Novel salt of dimethyl-2, 3-dihydro-1H-indene derivative and preparation method thereof

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., a (1S)-(+)-10-camphorsulfonate salt thereof, and a method for preparing the same, in particular, 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. According to the present invention, 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, which has high purity, high stability, high water solubility and low hygroscopicity, as well as a process for the preparation of the (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2, 2-dimethyl-2, 3-dihydro-1H-inden-1-yl) carbamate.

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 a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate having improved stability, water solubility and hygroscopicity and a method for preparing the same. Background Art

[0002] It is known that a dimethyl-2,3-dihydro-1H-indene derivative (including a compound of the following formula 1 or a pharmaceutically acceptable salt thereof) is a compound having excellent inhibitory activity against glucosylceramide synthase (GCS) (WO2021 / 096238).

[0003] <Formula 1>

[0004]

[0005] WO2021 / 096238 discloses a method for preparing dimethyl-2,3-dihydro-1H-indene derivatives, for example, as shown in the following reaction scheme 1.

[0006] <Reaction Scheme 1>

[0007]

[0008] The method according to Reaction Scheme 1 includes preparing the product (e.g., the compound of Formula 1 in the form of a free base) by a Suzuki coupling reaction between a compound of Formula 5 (e.g., (S)-quinuclidine-3-yl (5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl) carbamate) and an AW boronic acid substituted by X1, X2, X3 or X4 (e.g., 3-chloro-4-isopropoxyphenylboronic acid) in the last step. 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

[0009] Technical issues

[0010] The present inventors have found that the free base form of the compound of formula 1 obtained by the method disclosed in WO2021 / 096238 is obtained in an amorphous form. In addition, the present inventors have also found that it is difficult to formulate the amorphous form of the compound of formula 1 because it is obtained in low purity, exhibits low water solubility, exhibits low stability due to form changes under accelerated conditions, and has high hygroscopicity.

[0011] The inventors have conducted various studies to solve the problem. Specifically, the inventors have conducted physicochemical evaluations on various acid addition salts to improve the properties (low stability, low water solubility and high hygroscopicity) of the free base form of the compound of formula 1 obtained in amorphous form, particularly the stereoisomers (stereoisomers) of the free base form of the compound of formula 1 obtained in amorphous form. As a result, the inventors have found that when the stereoisomers of the compound of formula 1 (hereinafter also referred to as '(R)-compound of formula 1') are converted into specific acid addition salt forms (i.e. (1S)-(+)-10 camphorsulfonate forms), salts in the crystalline form with excellent stability, high water solubility and low hygroscopicity can be obtained with high purity.

[0012] Therefore, the present invention provides a (1S)-(+)-10-camphorsulfonate salt of the (R)-compound of Formula 1.

[0013] In addition, the present invention provides a method for preparing a (1S)-(+)-10-camphorsulfonic acid salt of the (R)-compound of Formula 1.

[0014] Technical Solution

[0015] According to one aspect of the present invention, there is provided a (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.

[0016] According to another aspect of the present invention, there is provided a method for preparing a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidine-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)-quinuclidine-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 conditions to obtain a solution; and (b) cooling the solution obtained in step (a) to form a precipitate.

[0017] According to another aspect of the present invention, there is provided a method for preparing a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidine-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)-quinuclidine-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.

[0018] According to another aspect of the present invention, there is provided a method for preparing a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidine-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)-quinuclidine-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).

[0019] Advantageous Effects of the Invention

[0020] The (1S)-(+)-10 camphorsulfonate of the (R)-compound of Formula 1 according to the present invention can be obtained in a crystalline form with high purity. In addition, the (1S)-(+)-10 camphorsulfonate of the (R)-compound of Formula 1 has excellent stability, high water solubility and low hygroscopicity. Therefore, the (1S)-(+)-10 camphorsulfonate of the (R)-compound of Formula 1 according to the present invention can be effectively formulated. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Shown is the XRD pattern of (S)-quinuclidine-3-yl((R)-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.

