New salts of dimethyl-2,3-dihydro-1H-indene derivatives and methods for producing the same

Abstract

The present invention provides a novel salt of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, i.e., its (1S)-(+)-10-camphorsulfonate salt, and a method for preparing the same. The (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate is obtained in a crystalline form and has high purity, high stability, high water solubility, and low hygroscopicity.

Description

[Technical Field]

[0001] The present invention relates to a novel salt of a dimethyl-2,3-dihydro-1H-indene derivative and a method for preparing the same. More specifically, the present invention relates to (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, which has improved stability, solubility, and hygroscopicity, and a method for preparing the same. [Background technology]

[0002] Dimethyl-2,3-dihydro-1H-indene derivatives or pharmaceutically acceptable salts thereof, including compounds of the following formula 1, are known as compounds having excellent inhibitory activity against glucosylceramide synthase (GCS) (WO2021 / 096238). <Expression 1> JPEG2025537478000002.jpg46150

[0003] WO2021 / 096238 discloses a method for producing a dimethyl-2,3-dihydro-1H-indene derivative, for example, a method as shown in the following reaction scheme 1. <Reaction Scheme 1> JPEG2025537478000003.jpg90165

[0004] The method according to Scheme 1 includes, in the final step, preparing a product (e.g., a compound of Formula 1 in the form of a free base) by Suzuki coupling between a compound of Formula 5 (e.g., (S)-quinuclidin-3-yl(5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate) and an AW-boronic acid (e.g., 3-chloro-4-isopropoxyphenylboronic acid) substituted with X1, X2, X3, or X4. The Suzuki coupling reaction involves the use of a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2). Summary of the Invention [Problem to be solved by the invention]

[0005] The present inventors have discovered that the free base form of the compound of formula 1 obtained by the method disclosed in WO2021 / 096238 is obtained in amorphous form. The present inventors have also discovered that the amorphous form of the compound of formula 1 is difficult to formulate because it is obtained in low purity, exhibits low water solubility, exhibits low stability due to morphological changes under accelerated conditions, and is highly hygroscopic.

[0006] The present inventors have conducted various studies to solve the above problems. In particular, the present inventors have conducted physicochemical evaluations of various acid addition salts to improve the properties (low stability, low water solubility, and high hygroscopicity) of the compound of formula 1 in the form of a free base obtained in an amorphous form, particularly the stereoisomers of the compound of formula 1 in the form of a free base obtained in an amorphous form. As a result, the present inventors have found that when a stereoisomer of the compound of formula 1 (hereinafter also referred to as the "(R)-compound of formula 1") is converted into a specific acid addition salt form (i.e., the (1S)-(+)-10-camphorsulfonate salt form), the salt can be obtained in a crystalline form with excellent stability, high water solubility, and low hygroscopicity, and in high purity.

[0007] Thus, the present invention provides the (1S)-(+)-10-camphorsulfonic acid salt of the (R)-compound of formula 1.

[0008] The present invention also provides a method for preparing the (1S)-(+)-10-camphorsulfonic acid salt of the (R)-compound of formula 1. [Means for solving the problem]

[0009] One aspect of the present invention provides (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate.

[0010] According to another aspect of the present invention, there is provided a method for preparing (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, the method comprising: (a) dissolving (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate and (1S)-(+)-10-camphorsulfonic acid in a solvent under heating to obtain a solution; and (b) cooling the solution obtained in step (a) to form a precipitate.

[0011] Yet another aspect of the present invention provides a method for preparing (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, the method comprising: (i) dissolving (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate and (1S)-(+)-10-camphorsulfonic acid in a solvent at 5°C to 30°C to obtain a solution; and (ii) adding an antisolvent to the solution obtained in step (i) to form a precipitate.

