yellow oil. MS ESI posi: m / z 434[M+H] + . Retention time: 0.794 min (method B)

[0184] The compound obtained in Reference Example 3-1 above can also be obtained as a hydrochloride salt by the method shown below. Reference Example 3-1a 1-{3-chloro-2,6-diethoxy-4-[(1R)-1-({2-[(1S)-1-phenylethoxy]ethyl}amino)ethyl]phenyl}ethan-1-one hydrochloride

[0185] [ka] (1)

[0186] [ka] 4-Bromo-3,5-diethoxybenzaldehyde (50.0 g) obtained in Reference Example 1-3(2), (S 2A mixture of S)-2-methylpropane-2-sulfinamide (26.6 g), copper(II) sulfate (30.0 g), and toluene (175 g) was heated and stirred at 58-63°C for 13 hours under an argon atmosphere. Water was added to the reaction mixture, which was then stirred and separated into an organic layer and an aqueous layer. The organic layer was filtered through Celite (registered trademark), and the resulting filtrate was washed with water and separated into an organic layer and an aqueous layer. The organic layer was concentrated, and the resulting residue was dissolved in 2-propanol with heating, followed by addition of water and cooling. The resulting suspension was filtered to obtain (S 2 S)-N-[(E)-(4-bromo-3,5-diethoxyphenyl)methylidene]-2-methylpropane-2-sulfinamide (63.0 g) was obtained as a colorless powder. 1 H NMR (600 MHz, CHLOROFORM-d): δ ppm 1.27 (s, 9 H) 1.50 (t, J = 7.0 Hz, 6 H) 4.17 (q, J = 7.0 Hz, 4 H) 7.02 (s, 2 H) 8.48 (s, 1 H). MS ESI / APCI dual posi: m / z 376[M+H] + . (2)

[0187] [ka] Under an argon atmosphere, methylmagnesium chloride (3.0 mol / L tetrahydrofuran solution, 6.20 mL) was added dropwise to a solution of the compound (5.00 g) obtained in (1) above in toluene (39.1 g) at -12 to -10°C over 55 minutes, and the mixture was stirred at -11 to -9°C for 3 hours. A 10% aqueous ammonium chloride solution (40.1 g) was added dropwise to the reaction solution over 11 minutes at 0 to 8°C, and the mixture was stirred at room temperature for 18.5 hours. Toluene (5.17 g) was added to the reaction solution, which was then separated into an organic layer and an aqueous layer. The aqueous layer was extracted with toluene (15.0 g), and the organic layer was separated into an organic layer and an aqueous layer. The organic layers were combined, washed with water (10.1 g), and concentrated. The resulting colorless solid was recrystallized from toluene-n-heptane to give (S 2S)-N-[(1R)-1-(4-bromo-3,5-diethoxyphenyl)ethyl]-2-methylpropane-2-sulfinamide (4.15 g) was obtained as a colorless powder. 1 H NMR (600 MHz, CHLOROFORM-d): δ ppm 1.22 (s, 9 H) 1.46 (t, J = 7.0 Hz, 6 H) 1.50 (d, J = 6.6 Hz, 3 H) 3.29 (d, J = 2.5 Hz, 1 H, exchangeable with D2O) 4.03 - 4.14 (m, 4 H) 4.51 (qd, J = 6.6, 2.5 Hz, 1 H) 6.53 (s, 2 H). MS ESI / APCI dual posi: m / z 392[M+H] + . The concentrated residue of the filtrate from the recrystallization was purified by silica gel column chromatography (n-hexane:ethyl acetate=50:50) to obtain the isomers (S 2 S)-N-[(1S)-1-(4-bromo-3,5-diethoxyphenyl)ethyl]-2-methylpropane-2-sulfinamide was obtained as a colorless powder.

[0188] [ka] 1 H NMR (600 MHz, CHLOROFORM-d) : δ ppm 1.24 (s, 9 H) 1.47 (t, J = 7.0 Hz, 6 H) 1.50 (d, J = 6.6 Hz, 3 H) 3.39 (d, J = 2.5 Hz, 1 H, exchangeable with D2O) 4.10 (q, J = 6.9 Hz, 4 H) 4.47 (qd, J = 6.5, 3.1 Hz, 1 H) 6.56 (s, 2 H). MS ESI / APCI dual posi: m / z 392[M+H] + . (3)

[0189] [ka] Under an argon atmosphere, the (S 2 To a solution of (S)-N-[(1R)-1-(4-bromo-3,5-diethoxyphenyl)ethyl]-2-methylpropane-2-sulfinamide (4.00 g) in methanol (6.34 g) and tert-butyl methyl ether (23.8 g), 2 mol / L hydrogen chloride-methanol solution (20.4 mL) was added dropwise over 23 minutes at 22-26°C, followed by stirring at 24-25°C for 2.5 hours. The resulting suspension was cooled and stirred in an ice-water bath for 1 hour, and then filtered to obtain (1R)-1-(4-bromo-3,5-diethoxyphenyl)ethan-1-amine hydrochloride (3.26 g) (containing tert-butyl methyl ether, content 89.2%) as a colorless powder. Melting point: 230℃ 1 H NMR (600 MHz, DMSO-d6): δ ppm 1.36 (t, J = 7.0 Hz, 6 H) 1.52 (d, J = 7.0 Hz, 3 H) 4.13 (q, J = 7.0 Hz, 4 H) 4.30 - 4.39 (m, 1 H) 7.00 (s, 2 H) 8.69 (br s, 3 H, exchangeable with D2O). (4)

[0190] [ka] Under an argon atmosphere, a solution of the compound (50.0 g) obtained in (1) above in tetrahydrofuran (250 g) was added dropwise to methylmagnesium bromide (1.06 mol / L tetrahydrofuran solution, 200 mL) at 0 to 2°C over 45 minutes, and the mixture was stirred at 0 to 1°C for 3 hours. A 10% aqueous ammonium chloride solution (400 g) was added dropwise to the reaction mixture at 1 to 8°C over 30 minutes, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and then extracted with tert-butyl methyl ether (300 g), and the organic layer and aqueous layer were separated. The organic layer was washed with water and separated, and (S2 S)-N-[(1R)-1-(4-bromo-3,5-diethoxyphenyl)ethyl]-2-methylpropane-2-sulfinamide and (S 2 A tert-butyl methyl ether solution (367 g) of a mixture of (S)-N-[(1S)-1-(4-bromo-3,5-diethoxyphenyl)ethyl]-2-methylpropane-2-sulfinamide was obtained. (5)

[0191] [ka] Under an argon atmosphere, a 2 mol / L hydrogen chloride-methanol solution (133 mL) was added dropwise over 50 minutes to a solution (367 g) of the mixture obtained in (4) above in tert-butyl methyl ether and methanol (75.1 g) at 26-27°C, followed by stirring at the same temperature for 17.5 hours. The resulting suspension was cooled and stirred in an ice-water bath, and then filtered to obtain a mixture (44.4 g) of (1R)-1-(4-bromo-3,5-diethoxyphenyl)ethan-1-amine hydrochloride and (1S)-1-(4-bromo-3,5-diethoxyphenyl)ethan-1-amine hydrochloride (containing tert-butyl methyl ether, content 86.2%) as a colorless powder. Melting point: 237℃ 1 H NMR (600 MHz, DMSO-d6): δ ppm 1.36 (t, J = 7.0 Hz, 6 H) 1.52 (d, J = 7.0 Hz, 3 H) 4.13 (q, J = 6.9 Hz, 4 H) 4.34 (q, J = 6.6 Hz, 1 H) 7.00 (s, 2 H) 8.70 (br s, 3 H, exchangeable with D2O). (6)