[0022] Figure 2The XRD pattern 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 (Example 1) obtained in the present invention is shown.

[0023] Figure 3 XRD patterns of the compounds obtained in Comparative Examples 1 to 3 (in the form of hydrochloride, tartrate, and citrate) are shown.

[0024] Figure 4 The DSC thermogram of (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 (Example 1) obtained in the present invention is shown.

[0025] Figure 5 The figure shows the XRD pattern measured after storing the (1S)-(+)-10-camphorsulfonate of (S)-quinuclidine-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate obtained in the present invention under accelerated conditions (Example 1).

[0026] Figure 6 The following is the appearance observed after the (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 (Example 1) obtained in the present invention was stored under accelerated conditions. DETAILED DESCRIPTION

[0027] 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 a (1S)-(+)-10-camphorsulfonate of (S)-quinuclidine-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl) carbamate, which has the chemical structure of the following formula 1a.

[0028] <Formula 1a>

[0029]

[0030] The present invention has found that the (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 is obtained in crystalline form. Therefore, the present invention also provides the (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.

[0031] In one embodiment, the XRD pattern of the (1S)-(+)-10-camphorsulfonate of 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 has peaks at 8.1, 11.0 and 16.3°2θ±0.2°2θ, preferably at 8.1, 9.3, 11.0, 16.3 and 17.6°2θ±0.2°2θ, more preferably 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±0.2°2θ. For example, 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 in crystalline form may have Figure 2 XRD pattern of .

[0032] In another embodiment, 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 in crystalline form may have a differential scanning calorimetry (DSC) thermogram showing an endothermic peak at 220° C. to 236° C., preferably at 229±2° C., for example Figure 4 Differential scanning calorimetry (DSC) thermogram.

[0033] 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.

[0034] In one embodiment, the method may include (a) dissolving (S)-quinuclidine-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 conditions to obtain a solution; and (b) cooling the solution obtained in step (a) to form a precipitate.

[0035] In the embodiment, step (a) can be carried out at a temperature of 35°C to 70°C, preferably 40°C to 60°C. The solvent used in step (a) can be a single solvent or a mixed solvent. For example, the single solvent can be selected from the group consisting of acetone, methyl ethyl ketone, C1-C5 alcohol, 2-methyltetrahydrofuran, isopropyl acetate, methyl tert-butyl ether and ethyl acetate. For example, the mixed solvent can 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 can be 3:0.1 to 30:0.1.

[0036] In the embodiment, the cooling in step (b) can 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., the (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 separated according to conventional methods. For example, the (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 separated by filtering (e.g., reduced pressure filtration) and then drying (e.g., vacuum drying) according to conventional methods. Therefore, in the method, step (b) can also include filtering and drying the formed precipitate. If necessary, a step of washing the wet cake product with the spent reagent may be additionally carried out after filtration and before drying.

[0037] 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 can be prepared by using a solvent / anti-solvent at a temperature including room temperature (e.g., about 5°C to 30°C) without performing 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 anti-solvent to the solution obtained in step (i) to form a precipitate. The solvent used in step (i) is selected from one or more of the group consisting of methanol, ethanol, isopropanol and acetone. The anti-solvent used in step (ii) is selected from the group consisting of diisopropyl ether, methyl tert-butyl ether, diethyl ether and heptane.

[0038] 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 can be prepared by using a dissolution / evaporation crystallization method at a temperature including room temperature (e.g., about 5°C to 30°C) without performing a heating step. For example, the method of the present invention may include (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) can be selected from one or more of the group consisting of methanol, ethanol, isopropanol and acetone. The evaporation of step (q) can be carried out, for example, at a temperature of 5°C to 30°C, preferably at a temperature of about 20°C to 25°C according to a conventional solvent evaporation method.

[0039] The present invention will be described in more detail below by way of 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.