[0012] Yet another aspect of the present invention provides a method for preparing (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, the method comprising: (p) dissolving (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate and (1S)-(+)-10-camphorsulfonic acid in a solvent at 5°C to 30°C to obtain a solution; and (q) evaporating the solvent from the solution obtained in step (p). [Effects of the Invention]

[0013] The (1S)-(+)-10-camphorsulfonate salt of the (R)-compound of formula 1 obtained by the present invention is obtained in a highly pure crystalline form. Furthermore, the (1S)-(+)-10-camphorsulfonate salt of the (R)-compound of formula 1 has excellent stability, high water solubility, and low hygroscopicity. Therefore, the (1S)-(+)-10-camphorsulfonate salt of the (R)-compound of formula 1 of the present invention can be effectively formulated. [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 shows the XRD spectrum of (S)-quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (free base form) prepared according to the method disclosed in WO2021 / 096238. [Figure 2] 1 shows the XRD spectrum of (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate obtained in the present invention (Example 1). [Figure 3] 1 shows XRD spectra of the compounds (in the form of hydrochloride, tartrate, and citrate) obtained in Comparative Examples 1 to 3. [Figure 4] 1 shows a DSC thermogram of (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate obtained in the present invention (Example 1). [Figure 5] 1 shows an XRD spectrum of (1S)-(+)-10-camphorsulfonate of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate obtained in the present invention (Example 1) after storage under accelerated conditions. [Figure 6] FIG. 1 shows the appearance of (1S)-(+)-10-camphorsulfonate of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate obtained in the present invention (Example 1) after storage under accelerated conditions. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention provides a novel salt of the (R)-compound of Formula 1, which has high purity, high stability, high water solubility, and low hygroscopicity. That is, the present invention provides (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, having the chemical structure of Formula 1a below. <Formula 1a> JPEG2025537478000004.jpg45149

[0016] It has been found by the present invention that (1S)-(+)-10-camphorsulfonate of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate can be obtained in crystalline form. Accordingly, the present invention also provides (1S)-(+)-10-camphorsulfonate of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate in crystalline form.

[0017] In an embodiment, the crystalline form of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (1S)-(+)-10-camphorsulfonate salt may have an XRD pattern with peaks at 8.1, 11.0, and 16.3 °2θ ± 0.2 °2θ, preferably 8.1, 9.3, 11.0, 16.3, and 17.6 °2θ ± 0.2 °2θ, and more preferably 8.1, 9.3, 11.0, 13.0, 13.1, 15.2, 16.3, 17.1, 17.6, 18.4, 18.7, 20.8, and 22.6 °2θ ± 0.2 °2θ. For example, a crystalline form of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (1S)-(+)-10-camphorsulfonate salt may have the XRD pattern of FIG. 2.

[0018] In another embodiment, the crystalline form of (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate may have a differential scanning calorimetry (DSC) thermogram showing an endothermic peak at 220 to 236°C, preferably 229±2°C, for example, the differential scanning calorimetry (DSC) thermogram of FIG. 4.

[0019] The present invention includes within its scope a process for preparing the (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate.

[0020] In one embodiment, the method may include the steps of: (a) dissolving (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate and (1S)-(+)-10-camphorsulfonic acid in a solvent under heating to obtain a solution; and (b) cooling the solution obtained in step (a) to form a precipitate.

[0021] In the above embodiment, step (a) may be performed at a temperature of 35°C to 70°C, preferably 40°C to 60°C. The solvent used in step (a) may be a single solvent or a mixed solvent. For example, the single solvent may be selected from the group consisting of acetone, methyl ethyl ketone, C1 to C5 alcohols, 2-methyltetrahydrofuran, isopropyl acetate, methyl t-butyl ether, and ethyl acetate. Alternatively, for example, the mixed solvent may be a mixed solvent of water and an organic solvent selected from the group consisting of acetone, ethyl acetate, isopropyl acetate, and methyl ethyl ketone. The volume ratio of the organic solvent to water in the mixed solvent may be 3:0.1 to 30:0.1.

[0022] In the above embodiment, the cooling in step (b) may be carried out at a temperature of 0°C to 30°C, preferably 5°C to 25°C. The precipitate formed in step (b), i.e., (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, may be isolated according to a conventional method. For example, (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate may be isolated by filtration (e.g., filtration under reduced pressure) followed by drying (e.g., vacuum drying) according to a conventional method. Therefore, in the above method, step (b) may further comprise filtering and drying the formed precipitate, and if necessary, an additional step of washing the wet cake product with used solvent may be carried out after filtering and before drying.

[0023] In another embodiment, the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate may be prepared by using a solvent / antisolvent at a temperature including room temperature (e.g., about 5° C. to 30° C.) without a heating step. For example, the method of the present invention may include: (i) dissolving (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate and (1S)-(+)-10-camphorsulfonic acid in a solvent at 5° C. to 30° C. to obtain a solution; and (ii) adding an antisolvent to the solution obtained in step (i) to form a precipitate. The solvent used in step (i) may be one or more selected from the group consisting of methanol, ethanol, isopropyl alcohol, and acetone. The anti-solvent used in step (ii) may be selected from the group consisting of diisopropyl ether, methyl t-butyl ether, diethyl ether, and heptane.