[0192] [ka] Under an argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (24.9 g) was added to a mixed solution of the mixture (40.6 g) (content 86.2%) obtained in (5) above, 1-hydroxybenzotriazole monohydrate (19.8 g), [(1S)-1-phenylethoxy]acetic acid (21.4 g) obtained in Reference Example 2-1(1)), and N,N-dimethylformamide (105 g) over 7 minutes at 1 to 5°C, followed by dropwise addition of N,N-diisopropylethylamine (16.8 g) over 15 minutes at 2 to 6°C. The reaction solution was stirred for 3 hours while warming to 26°C. Toluene (105 g) and water (175 g) were added to the reaction solution, and the mixture was stirred and separated into an organic layer and an aqueous layer. The organic layer was washed successively with a 5% aqueous sodium bicarbonate solution and water, and the organic layer and aqueous layer were separated. The organic layer was concentrated and crystallized from a mixed solvent of isopropyl acetate and n-heptane to give N-[(1R)-1-(4-bromo-3,5-diethoxyphenyl)ethyl]-2-[(1S)-1-phenylethoxy]acetamide (37.1 g) as a colorless powder. 1 H NMR (600 MHz, CHLOROFORM-d): δ ppm 1.46 (t, J = 7.0 Hz, 6 H) 1.50 (d, J = 6.6 Hz, 3 H) 1.51 (d, J = 6.6 Hz, 3 H) 3.81, 3.89 (AB quartet, J AB = 15.3 Hz, 2 H) 4.03 - 4.12 (m, 4 H) 4.45 (q, J = 6.6 Hz, 1 H) 5.04 - 5.11 (m, 1 H) 6.48 (s, 2 H) 6.81 (br d, J = 7.8 Hz, 1 H, exchangeable with D2O) 7.21 - 7.25 (m, 2 H) 7.26 - 7.33 (m, 3 H). MS ESI / APCI dual posi: m / z 472[M+Na] + , 474[(M+2)+Na] + . (7)

[0193] [ka] Under an argon atmosphere, borane-tetrahydrofuran complex (1 mol / L tetrahydrofuran solution, 233 mL) was added dropwise to a solution of the compound (35.0 g) obtained in (6) above in tetrahydrofuran (175 g) at 25-33°C over 45 minutes, followed by stirring at 26-33°C for 5 hours. Methanol (52.6 g) was added dropwise to the reaction solution at 26-34°C over 35 minutes, and the mixture was then heated to 55-57°C and stirred for 3 hours. The reaction solution was concentrated, and methanol (140 g) was added to the solution, to which 2 mol / L hydrochloric acid (42.8 g) was added at 43-46°C. Water and methanol were then added at 44-46°C for crystallization, yielding (1R)-1-(4-bromo-3,5-diethoxyphenyl)-N-{2-[(1S)-1-phenylethoxy]ethyl}ethan-1-amine hydrochloride (33.6 g) as a colorless powder. 1 H NMR (600 MHz, DMSO-d6): δ ppm 1.36 (t, J = 7.0 Hz, 6 H) 1.37 (d, J = 6.6 Hz, 3 H) 1.62 (d, J = 6.6 Hz, 3 H) 2.67 - 2.77 (m, 1 H) 2.87 - 2.97 (m, 1 H) 3.47 (dt, J = 10.8, 5.5 Hz, 1 H) 3.54 - 3.60 (m, 1 H) 4.08 - 4.17 (m, 4 H) 4.28 - 4.37 (m, 1 H) 4.49 (q, J = 6.6 Hz, 1 H) 7.05 (s, 2 H) 7.25 - 7.30 (m, 1 H) 7.30 - 7.37 (m, 4 H) 9.50 (br s, 1 H, exchangeable with D2O) 9.87 (br s, 1 H, exchangeable with D2O). MS ESI / APCI dual posi: m / z 436[M+H] + . (8)

[0194] [ka] A mixture of the compound obtained in (7) above (18.0 g), potassium carbonate (15.8 g), ethylene glycol monovinyl ether (6.74 g), and toluene (93.6 g) was degassed under reduced pressure and purged with argon. 1,3-bis(diphenylphosphino)propane (0.629 g) and palladium(II) acetate (0.172 g) were added. The mixture was degassed under reduced pressure, purged with argon, and stirred at 110-112°C for 6.5 hours. The reaction mixture was cooled, and 1-propanethiol silica gel (1.3 mmol / g) (3.61 g) was added at 40°C. The mixture was stirred at 58-62°C for 1 hour. After cooling to room temperature and stirring (at 25°C for 15 hours), the reaction mixture was filtered through a cellulose powder pad. 2 mol / L hydrogen chloride-ethanol solution (28.6 mL) was added dropwise to the filtrate over 30 minutes at 24-26°C, followed by stirring at 24-25°C for 1 hour. A 5% aqueous solution of sodium hydroxide (61.0 g) was added dropwise over 15 minutes at 23-26°C, followed by stirring at the same temperature for 15 minutes. The organic and aqueous layers were separated, and the organic layer was washed with water and then concentrated. The concentrated residue was dissolved in isopropyl acetate and n-heptane, and then crystallized by the addition of 2 mol / L hydrogen chloride-2-propanol solution (20.0 mL) at 43-45°C to obtain 1-{2,6-diethoxy-4-[(1R)-1-({2-[(1S)-1-phenylethoxy]ethyl}amino)ethyl]phenyl}ethan-1-one hydrochloride (13.9 g) as a colorless powder. 1H NMR (600 MHz, DMSO-d6): δ ppm 1.28 (t, J = 7.0 Hz, 6 H) 1.38 (d, J = 6.2 Hz, 3 H) 1.61 (d, J = 6.6 Hz, 3 H) 2.36 (s, 3 H) 2.69 - 2.78 (m, 1 H) 2.89 - 2.97 (m, 1 H) 3.48 (dt, J = 10.7, 5.4 Hz, 1 H) 3.55 - 3.61 (m, 1 H) 4.06 (qd, J = 7.0, 1.2 Hz, 4 H) 4.27 - 4.35 (m, 1 H) 4.49 (q, J = 6.6Hz, 1H) 7.02 (s, 2 H) 7.26 - 7.30 (m, 1 H) 7.31 - 7.37 (m, 4 H) 9.51 (br s, 1 H, exchangeable with D2O) 9.87 (br s, 1 H, exchangeable with D2O). MS ESI / APCI dual posi: m / z 400[M+H] + . (9) Under a nitrogen atmosphere, a solution of 1,3-dichloro-5,5-dimethylhydantoin (4.75 g) in toluene (90 mL) was added dropwise to a suspension of the compound (10.0 g) obtained in (8) above in toluene (50 mL) at 1 to 5°C over 15 minutes, followed by stirring at the same temperature for 3 hours. A 20% aqueous solution of sodium ascorbate (80 mL) was added dropwise to the reaction solution at 0 to 8°C over 28 minutes, followed by stirring for 18 hours while warming to room temperature. The reaction solution was separated into an organic layer and an aqueous layer. A 1 mol / L aqueous solution of sodium hydroxide (60 mL) was added dropwise to the organic layer at 23°C over 3 minutes, followed by stirring at the same temperature for 1.5 hours. The organic layer was separated into an organic layer and an aqueous layer, and the organic layer was washed twice with water and then concentrated. Ethanol and n-heptane were added to the resulting residue, and a 2 mol / L hydrogen chloride-ethanol solution (12.6 mL) was added dropwise over 3 minutes at 38 to 40° C. to cause crystallization, yielding the title compound (9.81 g) as a colorless powder. 1H NMR (600 MHz, CHLOROFORM-d) : δ ppm 1.37 (t, J = 7.0 Hz, 3 H) 1.39 (t, J = 7.0 Hz, 3 H) 1.45 (d, J = 6.2 Hz, 3 H) 1.84 (d, J = 6.6 Hz, 3 H) 2.51 (s, 3 H) 2.89 - 3.01 (m, 2 H) 3.59 - 3.71 (m, 2 H) 4.02 (q, J = 7.0 Hz, 2 H) 4.15 - 4.29 (m, 2 H) 4.44 (q, J = 6.3 Hz, 1 H) 4.89 - 4.99 (m, 1 H) 7.23 - 7.27 (m, 3 H) 7.28 - 7.33 (m, 2 H) 7.62 (s, 1 H) 9.66 (br s, 1 H, exchangeable with D2O) 10.60 (br s, 1 H, exchangeable with D2O). MS ESI / APCI dual posi: m / z 434[M+H] + . Reference example 3-2 (1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)-N-{2-[(1S)-1-phenylethoxy]ethyl}ethan-1-amine