[0024] In another embodiment, the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate may be prepared by using a solution / evaporation crystallization method at a temperature including room temperature (e.g., about 5° C. to 30° C.) without a heating step. For example, the method of the present invention may include the steps of: (p) dissolving (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate and (1S)-(+)-10-camphorsulfonic acid in a solvent at 5° C. to 30° C. to obtain a solution; and (q) evaporating the solvent from the solution obtained in step (p). The solvent used in step (p) may be one or more selected from the group consisting of methanol, ethanol, isopropyl alcohol, and acetone. The evaporation in step (q) may be carried out according to a conventional solvent evaporation method, for example, at a temperature of 5°C to 30°C, preferably about 20°C to 25°C.

[0025] The present invention will be described in more detail below with reference to examples and test examples. However, these examples and test examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. [Example]

[0026] Example 1: Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (1 g, 2.07 mmol) was dissolved in ethyl acetate (20 mL), and then a solution of (1S)-(+)-10-camphorsulfonic acid (0.48 g, 2.07 mmol) in purified water (0.2 mL) was added. The reaction mixture was heated to about 50°C and stirred for about 1 hour, cooled to about 25°C, and stirred for about 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with ethyl acetate (3 mL). The resulting solid was dried under vacuum to give 1.2 g of the title compound. (Yield: 81%) 1 H-NMR (400MHz, DMSO-d6) δ 9.47(s, 1H), 7.68-7.67(d, 1H), 7.64-7.62 (d, 1H), 7.57-7.54(m, 1H), 7.46-7.44(m, 2H), 7.27-7.22 (m, 2H), 4.93-4.90 (m, 1H), 4.82-4.66(m, 2H), 3.73-3.68(m, 1H), 3.28-3.19(m, 5H), 2.89-2.85(d, 1H), 2 .80-2.64(m, 3H), 2.39-2.36(d, 1H), 2.28-2.20(m, 2H), 2.08-2.03(m, 1H), 1.95-1.73 (m, 6H), 1.33-1.31(d, 6H), 1.30-1.26(m, 2H), 1.16 (s, 3H), 1.05(s, 3H), 0.90(s, 3H), 0.74(s, 3H)

[0027] Example 2 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (500 mg, 1.04 mmol) was dissolved in ethyl acetate (10 mL), and then a solution of (1S)-(+)-10-camphorsulfonic acid (0.24 g, 1.04 mmol) in purified water (0.04 mL) was added. The reaction mixture was heated to about 45°C and stirred for about 1 hour, cooled to about 25°C, and stirred for about 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with ethyl acetate (0.6 mL). The resulting solid was dried under vacuum to give 470 mg of the title compound. (Yield: 63%)

[0028] Example 3 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (200 mg, 0.41 mmol) was dissolved in acetone (2 mL), and then (1S)-(+)-10-camphorsulfonic acid (100 mg, 0.41 mmol) was added. The reaction mixture was heated to about 45°C and stirred for about 1 hour, cooled to about 25°C, and stirred for about 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with acetone (0.6 mL). The resulting solid was dried under vacuum to give 280 mg of the title compound. (Yield: 95%)

[0029] Example 4 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (200 mg, 0.41 mmol) was dissolved in 2-methyltetrahydrofuran (2 mL), and then (1S)-(+)-10-camphorsulfonic acid (100 mg, 0.41 mmol) was added. The reaction mixture was heated to about 45°C and stirred for about 1 hour, cooled to about 25°C, and stirred for about 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with 2-methyltetrahydrofuran (0.6 mL). The resulting solid was dried under vacuum to give 206 mg of the title compound. (Yield: 70%)

[0030] Example 5 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (2.9 g, 0.006 mol) was dissolved in ethyl acetate (58 mL), and then a solution of (1S)-(+)-10-camphorsulfonic acid (1.4 g, 0.006 mol) in purified water (0.6 mL) was added. The reaction mixture was heated to about 50°C and stirred for about 1 hour, cooled to about 25°C, and stirred for about 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with ethyl acetate (30 mL). The resulting solid was dried under vacuum to give 3.4 g of the title compound. (Yield: 79%)

[0031] Example 6 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (200 mg, 0.41 mmol) was dissolved in n-butanol (2 mL), and then (1S)-(+)-10-camphorsulfonic acid (96 mg, 0.41 mmol) was added. The reaction mixture was heated to about 45°C and stirred for about 1 hour, cooled to about 25°C, and stirred for about 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with n-butanol (0.6 mL). The resulting solid was dried under vacuum to give 178 mg of the title compound. (Yield: 60%)

[0032] Example 7 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (500 mg, 1.04 mmol) was dissolved in methyl ethyl ketone (7.5 mL), and the resulting solution was heated to about 55° C. A solution of (1S)-(+)-10-camphorsulfonic acid (240 mg, 1.04 mmol) in methyl ethyl ketone (2.5 mL) was added to the above solution. The reaction mixture was cooled to about 25° C. and stirred for about 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with methyl ethyl ketone (1.5 mL). The resulting solid was dried in vacuo to give 510 mg of the title compound. (Yield: 69%)

[0033] Example 8 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (500 mg, 1.04 mmol) was dissolved in 2-propanol (10 mL), and then (1S)-(+)-10-camphorsulfonic acid (240 mg, 1.04 mmol) was added. The reaction mixture was heated to about 55°C and stirred for about 2 hours, cooled to about 25°C, and stirred for about 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with 2-propanol (1.5 mL). The resulting solid was dried under vacuum to give 0.51 g of the title compound. (Yield: 69%)

[0034] Example 9 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (1) Concentrated residue of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate A mixture of (S)-3-quinuclidinol (4.6 g, 0.036 mol), tetrahydrofuran (120 mL), and bis(4-nitrophenyl)carbonate (11.5 g, 0.038 mol) was stirred at 30 °C for 8 hours. To the reaction mixture, (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (10.0 g, 0.03 mol) and tetrahydrofuran (30 mL) were added. The reaction mixture was refluxed under stirring for approximately 15 hours and then cooled to room temperature. Purified water (80 mL) was added to the reaction mixture. The reaction mixture was concentrated under reduced pressure, and then 50% sodium hydroxide (6.1 g, 0.076 mol) was added. The reaction mixture was stirred at room temperature for approximately 4 hours and then concentrated under reduced pressure. Purified water (120 mL) and ethyl acetate (170 mL) were added to the resulting residue. The separated organic layer was washed twice with 5% sodium carbonate (100 mL) and then concentrated under reduced pressure to give 13.5 g of concentrated residue of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (yield: 92%).

[0035] (2) (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate The concentrated residue (13.5 g, 27.9 mmol) obtained in (1) was dissolved in ethyl acetate (20 mL), and then (1S)-(+)-10-camphorsulfonic acid (6.5 g, 27.9 mmol) was added. The reaction mixture was stirred at about 50°C for about 1 hour, cooled to about 25°C, and stirred for about 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with ethyl acetate (30 mL). The resulting solid was dried in vacuo to give 18.3 g of the title compound. (Yield: 92%)

[0036] Example 10 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (1.0 g, 2.07 mmol) was dissolved in ethyl acetate (20 mL), and the resulting solution was heated to 50° C. A solution of (1S)-(+)-10-camphorsulfonic acid (0.48 g, 2.07 mmol) in purified water (0.2 mL) was added to the above solution. The reaction mixture was stirred at about 45° C. for about 1 hour, cooled to about 25° C., and then stirred for about 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with ethyl acetate (3 mL). The resulting solid was dried under vacuum to give 1.19 g of the title compound. (Yield: 80%)

[0037] Example 11 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (2.9 g, 0.006 mol) was dissolved in isopropyl acetate (20 mL), and the resulting solution was heated to 50° C. (1S)-(+)-10-camphorsulfonic acid (1.4 g, 0.006 mol) was added to the above solution. The reaction mixture was stirred at about 50° C. for about 1 hour, cooled to about 25° C., and then stirred for about 15 hours. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with ethyl acetate (30 mL). The resulting solid was dried under vacuum to give 3.5 g of the title compound. (Yield: 82%)