[0195] [ka] To a solution of the compound obtained in Reference Example 1-2 (118 mg) in acetonitrile (2.5 mL), the compound obtained in Reference Example 2-1 (239 mg) and N,N-diisopropylethylamine (433 μL) were added, and the mixture was stirred at 85°C for 2 hours, at room temperature for 17 hours, at 85°C for 12 hours, and at room temperature for 19 hours. The reaction mixture was ice-cooled, and saturated aqueous sodium bicarbonate solution was added, followed by extraction with chloroform. The organic layer was filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only, then ethyl acetate only) and silica gel column chromatography (n-hexane:ethyl acetate = 70:30, then ethyl acetate only) to obtain the title compound (77 mg) as a brown oil. MS ESI posi: 386[M+H] + . Retention time: 0.629 min (method A)

[0196] The compound obtained in Reference Example 3-2 above can also be obtained by the method shown below. Reference example 3-2a (1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)-N-{2-[(1S)-1-phenylethoxy]ethyl}ethan-1-amine

[0197] [ka] (1) Under a nitrogen atmosphere, methylboronic acid (3.22 g), potassium carbonate (14.9 g), palladium(II) acetate (402 mg), and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos, 1.67 g) were added to a solution of the compound (5.51 g) obtained in Reference Example 1-1(4) in toluene (90 mL), and the mixture was stirred under reflux for 39 hours. Water (968 μL) was added under a nitrogen atmosphere, and the mixture was stirred under reflux for 6 hours. The reaction mixture was allowed to cool, then filtered through Celite®, water was added, and the mixture was extracted twice with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated. The resulting residue was purified twice by silica gel column chromatography (n-hexane:ethyl acetate=99:1 to 90:10) to obtain 3,5-diethoxy-2,4-dimethylbenzaldehyde (4.19 g) as a yellow oily substance. (2) To a solution of the compound (7.05 g) (content 95.23%) obtained in (1) above in toluene (60 mL) were added (S)-(-)-tert-butylsulfinamide (4.88 g) and copper(II) sulfate (4.82 g), and the mixture was stirred at 60°C for 2 hours, then allowed to return to room temperature for 11 hours. The reaction solution was ice-cooled, and water (60 mL) was added, followed by vigorous stirring at room temperature for 30 minutes. The reaction solution was filtered through Celite (registered trademark), and the filtrate was partitioned into two layers. The organic layer was washed with water (120 mL), and the combined aqueous layer was extracted again with toluene. The combined organic layer was filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 97:3 to 70:30), and the purified product was azeotroped with toluene to obtain (S 2 S)-N-[(E)-(3,5-diethoxy-2,4-dimethylphenyl)methylidene]-2-methylpropane-2-sulfinamide (9.77 g) was obtained as a yellow oil. (3) This reaction was carried out with reference to the method described in the literature (Chemical Reviews, Vol. 110, p. 3600, 2010). Under a nitrogen atmosphere, a solution of the compound (9.77 g) obtained in (2) above in 1,2-dichloroethane (85 mL) was ice-cooled, and methylmagnesium bromide (3 mol / L diethyl ether solution, 25.5 mL) was added dropwise over 10 minutes at 2.7 to 10.1°C. The mixture was then stirred for 16 hours while returning to room temperature. The reaction solution was ice-cooled, and a mixed solution of saturated aqueous ammonium chloride and water (1:1) was slowly added at 5.0 to 17.0°C. Chloroform, saturated saline, and water were added to the reaction solution, and the mixture was partitioned into two layers. The organic layer was filtered through Celite®, and the filtrate was washed with water. The organic layer was filtered through a phase separator and concentrated. The resulting residue was purified four times by silica gel column chromatography (n-hexane:ethyl acetate = 88:12, then ethyl acetate only) to obtain (S 2 S)-N-[(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]-2-methylpropane-2-sulfinamide (7.34 g) was obtained as a colorless powder. (4) (1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethan-1-amine hydrochloride

[0198] [ka] To a mixed solution (22 mL-86 mL) of the compound (7.34 g) obtained in (3) above in methanol and tert-butyl methyl ether, a hydrogen chloride-methanol solution (Tokyo Chemical Industry Co., Ltd.; concentration: 5-10%; 31.3 g) was added and stirred at room temperature for 50 minutes. The reaction solution was concentrated, and tert-butyl methyl ether (30 mL) was added to form a suspension. The suspension was ice-cooled and stirred for 20 minutes. The solid was collected by filtration to obtain the title compound, (1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethan-1-amine hydrochloride (4.72 g), as a colorless powder. 1H NMR (600 MHz, CHLOROFORM-d) : δ ppm 1.21 - 1.25 (m, 3 H) 1.38 - 1.43 (m, 3 H) 1.55 - 1.58 (m, 3 H) 2.12 (s, 3 H) 2.19 (s, 3 H) 3.70 - 3.84 (m, 3 H) 3.90 - 4.01 (m, 1 H) 4.60 - 4.68 (m, 1 H) 6.97 (s, 1 H) 8.76 (br s, 3 H). (5) N-[(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]-2-[(1S)-1-phenylethoxy]acetamide

[0199] [ka] To a solution of the compound obtained in (4) above (1.00 g) in N,N-dimethylformamide (18 mL), [(1S)-1-phenylethoxy]acetic acid (696 mg) obtained in Reference Example 2-1(1) and N,N-diisopropylethylamine (1.53 mL) were added, and the mixture was stirred on ice for 5 minutes. HATU (1.60 g) was added to the reaction mixture, and the mixture was stirred for 3 hours while returning to room temperature. Water (30 mL), ethyl acetate (30 mL), and n-hexane (1 mL) were added to the reaction mixture, and after stirring, the mixture was partitioned into two layers. Water (30 mL), ethyl acetate (10 mL), and n-hexane (5 mL) were added to the organic layer, and after stirring, the mixture was partitioned into two layers. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=93:7 to 40:60) to obtain the title compound, N-[(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]-2-[(1S)-1-phenylethoxy]acetamide (1.41 g) as a brown oil. MS ESI positron: m / z 400[M+H] + , 422[M+Na] + . Retention time: 1.268 min (method B) (6) Under a nitrogen atmosphere, borane-tetrahydrofuran complex (1 mol / L tetrahydrofuran solution, 9.86 mL) was cooled with water, and a solution of the compound obtained in (5) (1.41 g) in tetrahydrofuran (3.2 mL) was slowly added and stirred at room temperature for 5 hours. 1 mol / L hydrochloric acid (2.0 mL) was added to the reaction mixture, and the mixture was stirred at 60°C for 30 minutes, overnight while returning to room temperature, and then at 60°C for 7 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 88:12 to ethyl acetate only) to obtain the title compound, (1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)-N-{2-[(1S)-1-phenylethoxy]ethyl}ethan-1-amine (878 mg) as a pale yellow oil. Reference example 3-3 1-{2,6-diethoxy-4-[(1R)-1-({2-[(1S)-1-phenylethoxy]ethyl}amino)ethyl]phenyl}ethan-1-one hydrochloride

[0200] [ka] (1) A saturated aqueous solution of sodium bicarbonate was added to a chloroform solution of the compound (600 mg) obtained in Reference Example 1-3, and the mixture was extracted with chloroform. The organic layer was filtered through a phase separator and concentrated to give 1-{4-[(1R)-1-aminoethyl]-2,6-diethoxyphenyl}ethan-1-one. (2) To a solution of the compound obtained in (1) above in acetonitrile (10 mL) were added the compound obtained in Reference Example 2-1 (735 mg) and N,N-diisopropylethylamine (1.09 mL), and the mixture was stirred at 80°C for 25 hours. The reaction mixture was ice-cooled, and saturated aqueous sodium bicarbonate solution was added, followed by extraction twice with ethyl acetate. The organic layer was filtered through a phase separator and concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane only, then ethyl acetate only) to give 1-{2,6-diethoxy-4-[(1R)-1-({2-[(1S)-1-phenylethoxy]ethyl}amino)ethyl]phenyl}ethan-1-one (917 mg) as a pale yellow oil. (3) To a solution of the compound (917 mg) obtained in (2) above in ethyl acetate (6.9 mL) was added 4 mol / L hydrogen chloride-ethyl acetate solution (2.09 mL) and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated, and a mixed solvent of n-hexane and ethyl acetate (2:1, 4.0 mL) was added. The precipitated solid was collected by filtration to obtain the title compound (418 mg) as a colorless solid. MS ESI positron: m / z 400[M+H] + . Retention time: 0.823 min (method B) Reference example 3-4 (1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)-N-{2-[(1S)-1-phenylethoxy]ethyl}ethan-1-amine hydrochloride

[0201] [ka] (1) A saturated aqueous solution of sodium bicarbonate was added to a solution of the compound obtained in Reference Example 1-4 (240 mg) in chloroform (1.0 mL), and the mixture was stirred for 30 minutes at 50° C. The mixture was partitioned into two layers, and the organic layer was dried over anhydrous magnesium sulfate, filtered through a phase separator, and concentrated to give (1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethan-1-amine (229 mg). (2) To a solution of the compound obtained in (1) above (229 mg) in acetonitrile (4.2 mL), the compound obtained in Reference Example 2-1 (283 mg) and N,N-diisopropylethylamine (585 μL) were added, and the mixture was stirred at 80-84°C for 40 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered through a phase separator, and concentrated. The resulting residue was purified by preparative HPLC to give (1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)-N-{2-[(1S)-1-phenylethoxy]ethyl}ethan-1-amine (210 mg) as a colorless oil. MS ESI positron: m / z 398[M+H] + . Retention time: 0.869 min (method B) (3) To a solution of the compound (210 mg) obtained in (2) above in chloroform (3.0 mL), 2 mol / L hydrogen chloride-methanol solution (0.840 mL) was added and stirred at room temperature for 5 minutes. The reaction solution was concentrated to obtain the title compound (212 mg) as a colorless solid. MS ESI / APCI dual posi: m / z 398[M+H] + . Reference example 4-1 Ethyl trans-1-amino-3-ethoxycyclobutane-1-carboxylate hydrochloride

[0202] [ka] This reaction was carried out with reference to the method described in the literature (Bioorganic & Medicinal Chemistry, Vol. 17, p. 1982, 2009). (1) To a solution of ethyl 1-[(tert-butoxycarbonyl)amino]-3-oxocyclobutane-1-carboxylate (15 g) in 1,4-dioxane (30 mL), 4 mol / L hydrogen chloride in 1,4-dioxane (120 mL) was added and stirred at room temperature for 14 hours. The precipitated solid was collected by filtration to give ethyl 1-amino-3-oxocyclobutane-1-carboxylate hydrochloride (11.0 g) as a colorless solid. (2) To a solution of the compound obtained in (1) (200 mg) in toluene (5.2 mL), phthalic anhydride (306 mg) and triethylamine (288 μL) were added and the mixture was stirred under reflux for 4.5 hours. The reaction mixture was returned to room temperature, and water and 1 mol / L hydrochloric acid were added to adjust the pH to 2. The mixture was then extracted twice with ethyl acetate. The organic layer was filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate = 50:50) to give ethyl 1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxocyclobutane-1-carboxylate (404 mg) as a colorless solid. (3) Under a nitrogen atmosphere, zinc chloride (0.5 mol / L tetrahydrofuran solution, 2.78 mL) was added to a solution of the compound (200 mg) obtained in (2) above in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to -78°C, and lithium tri-sec-butylborohydride (L-Selectride (registered trademark), 1 mol / L tetrahydrofuran solution, 1.04 mL) was slowly added dropwise, followed by stirring at the same temperature for 2 hours and then at room temperature for 50 minutes. The reaction solution was ice-cooled, and saturated aqueous ammonium chloride solution (10 mL) was added, followed by extraction twice with ethyl acetate. The organic layer was washed with saturated brine, filtered through a phase separator, and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=50:50) to obtain ethyl trans-1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-hydroxycyclobutane-1-carboxylate (179 mg) as a colorless oil. (4) To a solution of the compound obtained in (3) (2.0 g) in acetonitrile (35 mL), silver(I) oxide (16 g) and iodoethane (2.8 mL) were added, and the mixture was stirred at 80°C for 24 hours, at room temperature for 2 days, at 80°C for 12 hours, and at room temperature overnight. The reaction mixture was filtered through Celite®, and the filtrate was concentrated. The resulting residue was purified by column chromatography using an NH silica gel column cartridge and a silica gel column cartridge (n-hexane:ethyl acetate = 95:5 to 50:50, followed by chloroform:methanol = 90:10) to obtain ethyl trans-1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-ethoxycyclobutane-1-carboxylate (1.38 g) as a pale yellow solid. 1 H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.16 - 1.30 (m, 6 H) 2.76 - 2.96 (m, 2 H) 3.38 - 3.51 (m, 2 H) 3.51 - 3.66 (m, 2 H) 4.05 - 4.26 (m, 3 H) 7.71 - 7.79 (m, 2 H) 7.79 - 7.91 (m, 2 H). The resulting pale yellow solid was recrystallized from ethanol to obtain a single crystal, which was confirmed to have the desired structure shown below by X-ray structural analysis.

[0203] [ka] (5) To a solution of the compound (2.00 g) obtained in (4) above in ethanol (21 mL) was added hydrazine monohydrate (313 μL) and stirred at 40°C for 1.2 hours. Hydrazine monohydrate (6.14 μL) was added to the reaction solution, and the mixture was stirred at 40°C for 0.8 hours, heated under reflux for 6.5 hours, and then overnight at room temperature. The insoluble matter was filtered off, and the filtrate was concentrated. Ethanol was added to the resulting residue, the insoluble matter was filtered off, and the filtrate was concentrated. Chloroform (15 mL) and 1 mol / L hydrochloric acid (12 mL) were added to the resulting residue, and the aqueous layer was washed with chloroform. The organic layers were combined and extracted with 1 mol / L hydrochloric acid (10 mL). The aqueous layers were combined, and a solution of sodium hydroxide (1.4 g) in water (3.5 mL) was added to adjust the pH to 10, followed by extraction with chloroform. The organic layer was filtered through a phase separator and concentrated to give ethyl trans-1-amino-3-ethoxycyclobutane-1-carboxylate (475 mg) as a pale brown oil. (6) To the compound (400 mg) obtained in (5) above, a 2 mol / L hydrogen chloride-ethanol solution (3.20 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and toluene was added to the resulting residue and concentrated to give the title compound (469 mg) as a colorless powder. MS ESI posi: m / z 188[M+H] + . Retention time: 0.415 min (method C) Reference example 5-1 trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid

[0204] [ka] (1) A solution of the compound obtained in Reference Example 4-1 (24.7 mg) in tetrahydrofuran (0.3 mL) was ice-cooled, and N,N-diisopropylethylamine (80.3 μL) was added and stirred at room temperature for 10 minutes. The reaction solution was ice-cooled, and a solution of 4-nitrophenyl chloroformate (22.3 mg) in tetrahydrofuran (0.3 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was ice-cooled, and a solution of the compound obtained in Reference Example 3-1 (40 mg) in tetrahydrofuran (0.3 mL) was added, and the mixture was stirred at 60°C for 10 minutes and at room temperature for 15 hours. (2) To the reaction solution of (1) above, methanol (922 μL) and 2 mol / L aqueous sodium hydroxide solution (230 μL) were added and stirred for 1 hour at 60° C. The reaction solution was concentrated, and the resulting residue was purified by preparative HPLC and lyophilized to obtain the title compound (31.2 mg) as a colorless powder. 1 H NMR (400 MHz, METHANOL-d4) : δ ppm 1.14 - 1.20 (m, 3 H) 1.30 - 1.37 (m, 6 H) 1.38 - 1.42 (m, 3 H) 1.44 - 1.48 (m, 3 H) 2.32 - 2.50 (m, 6 H) 2.54 - 2.63 (m, 1 H) 2.64 - 2.76 (m, 1 H) 3.03 - 3.16 (m, 1 H) 3.23 - 3.47 (m, 4 H) 3.94 - 4.03 (m, 2 H) 4.03 - 4.13 (m, 3 H) 4.27 - 4.37 (m, 1 H) 5.55 - 5.63 (m, 1 H) 6.86 (s, 1 H) 7.20 - 7.34 (m, 5 H). MS ESI positron: m / z 619[M+H] + , 641[M+Na] + . MS ESI negative: m / z 617[MH] - . Retention time: 0.947 min (method A)