[0038] Example 12 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (1.0 g, 2.07 mmol) was dissolved in isopropyl acetate (20 mL), and the resulting solution was heated to 55° C. A solution of (1S)-(+)-10-camphorsulfonic acid (0.48 g, 2.07 mmol) in purified water (0.2 mL) was added to the above solution. The reaction mixture was stirred at about 45° C. for about 1 hour, cooled to about 25° C., and then stirred for about 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with isopropyl acetate (3 mL). The resulting solid was dried in vacuo to give 1.29 g of the title compound. (Yield: 87%)

[0039] Example 13 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (1.0 g, 2.07 mmol) was dissolved in methyl ethyl ketone (20 mL), and the resulting solution was heated to 55° C. A solution of (1S)-(+)-10-camphorsulfonic acid (0.48 g, 2.07 mmol) in purified water (0.2 mL) was added to the above solution. The reaction mixture was stirred at about 55° C. for about 1 hour, cooled to about 5° C., and then stirred for about 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with methyl ethyl ketone (3 mL). The resulting solid was dried under vacuum to give 1.19 g of the title compound. (Yield: 80%)

[0040] Example 14 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate was dissolved in methanol (483 mg, 10 mL) at a concentration of approximately 0.1 M. A solution of (1S)-(+)-10-camphorsulfonic acid dissolved in methanol (232 mg, 1 mL) at a concentration of approximately 1 M was added to the above solution. The reaction mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated at approximately 20°C for 24 hours to obtain approximately 715 mg of the title compound. (Yield: 100%)

[0041] Example 15 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate was dissolved in ethanol (483 mg, 10 mL) at a concentration of approximately 0.1 M. A solution of (1S)-(+)-10-camphorsulfonic acid dissolved in methanol (348 mg, 1.5 mL) at a concentration of approximately 1 M was added to the above solution. The reaction mixture was stirred at room temperature for 1 hour, and then diisopropyl ether (20 mL) was added. The resulting precipitate was filtered and dried at room temperature to give approximately 600 mg of the title compound. (Yield: 84%)

[0042] Example 16 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate was dissolved in ethanol (483 mg, 10 mL) at a concentration of approximately 0.1 M. A solution of (1S)-(+)-10-camphorsulfonic acid dissolved in methanol (232 mg, 1 mL) at a concentration of approximately 1 M was added to the above solution. The reaction mixture was stirred at room temperature for 1 hour, and then methyl t-butyl ether (30 mL) was added. The reaction mixture was stirred at room temperature for approximately 12 hours and then filtered under reduced pressure. The resulting material was washed with methyl t-butyl ether and then dried under vacuum at 40° C. to give approximately 610 mg of the title compound. (Yield: 85%)

[0043] Example 17 Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate was dissolved in acetone (483 mg, 10 mL) at a concentration of approximately 0.1 M. A solution of (1S)-(+)-10-camphorsulfonic acid dissolved in methanol (232 mg, 1 mL) at a concentration of approximately 1 M was added to the above solution. The reaction mixture was stirred at room temperature for 1 hour, and then methyl t-butyl ether (20 mL) was added. The reaction mixture was stirred at approximately 5°C for approximately 12 hours and then filtered under reduced pressure while maintaining the temperature at approximately 5°C. The resulting material was washed with methyl t-butyl ether and then dried under vacuum at room temperature to give approximately 600 mg of the title compound. (Yield: 84%)

[0044] Comparative Example 1: Preparation of the HCl salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate was dissolved in methanol (483 mg, 10 mL) to a concentration of approximately 0.1 M. 1 M hydrochloric acid solution (36 mg, 1 mL) was added to the above solution. The reaction mixture was stirred at room temperature for 1 hour, and then methyl t-butyl ether (40 mL) was added. The reaction mixture was stirred for approximately 5 hours and then filtered under reduced pressure. The resulting material (solid) was dried under vacuum at room temperature to give 450 mg of the title compound. (Yield: 87%)

[0045] Comparative Example 2: Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate tartrate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate was dissolved in methanol (483 mg, 10 mL) to a concentration of approximately 0.1 M. A 1 M tartaric acid solution (150 mg, 1 mL) was added to the above solution. The reaction mixture was stirred at room temperature for 1 hour, and then methyl t-butyl ether (40 mL) was added. The reaction mixture was stirred for approximately 5 hours and then filtered under reduced pressure. The resulting material (solid) was dried under vacuum at room temperature to give 505 mg of the title compound. (Yield: 80%)