[0205] The ethyl trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylate (ethyl (1r,3R)-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylate) obtained in Reference Example 5-1(1) above can also be obtained by the method shown below. Reference Example 5-1a Ethyl (1r,3R)-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylate

[0206] [ka] To a solution of the compound obtained in Reference Example 4-1 (0.100 g) and 4-nitrophenyl chloroformate (0.092 g) in tetrahydrofuran (2.00 mL), a solution of N,N-diisopropylethylamine (0.283 g) in tetrahydrofuran (0.500 mL) was added dropwise over 13 minutes at 4°C. The resulting suspension was stirred at 3-5°C for 2 hours, and then the compound obtained in Reference Example 3-1a (0.200 g) was added at 5-6°C. The mixture was stirred for 21 hours while warming to room temperature. Water (1.00 mL) was added to the reaction mixture, which was then concentrated. tert-butyl methyl ether (10.0 mL) and 5% aqueous sodium hydroxide solution (5.00 mL) were added and the mixture was stirred, and the organic and aqueous layers were separated. The organic layer was washed sequentially with 5% aqueous sodium hydroxide solution (5.00 mL) and saturated brine (5.00 mL) and then dried over anhydrous magnesium sulfate. After filtering off the insoluble matter, the filtrate was concentrated, and the resulting residue was crystallized from a 2-propanol-n-heptane mixed solvent to obtain the title compound (0.203 g) as a colorless powder. 1H NMR (600 MHz, CHLOROFORM-d) : δ ppm 1.20 (t, J = 7.0 Hz, 3 H) 1.30 (t, J = 7.0 Hz, 3 H) 1.35 (t, J = 7.0 Hz, 3 H) 1.37 (t, J = 7.0 Hz, 3 H) 1.44 (d, J = 6.6 Hz, 3 H) 1.45 (d, J = 6.2 Hz, 3 H) 2.34 - 2.40 (m, 1 H) 2.43 - 2.50 (m, 2 H) 2.46 (s, 3 H) 2.71 (dd, J = 11.6, 7.8 Hz, 2 H) 3.05 - 3.12 (m, 1H) 3.15 (ddd, J = 9.8, 4.4, 1.9 Hz, 1 H) 3.37 - 3.46 (m, 3 H) 3.99 (q, J = 7.0 Hz, 2 H) 4.02 (q, J = 7.0 Hz, 2 H) 4.12 (quin, J = 7.3 Hz, 1 H) 4.16 - 4.28 (m, 2 H) 4.34 (q, J = 6.6 Hz, 1 H) 5.61 (q, J = 6.7 Hz, 1 H) 6.70 (s, 1 H) 7.02 (br s, 1 H, exchangeable with D2O) 7.22 - 7.28 (m, 3 H) 7.29 - 7.33 (m, 2 H). MS ESI / APCI dual posi: m / z 647[M+H] + , 649[(M+2)+H] + . MS ESI / APCI dual nega: m / z 645[MH] - . Reference example 5-2 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid

[0207] [ka] Using ethyl 1-aminocyclopropane-1-carboxylate hydrochloride (18.3 mg) and the compound obtained in Reference Example 3-1 (40.0 mg), a reaction was carried out according to the method described in Reference Example 5-1 to obtain the title compound (31.6 mg) as a colorless powder. 1 H NMR (400 MHz, METHANOL-d4) : δ ppm 0.94 - 1.11 (m, 2 H) 1.21 - 1.54 (m, 16 H) 2.42 (s, 3 H) 2.74 - 2.84 (m, 1 H) 2.99 - 3.07 (m, 1 H) 3.91 - 4.14 (m, 4 H) 4.27 - 4.36 (m, 1 H) 5.56 - 5.65 (m, 1 H) 6.86 (s, 1 H) 7.19 - 7.33 (m, 5 H). MS ESI positron: m / z 561[M+H] + , 583[M+Na] + . MS ESI negative: m / z 559[MH] - . Retention time: 0.889 min (method A) Reference example 5-3 trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid

[0208] [ka] The compound obtained in Reference Example 4-1 (18.1 mg) and the compound obtained in Reference Example 3-2 (26 mg) were reacted according to the method described in Reference Example 5-1 to obtain the title compound (29.4 mg) as a colorless amorphous substance. 1H NMR (400 MHz, METHANOL-d4) : δ ppm 1.12 - 1.21 (m, 3 H) 1.27 -1.46 (m, 12 H) 2.05 - 2.19 (m, 6 H) 2.27 - 2.50 (m, 5 H) 2.60 - 2.69 (m, 1 H) 2.85 - 2.94 (m, 1 H) 3.11 - 3.21 (m, 1 H) 3.38 - 3.47 (m, 2 H) 3.68 - 3.80 (m, 2 H) 3.94 - 4.03 (m, 2 H) 4.03 - 4.22 (m, 2 H) 5.48 - 5.57 (m, 1H) 6.68 (s, 1 H) 7.12 - 7.31 (m, 5 H). MS ESI posi: m / z 571[M+H] + , 593[M+Na] + . Retention time: 1.043 min (method A) Reference example 5-4 trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid

[0209] [ka] The compound obtained in Reference Example 4-1 (23.3 mg) and the compound obtained in Reference Example 3-3(2) (29.7 mg) were reacted according to the method described in Reference Example 5-1 to obtain the title compound (30.4 mg) as a colorless amorphous substance. 1H NMR (600 MHz, METHANOL-d4) : δ ppm 1.13 - 1.20 (m, 3 H) 1.27 - 1.51 (m, 12 H) 2.34 - 2.60 (m, 7 H) 3.12 - 3.37 (m, 4 H) 3.37 - 3.46 (m, 3 H) 3.91 - 4.14 (m, 5 H) 5.47 - 5.56 (m, 1 H) 6.51 - 6.62 (m, 2 H) 7.22 - 7.38 (m, 5 H). MS ESI positron: m / z 585[M+H] + , 607[M+Na] + . MS ESI negative: m / z 583[MH] - . Retention time: 0.924 min (method A) The title compound can also be obtained by the following method. Reference example 5-5 (1) N,N-Diisopropylethylamine (2.18 mL) was added to a solution of the compound obtained in Reference Example 4-1 (672 mg) in tetrahydrofuran (15 mL) and stirred at room temperature for 5 minutes. The reaction solution was ice-cooled, and a solution of 4-nitrophenyl chloroformate (605 mg) in tetrahydrofuran (5 mL) was slowly added, followed by stirring at room temperature for 1 hour. The reaction solution was ice-cooled, and a solution of the compound obtained in Reference Example 3-3(2) (1.00 g) in tetrahydrofuran (5 mL) was added, followed by stirring at 60°C for 30 minutes and then overnight while returning to room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated. Ethyl acetate was added to the resulting residue, and the precipitated solid was collected by filtration to give ethyl trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylate (648 mg) as a colorless powder. (2) Ethanol (3.4 mL) was added to the compound obtained in (1) above (422 mg), and the mixture was dissolved at 60°C. 3 mol / L aqueous potassium hydroxide solution (689 μL) was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was ice-cooled, and 0.5 mol / L aqueous citric acid solution (3 mL) was added (pH 3-4). The mixture was concentrated to give trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid as a residue. Reference example 5-6 trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid

[0210] [ka] (1) To the compound obtained in Reference Example 3-4 (23.5 mg), chloroform and saturated aqueous sodium bicarbonate were added and stirred at room temperature for 10 minutes. The reaction mixture was partitioned into two layers, and the organic layer was filtered through a phase separator and concentrated to give (1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)-N-{2-[(1S)-1-phenylethoxy]ethyl}ethan-1-amine as a pale yellow oil. (2) Using the compound obtained in Reference Example 4-1 (14.5 mg) and the compound obtained in (1) above, a reaction was carried out in accordance with the method described in Reference Example 5-1 to obtain the title compound (28.2 mg) as a colorless solid. 1H NMR (400 MHz, METHANOL-d4) : δ ppm 0.68 - 0.78 (m, 2 H) 0.96 - 1.05 (m, 2 H) 1.12 - 1.21 (m, 3 H) 1.26 - 1.47 (m, 12 H) 1.82 - 1.97 (m, 1 H) 2.32 - 2.61 (m, 4 H) 3.05 - 3.45 (m, 6 H) 3.91 - 4.02 (m, 4 H) 4.02 - 4.13 (m, 1 H) 4.30 - 4.38 (m, 1 H) 5.43 - 5.53 (m, 1 H) 6.47 (s, 2 H) 7.21 - 7.45 (m, 5 H). MS ESI / APCI dual posi: m / z 583[M+H] + . MS ESI / APCI dual nega: m / z 581[MH] - . Retention time: 1.287 min (method E) The title compound can also be obtained by the following method. Reference example 5-7 (1) A solution of the compound obtained in Reference Example 4-1 (75.5 mg) and 4-nitrophenyl chloroformate (68.1 mg) in tetrahydrofuran (2.8 mL) was cooled in an ice bath containing added salt and stirred at the same temperature for 5 minutes. N,N-Diisopropylethylamine (245 μL) was added dropwise to the reaction solution, and the mixture was stirred at the same temperature for 3 hours. A solution of the compound obtained in Reference Example 3-4(2) (114 mg) in tetrahydrofuran (1.0 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 19 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by column chromatography using an NH silica gel column cartridge and a silica gel column cartridge connected together (n-hexane only to ethyl acetate only) to give ethyl trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylate (145 mg) as a colorless powder. (2) Ethanol (3.6 mL) was added to the compound obtained in (1) above (145 mg) and dissolved at 60°C. 3 mol / L aqueous potassium hydroxide solution (237 μL) was added, and the mixture was stirred at room temperature for 18 hours, at 50°C for 1 hour, and at 60°C for 1 hour. The reaction solution was ice-cooled, and 0.5 mol / L aqueous citric acid solution (1 mL) was added. The reaction solution was concentrated to give trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid as a residue. Example 1-1 Crystalline N-methyl-D-glucamine salt hydrate of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid

[0211] [ka] (1) Acetonitrile (2 mL) and water (2 mL) were added to trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid (500 mg) obtained in the above-mentioned Reference Example 5-1 and N-methyl-D-glucamine (158 mg), and the mixture was lyophilized to obtain a colorless powder (654 mg). (2) To the compound obtained in (1) above (50 mg), a mixed solvent of tert-butyl methyl ether and water (100:1, 500 μL) and n-heptane (50 μL) were added, and the mixture was dissolved at 40° C. and stirred overnight at room temperature. The precipitated solid was collected by filtration to obtain a colorless solid (46 mg).

[0212] The powder X-ray diffraction pattern and differential thermal analysis / thermogravimetry (TG / DTA) of the solid indicated that it was a crystalline hydrate of the N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. In the powder X-ray diffraction pattern, peaks were observed at 2θ=3.5 degrees, 8.0 degrees, 10.0 degrees, and 14.6 degrees. Differential thermal analysis / thermogravimetry (TG / DTA) showed endothermic peaks at 50.1°C and 76.3°C. The above-mentioned title crystal was identified as a hydrate by X-ray structural analysis.

[0213] The above-mentioned title crystal can also be obtained by the method described in Example 1-2 below. Example 1-2 N-methyl-D-glucamine salt hydrate (0.30 g) of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid obtained by the method described in Example 1-1(2) was dissolved in a mixed solvent of ethyl acetate and water (100:1, 1.515 g). To this solution was added a mixed solvent of ethyl acetate and n-heptane (1:1, 6.00 g), and the mixture was stirred at room temperature for 40 hours to crystallize, yielding a colorless solid (0.118 g).

[0214] The powder X-ray diffraction pattern, infrared absorption spectrum, and differential thermal analysis / thermogravimetry (TG / DTA) of the solid were measured, and the results were as follows: In the powder X-ray diffraction pattern, peaks were observed at 2θ=3.5 degrees, 8.1 degrees, 10.1 degrees, and 14.6 degrees. Infrared absorption spectrum (ATR method) at 1610 cm -1 , 1556cm -1 , 1412cm -1 , and 1075 cm -1 A characteristic absorption band was observed. Differential thermal analysis / thermogravimetry (TG / DTA) showed endothermic peaks at 52.9°C and 76.2°C. Example 2-1 Crystals of anhydrous N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid

[0215] [ka] The crystals (50 mg) obtained in Example 1-1 were dried by standing at room temperature for 3 days together with a synthetic zeolite desiccant to obtain a colorless solid (46 mg).

[0216] The powder X-ray diffraction pattern, infrared absorption spectrum, and differential thermal analysis / thermogravimetry (TG / DTA) of the solid were measured, and it was found to be a crystalline anhydrous N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. In the powder X-ray diffraction pattern, peaks were observed at 2θ=3.6 degrees, 10.2 degrees, 15.1 degrees, and 20.6 degrees. Infrared absorption spectrum (ATR method) -1 , 1591cm -1 , 1242cm -1 , and 1075 cm -1 A characteristic absorption band was observed. Differential thermal analysis / thermogravimetry (TG / DTA) showed an endothermic peak at 77.1°C. Example 3-1 Crystal of potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid (crystal form A)

[0217] [ka] (1) To a tetrahydrofuran-water mixture (11 mL-2.7 mL) of the compound obtained in Reference Example 5-2 (603 mg), a 3 mol / L aqueous potassium hydroxide solution (358 μL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated. A mixed solvent of acetonitrile and water (3 mL-3 mL) was added to the resulting residue, and the mixture was lyophilized to obtain a colorless amorphous product (648 mg). (2) To the compound obtained in (1) above (648 mg), acetonitrile (0.5 mL), tert-butyl methyl ether (10 mL), and ethyl acetate (1 mL) were added, and the resulting suspension was stirred at room temperature overnight. The solid in the suspension was filtered to give a colorless solid (315 mg).

[0218] The powder X-ray diffraction pattern and differential thermal analysis / thermogravimetry (TG / DTA) of the solid were measured, and it was found to be a crystal of the potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid (crystal type A). In the powder X-ray diffraction pattern, peaks were observed at 2θ=3.7 degrees, 7.3 degrees, 8.2 degrees, and 18.3 degrees. Differential thermal analysis / thermogravimetry (TG / DTA) showed an endothermic peak at 95.9°C. Example 4-1 Crystal of potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid (crystal type B)

[0219] [ka] (1) To a solution of the compound (500 mg) obtained in Reference Example 5-2 in ethanol (4.5 mL), a 3 mol / L aqueous potassium hydroxide solution (297 μL) was added, and the mixture was stirred at room temperature for 50 minutes. The reaction solution was then concentrated. Acetonitrile was added to the resulting residue, which was then concentrated. Water (5 mL) was added to the resulting residue, which was then freeze-dried to obtain a pale yellow powder (538 mg). (2) The compound obtained in (1) above (200 mg) was dissolved in a mixed solvent of tert-butyl methyl ether and water (100:1, 1.0 mL), and n-heptane (300 μL) was slowly added and stirred at room temperature overnight. The precipitated solid was collected by filtration to obtain a colorless solid (220 mg). The obtained solid was left standing at room temperature exposed to the atmosphere for 4 days to obtain a colorless solid.