[0046] Comparative Example 3: Preparation of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate citrate (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate was dissolved in methanol (483 mg, 1 mL) to a concentration of approximately 1 M. 1 M citric acid solution (192 mg, 1 mL) was added to the above solution. The reaction mixture was stirred at room temperature for 1 hour, and then methyl t-butyl ether (20 mL) was added. The reaction mixture was stirred for approximately 5 hours and then filtered under reduced pressure. The resulting material (solid) was dried under vacuum at room temperature to give 530 mg of the title compound. (Yield: 79%)

[0047] Test example 1: Characterization (1)XRD analysis X-ray diffraction (XRD) analysis was performed using a Bruker D8 Advance X-ray powder diffractometer. CuK was generated at 40 mA and 40 kV. α1 Radiation (λ α1 = 1.54060 Å) was used to perform measurements over angles ranging from 4 to 40° 2θ values ​​at a scan rate of 0.1 s per step.

[0048] The XRD analysis results for (S)-quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ("the compound of WO2021 / 096238", in the form of the free base) prepared according to the method disclosed in WO2021 / 096238 are shown in Figure 1. The results in Figure 1 indicate that the free base prepared according to the method disclosed in WO2021 / 096238 is in an amorphous form.

[0049] The XRD analysis results for the compound obtained in Example 1 are shown in Figure 2. The results in Figure 2 show that the compound obtained in Example 1 is in a crystalline form. The main XRD peaks (2θ) for the compound obtained in Example 1 are observed at 8.1, 9.3, 11.0, 13.0, 13.1, 15.2, 16.3, 17.1, 17.6, 18.4, 18.7, 20.8, and 22.6°2θ.

[0050] The XRD analysis results of the compounds obtained in Comparative Examples 1 to 3 are shown in Figure 3. The results in Figure 3 show that the compounds in the form of HCl salt (hydrochloride), tartrate salt (tartrate), and citrate salt were obtained in amorphous form.

[0051] (2) Differential scanning calorimetry (DSC) thermogram analysis Differential scanning calorimetry (DSC) analysis was performed using a Mettler-Toledo DSC1 differential scanning calorimeter under the following conditions: starting temperature 30 °C, ending temperature 300 °C, heating rate 10 °C / min, and nitrogen gas flow rate 50 mL / min.

[0052] The DSC analysis results for the compound obtained in Example 1 are shown in Figure 4. The results in Figure 4 show that the compound obtained in Example 1 exhibits an endothermic peak at 229±2°C.

[0053] (3) Moisture content analysis The water content of the compound obtained in Example 1 was measured by Karl Fischer titration, and it was confirmed that the compound obtained in Example 1 had a low water content in the range of about 0.3% to 0.5%.

[0054] Test Example 2: Stability evaluation (1) Stability test (accelerated conditions) The compound obtained in Example 1 was subjected to a stability test while being stored in a stability test chamber (CARON) under accelerated conditions (40±2°C, 75±5% RH) for 0, 1, and 3 months. The purity (HPLC purity) and water content (Karl Fischer method) were measured, and the results are shown in Table 1 below.

[0055] [Table 1]

[0056] The results in Table 1 show that the purity of the compound in the form of (1S)-(+)-10-camphorsulfonate obtained by the present invention remains stable under accelerated conditions, and there is no significant difference (within 1.0%) in the water content under accelerated conditions.

[0057] The XRD analysis results (measured in the same manner as in Test Example 1) and appearance of the compound obtained in Example 1 under the above-mentioned accelerated conditions are shown in Figures 5 and 6, respectively. The results in Figures 5 and 6 confirm that the compound in the form of (1S)-(+)-10-camphorsulfonate obtained according to the present invention has excellent stability under accelerated conditions.

[0058] (2) Photostability test The photostability test was carried out in accordance with ICH guideline Q1B. That is, the compounds obtained in Example 1 were each exposed to UV light (20 W / m 2 A photostability test was performed by exposing the solution to ultraviolet light (UV) for 10 hours and to visible light (30,000 lux) for 40 hours. The purity (HPLC purity) and water content (Karl Fischer method) were measured and the results are shown in Table 2 below.

[0059] [Table 2]

[0060] The results in Table 2 show that the compound in the form of (1S)-(+)-10-camphorsulfonate obtained according to the present invention has excellent photostability.