[0220] The powder X-ray diffraction pattern, infrared absorption spectrum, and differential thermal analysis / thermogravimetry (TG / DTA) of the above solid were measured, and it was found to be a crystal of the potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid (type B crystal). In the powder X-ray diffraction pattern, peaks were observed at 2θ=3.5 degrees, 9.1 degrees, 10.3 degrees, and 15.0 degrees. Infrared absorption spectrum (ATR method) was 1707 cm -1 , 1636cm -1 , 1407cm -1 , and 1101 cm -1 A characteristic absorption band was observed. Differential thermal analysis / thermogravimetry (TG / DTA) showed an endothermic peak at 53.7°C. Example 5-1 Crystals of the potassium salt of trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid

[0221] [ka] (1) To a solution of the compound (101 mg) obtained in Reference Example 5-3 in acetonitrile (0.5 mL), 3 mol / L aqueous potassium hydroxide solution (59 μL) and water (0.5 mL) were added to dissolve the compound, and the mixture was freeze-dried to obtain a colorless amorphous substance (110 mg). (2) tert-Butyl methyl ether and water were mixed and then partitioned into two layers. (3) The compound (80 mg) obtained in (1) above was added to the organic layer (240 μL) obtained in (2) above and n-heptane (1.2 mL), and the mixture was stirred at room temperature for 14 hours. n-heptane (2 mL) was added to the solution, and the precipitated solid was collected by filtration to obtain a colorless powder (71 mg). The obtained powder was transferred to a bottle and stored at room temperature under a sealed condition to obtain a colorless powder.

[0222] The powder X-ray diffraction pattern and differential thermal analysis / thermogravimetry (TG / DTA) of the powder indicated that it was a crystal of the potassium salt of trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. The powder X-ray diffraction pattern showed peaks at 2θ = 4.0, 4.9, 7.9, and 15.0 degrees. Differential thermal analysis / thermogravimetry (TG / DTA) showed an endothermic peak at 76.2°C. The above-mentioned title crystal can also be obtained by the method described in Example 5-2 below. Example 5-2 The organic layer (300 μL) obtained in Example 5-1(2) and n-heptane (1.5 mL) were added to the compound (100 mg) obtained in Example 5-1(1), and the mixture was stirred at room temperature for 12 hours. The solution was heated to 55°C and stirred while returning to room temperature. A small amount of the powder obtained in Example 5-1 was added as seed crystals, and the mixture was stirred at room temperature overnight. n-heptane (2 mL) was added to the solution, and the precipitated solid was collected by filtration to obtain a colorless powder (69 mg). This powder was left to stand at room temperature exposed to the atmosphere for one week, yielding a colorless powder.

[0223] The powder X-ray diffraction pattern, infrared absorption spectrum, and differential thermal analysis / thermogravimetry (TG / DTA) of the powder revealed that it was a crystal of the potassium salt of trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. In the powder X-ray diffraction pattern, peaks were observed at 2θ=4.0 degrees, 4.9 degrees, 7.9 degrees, and 15.0 degrees. Infrared absorption spectrum (ATR method) was measured at 1625 cm -1 , 1572cm -1 , 1255cm -1 , and 1124 cm-1 A characteristic absorption band was observed. Differential thermal analysis / thermogravimetry (TG / DTA) showed an endothermic peak at 73.1°C. Example 6-1 Crystals of trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid

[0224] [ka] Water was added to the residue obtained in Reference Example 5-5, and the solid in the suspension was collected by filtration to obtain a colorless powder (371 mg).

[0225] The powder X-ray diffraction pattern, infrared absorption spectrum, and differential thermal analysis / thermogravimetry (TG / DTA) of the powder revealed that it was a crystal of trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. In the powder X-ray diffraction pattern, peaks were observed at 2θ=13.9 degrees, 14.9 degrees, 15.8 degrees, and 20.1 degrees. Infrared absorption spectrum (ATR method) -1 , 1695cm -1 , 1121cm -1 , and 1082 cm -1 A characteristic absorption band was observed. Differential thermal analysis / thermogravimetry (TG / DTA) showed an endothermic peak at 95.5°C. Example 7-1 Crystals of trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid

[0226] [ka] To the residue obtained in Reference Example 5-7, water (10 mL) was added (pH 4), and the mixture was stirred at room temperature for 15 minutes. The solid in the suspension was collected by filtration to obtain a colorless powder (121 mg).

[0227] The powder X-ray diffraction pattern, infrared absorption spectrum, and differential thermal analysis / thermogravimetry (TG / DTA) of the powder were measured, and it was found to be a crystal of trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid. In the powder X-ray diffraction pattern, peaks were observed at 2θ=4.6 degrees, 13.9 degrees, 19.9 degrees, and 22.2 degrees. Infrared absorption spectrum (ATR method) -1 , 1424cm -1 , 1146cm -1 , and 1068 cm -1 A characteristic absorption band was observed. Differential thermal analysis / thermogravimetry (TG / DTA) showed an endothermic peak at 86.9°C. The LPA1 receptor antagonistic activity of the compounds of the present invention was evaluated by the method shown in Test Example 1 below.

[0228] Test Example 1 (1) Creation of RH7777 cells stably expressing human LPAR1 Human LPAR1-expressing cells were obtained by transfecting RH7777 cells with a human LPAR1 expression vector. (2) LPA-induced intracellular Ca 2+ Antagonism test for concentration-escalation response Cells stably expressing human LPAR1 showed LPA-induced intracellular Ca 2+ It was used in a concentration-escalation response antagonism test. Cells were seeded onto a 96-well poly-D-lysine black plate and cultured overnight. After culturing in FBS-free medium for at least 2 hours, the medium was aspirated and 100 μL of loading buffer (1x HBSS, 20 mM HEPES, 2.5 mM Probenecid, 0.05% BSA, 0.25 mg / mL Amaranth, 0.05% Pluronic F-127, 2 μM Fluo-4, pH 7.4) was added and incubated for 60 minutes. 50 μL of basal buffer (1x HBSS, 20 mM HEPES, 2.5 mM Probenecid, 0.05% BSA, 0.25 mg / mL Amaranth, pH 7.4) containing the test compound was added and the plate was cultured at 37°C for 30 minutes. LPA was added to the FDSS6000 (Hamamatsu Photonics), and intracellular Ca was measured using the fluorescence intensity at 540 nm wavelength at an excitation wavelength of 480 nm. 2+ The change in concentration was detected, and the ratio of the basal fluorescence value to the maximum fluorescence value (Rmax) was calculated to measure LPA-induced intracellular Ca 2+ The 50% antagonistic concentration (IC 50 The Rmax under stimulation with basal buffer containing no test compound was used as the control value. The Rmax under stimulation with basal buffer containing no LPA or test compound was used as the basal value. Intracellular Ca 2+ The concentration increase rate (%) was calculated by subtracting the basal value from Rmax in the presence of LPA and each concentration of the test compound, and dividing the result by the value obtained by subtracting the basal value from the control value. The concentration of each test compound is shown on the X axis, and the intracellular Ca 2+ The concentration increase rate (%) was plotted on the Y-axis, and IC was calculated by nonlinear regression using XLfit. 50 The values ​​were calculated, and the test results are shown in Table 2.

[0229] [Table 2]

[0230] Furthermore, the LPA3 receptor antagonistic activity of the compound of the present invention can also be evaluated by the method shown in Test Example 2 below. Test Example 2 (1) LPA-induced intracellular Ca 2+ Antagonism test for concentration-escalation response Cells stably expressing human LPAR3 were used to measure LPA-induced intracellular Ca 2+ Used in antagonism tests against increasing concentration responses. Cells were seeded onto a Poly-D-Lysine 96-well black plate and cultured overnight. After washing with PBS, 100 μL of Loading Buffer (1×HBSS, 20 mM HEPES, 2.5 mM Probenecid, 0.05% BSA, 0.25 mg / mL Amaranth, 0.05% Pluronic F-127, 200 nM Fluo-8, pH 7.4) was added and incubated for 60 minutes. 50 μL of Basal Buffer (1×HBSS, 20 mM HEPES, 2.5 mM Probenecid, 0.05% BSA, 0.25 mg / mL Amaranth, pH 7.4) containing the test compound was added and cultured at 37°C for 30 minutes. LPA was added in an FDSS7000 (Hamamatsu Photonics), and intracellular Ca was measured using the fluorescence intensity at 540 nm with an excitation wavelength of 480 nm as an index. 2+ The change in concentration was detected, and the ratio of the basal fluorescence value to the maximum fluorescence value (Rmax) was calculated to measure LPA-induced intracellular Ca 2+ The 50% antagonistic concentration (IC 50 The Rmax under stimulation with basal buffer containing no test compound is taken as the control value. The Rmax under stimulation with basal buffer containing no LPA or test compound is taken as the basal value. Intracellular Ca 2+ The concentration increase rate (%) was calculated by subtracting the basal value from Rmax in the presence of LPA and each concentration of the test compound, and dividing the result by the value obtained by subtracting the basal value from the control value. The concentration of each test compound is plotted on the X axis, and the intracellular Ca 2+ The concentration increase rate (%) was plotted on the Y-axis, and IC was calculated by nonlinear regression using XLfit. 50 Calculate the value. [Industrial Applicability]

[0231] Compound [I] of the present invention has been shown to have excellent LPA1 receptor antagonistic activity. Therefore, the present invention makes it possible to provide pharmaceuticals effective in preventing or treating diseases such as those caused by systemic sclerosis, which is expected to reduce the burden on patients and contribute to the development of the pharmaceutical industry. Furthermore, compound [I] of the present invention or its pharmaceutically acceptable salt, or hydrate crystals thereof have excellent storage stability and other physical properties, and are useful as pharmaceutical ingredients.

Claims

1. A crystalline hydrate of the N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid, having the following physical properties (a) and (b): (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=3.5 degrees, 8.1 degrees, 10.1 degrees, and 14.6 degrees; and (b) Infrared absorption spectrum (ATR method), the characteristic absorption band is 1610 cm -1 , 1556 cm -1 , 1412 cm -1 , and 1075 cm -1 is located.

2. The crystal according to claim 1, further having the following physical property (c): (c) In differential thermal analysis / thermogravimetry (TG / DTA), endothermic peaks are observed at 45°C to 55°C and 70°C to 79°C.

3. a solution of N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid in a mixed solvent of water and one or more solvents selected from the group consisting of tert-butyl methyl ether and ethyl acetate, (i) n-heptane, or (ii) A mixed solvent of n-heptane and one or more solvents selected from the group consisting of tert-butyl methyl ether and ethyl acetate and then crystallizing the mixture. (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=3.5 degrees, 8.1 degrees, 10.1 degrees, and 14.6 degrees; and (b) Infrared absorption spectrum (ATR method), the characteristic absorption band is 1610 cm -1 , 1556 cm -1 , 1412 cm -1 , and 1075 cm -1 is located.

4. A crystal of anhydrous N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid, having the following physical properties (a), (b), and (c): (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=3.6 degrees, 10.2 degrees, 15.1 degrees, and 20.6 degrees; (b) Infrared absorption spectrum (ATR method), the characteristic absorption band is 1643 cm -1 , 1591 cm -1 , 1242 cm -1 , and 1075 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed between 72°C and 82°C.

5. A method for producing crystals of anhydrous N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid, which has the following physical properties (a), (b), and (c), characterized by drying crystals of hydrated N-methyl-D-glucamine salt of trans-1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid using a desiccant: (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=3.6 degrees, 10.2 degrees, 15.1 degrees, and 20.6 degrees; (b) Infrared absorption spectrum (ATR method), the characteristic absorption band is 1643 cm -1 , 1591 cm -1 , 1242 cm -1 , and 1075 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed between 72°C and 82°C.

6. A crystal of potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid, having the following physical properties (a) and (b): (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=3.7 degrees, 7.3 degrees, 8.2 degrees, and 18.3 degrees; and (b) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed between 89°C and 99°C.

7. A method for producing crystals having the following physical properties (a) and (b), characterized by stirring a suspension of potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid in a mixed solvent of tert-butyl methyl ether, ethyl acetate, and acetonitrile, and obtaining a solid in the suspension: (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=3.7 degrees, 7.3 degrees, 8.2 degrees, and 18.3 degrees; and (b) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed between 89°C and 99°C.

8. A crystal of potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid, having the following physical properties (a), (b), and (c): (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=3.5 degrees, 9.1 degrees, 10.3 degrees, and 15.0 degrees; (b) Infrared absorption spectrum (ATR method), the characteristic absorption band is 1707 cm －１ , 1636 cm －１ , 1407 cm －１ , and 1101 cm －１ in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 49°C to 59°C.

9. A solution of potassium salt of 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1-carboxylic acid in a mixed solvent of tert-butyl methyl ether and water, (i) n-heptane, or (ii) Mixed solvent of tert-butyl methyl ether and n-heptane and then crystallizing the mixture. (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=3.5 degrees, 9.1 degrees, 10.3 degrees, and 15.0 degrees; (b) Infrared absorption spectrum (ATR method), the characteristic absorption band is 1707 cm －１ , 1636 cm －１ , 1407 cm －１ , and 1101 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 49°C to 59°C.

10. A crystal of potassium salt of trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid, having the following physical properties (a), (b), and (c): (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=4.0 degrees, 4.9 degrees, 7.9 degrees, and 15.0 degrees; (b) Infrared absorption spectrum (ATR method), the characteristic absorption band is 1625 cm －１ , 1572 cm －１ , 1255 cm －１ , and 1124 cm －１ in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 69°C to 79°C.

11. A solution of potassium salt of trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid in a mixed solvent of tert-butyl methyl ether and water, (i) n-heptane, or (ii) Mixed solvent of tert-butyl methyl ether and n-heptane and then crystallizing the mixture. (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=4.0 degrees, 4.9 degrees, 7.9 degrees, and 15.0 degrees; (b) Infrared absorption spectrum (ATR method), the characteristic absorption band is 1625 cm -1 , 1572 cm -1 , 1255 cm -1 , and 1124 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 69°C to 79°C.

12. A crystal of trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid having the following physical properties (a), (b), and (c): (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=13.9 degrees, 14.9 degrees, 15.8 degrees, and 20.1 degrees; (b) Infrared absorption spectrum (ATR method), the characteristic absorption band is 1746 cm －１ , 1695 cm －１ , 1121 cm －１ , and 1082 cm －１ in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 90°C to 100°C.

13. A method for producing a crystal having the following physical properties (a), (b), and (c), characterized by adding water to trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid to cause crystallization: (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=13.9 degrees, 14.9 degrees, 15.8 degrees, and 20.1 degrees; (b) Infrared absorption spectrum (ATR method), the characteristic absorption band is 1746 cm -1 , 1695 cm -1 , 1121 cm -1 , and 1082 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 90°C to 100°C.

14. A crystal of trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid having the following physical properties (a), (b), and (c): (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=4.6 degrees, 13.9 degrees, 19.9 degrees, and 22.2 degrees; (b) Infrared absorption spectrum (ATR method), the characteristic absorption band is 1745 cm -1 , 1424 cm -1 , 1146 cm -1 , and 1068 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 81°C to 91°C.

15. A method for producing a crystal having the following physical properties (a), (b), and (c), characterized by adding water to trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylic acid to cause crystallization: (a) In powder X-ray diffraction (Cu-Kα), it has peaks at 2θ=4.6 degrees, 13.9 degrees, 19.9 degrees, and 22.2 degrees; (b) Infrared absorption spectrum (ATR method), the characteristic absorption band is 1745 cm -1 , 1424 cm -1 , 1146 cm -1 , and 1068 cm -1 in; and (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is observed at 81°C to 91°C.

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