[0061] Test Example 3: Moisture absorption evaluation The hygroscopicity of the compound obtained in Example 1 and the compounds obtained in Comparative Examples 1 to 3 was measured using a moisture sorption analyzer (Dynamic Vapor Sorption, DVS). Specifically, the compound of WO2021 / 096238, the compound obtained in Example 1, and the compounds obtained in Comparative Examples 1 to 3 were each exposed to a moisture sorption analyzer (Surface Measurement System, DVS intrinsic) for 24 hours under conditions of room temperature (about 25 ° C.) and RH 80%, and the weight change of each was measured. The results are shown in Table 3 below.

[0062] [Table 3]

[0063] The results in Table 3 show that the compound in the form of (1S)-(+)-10-camphorsulfonate obtained according to the present invention exhibits significantly low hygroscopicity.

[0064] Test Example 4: Water solubility evaluation The water solubility at 20°C was measured for (S)-quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ("the compound of WO2021 / 096238", in the form of a free base) prepared according to the method disclosed in WO2021 / 096238 and the compound obtained in Example 1. The results are shown in Table 4 below.

[0065] [Table 4]

[0066] The results in Table 4 show that the compound in the form of (1S)-(+)-10-camphorsulfonate obtained according to the present invention exhibits significantly high water solubility.

Claims

1. (1S)-(+)-10-Camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate.

2. The (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate according to claim 1 in crystalline form.

3. 3. The (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate of claim 2, wherein the crystalline form has an XRD pattern with peaks at 8.1, 11.0, and 16.3°2θ±0.2°2θ.

4. The (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate according to claim 3, wherein the crystalline form has the XRD pattern of FIG.

5. The (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate of claim 2, wherein the crystalline form has a differential scanning calorimetry (DSC) thermogram exhibiting an endothermic peak at 220 to 236°C.

6. The (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate of claim 5, wherein the crystalline form has the differential scanning calorimetry (DSC) thermogram of FIG.

7. 1. A method for preparing (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, comprising: (a) dissolving (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate and (1S)-(+)-10-camphorsulfonic acid in a solvent under heating to obtain a solution; and (b) cooling the solution obtained in step (a) to form a precipitate. A manufacturing method comprising:

8. The process of claim 7, wherein step (a) is carried out at a temperature of from 35°C to 70°C.

9. The process of claim 7, wherein step (a) is carried out at a temperature of from 40°C to 60°C.

10. The solvent is acetone, methyl ethyl ketone, C １ ~C ５ 8. The method according to claim 7, wherein the organic solvent is selected from the group consisting of alcohol, 2-methyltetrahydrofuran, isopropyl acetate, methyl t-butyl ether, and ethyl acetate.

11. 8. The method according to claim 7, wherein the solvent is a mixed solvent of water and an organic solvent selected from the group consisting of acetone, ethyl acetate, isopropyl acetate, and methyl ethyl ketone.

12. The method according to claim 11, wherein the volume ratio of the organic solvent to water is 3:0.1 to 30:0.

1.

13. The method of claim 7, wherein the cooling is carried out at a temperature of 0°C to 30°C.

14. The method of claim 7, wherein the cooling is carried out at a temperature of from 5°C to 25°C.

15. The method of claim 7, wherein step (b) further comprises filtering and drying the formed precipitate.

16. 1. A method for preparing (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, comprising: (i) dissolving (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate and (1S)-(+)-10-camphorsulfonic acid in a solvent at 5°C to 30°C to obtain a solution; and (ii) adding an anti-solvent to the solution obtained in step (i) to form a precipitate; A manufacturing method comprising:

17. The method according to claim 16, wherein the solvent is one or more selected from the group consisting of methanol, ethanol, isopropyl alcohol, and acetone.

18. 17. The process of claim 16, wherein the antisolvent is selected from the group consisting of diisopropyl ether, methyl t-butyl ether, diethyl ether, and heptane.

19. 1. A method for preparing (1S)-(+)-10-camphorsulfonate salt of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, comprising: (p) dissolving (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate and (1S)-(+)-10-camphorsulfonic acid in a solvent at 5°C to 30°C to obtain a solution; and (q) evaporating the solvent from the solution obtained in step (p). A manufacturing method comprising:

20. 20. The method according to claim 19, wherein the solvent is one or more selected from the group consisting of methanol, ethanol, isopropyl alcohol, and acetone.

Images