[0040] Example 1: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0041] After (S)-quinuclidine-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), a solution of (1S)-(+)-10-camphorsulfonic acid (0.48 g, 2.07 mmol) dissolved in pure water (0.2 mL) was added thereto. The reaction mixture was heated to about 50°C, stirred for about 1 hour, cooled to about 25°C, and then stirred for about 1 hour. After the reaction mixture was filtered under reduced pressure, the resulting wet cake was washed with ethyl acetate (3 mL). The resulting solid was vacuum dried to obtain 1.2 g of the title compound. (Yield: 81%)

[0042] 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)

[0043] Example 2: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0044] After (S)-quinuclidine-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), a solution of (1S)-(+)-10-camphorsulfonic acid (0.24 g, 1.04 mmol) dissolved in pure water (0.04 mL) was added thereto. The reaction mixture was heated to about 45°C, stirred for about 1 hour, cooled to about 25°C, and then stirred for about 1 hour. After the reaction mixture was filtered under reduced pressure, the resulting wet cake was washed with ethyl acetate (0.6 mL). The resulting solid was vacuum dried to obtain 470 mg of the title compound. (Yield: 63%)

[0045] Example 3: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0046] After (S)-quinuclidine-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), (1S)-(+)-10-camphorsulfonic acid (100 mg, 0.41 mmol) was added thereto. The reaction mixture was heated to about 45°C, stirred for about 1 hour, cooled to about 25°C, and then stirred for about 1 hour. After the reaction mixture was filtered under reduced pressure, the obtained wet cake was washed with acetone (0.6 mL). The obtained solid was vacuum dried to obtain 280 mg of the title compound. (Yield: 95%)

[0047] Example 4: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0048] After (S)-quinuclidine-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl) carbamate (200 g, 0.41 mmol) was dissolved in 2-methyltetrahydrofuran (2 mL), (1S)-(+)-10-camphorsulfonic acid (100 mg, 0.41 mmol) was added thereto. The reaction mixture was heated to about 45° C., stirred for about 1 hour, cooled to about 25° C., and then stirred for about 1 hour. After the reaction mixture was filtered under reduced pressure, the obtained wet cake was washed with 2-methyltetrahydrofuran (0.6 mL). The obtained solid was vacuum dried to obtain 206 mg of the title compound. (Yield: 70%)

[0049] Example 5: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0050] After (S)-quinuclidine-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), a solution of (1S)-(+)-10-camphorsulfonic acid (1.4 g, 0.006 mol) dissolved in pure water (0.6 mL) was added thereto. The reaction mixture was heated to about 50° C., stirred for about 1 hour, cooled to about 25° C., and then stirred for about 1 hour. After the reaction mixture was filtered under reduced pressure, the resulting wet cake was washed with ethyl acetate (30 mL). The resulting solid was vacuum dried to obtain 3.4 g of the title compound. (Yield: 79%)

[0051] Example 6: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0052] After (S)-quinuclidine-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), (1S)-(+)-10-camphorsulfonic acid (96 mg, 0.41 mmol) was added thereto. The reaction mixture was heated to about 45°C, stirred for about 1 hour, cooled to about 25°C, and then stirred for about 1 hour. After the reaction mixture was filtered under reduced pressure, the obtained wet cake was washed with n-butanol (0.6 mL). The obtained solid was vacuum dried to obtain 178 mg of the title compound. (Yield: 60%)

[0053] Example 7: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0054] (S)-quinuclidine-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) dissolved in methyl ethyl ketone (2.5 mL) was added to the solvent. After the reaction mixture was filtered under reduced pressure, the resulting wet cake was washed with methyl ethyl ketone (1.5 mL). The resulting solid was vacuum dried to obtain 510 mg of the title compound. (Yield: 69%)

[0055] Example 8: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0056] After (S)-quinuclidine-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), (1S)-(+)-10-camphorsulfonic acid (240 mg, 1.04 mmol) was added thereto. The reaction mixture was heated to about 55°C, stirred for about 1 hour, cooled to about 25°C, and then stirred for about 1 hour. After the reaction mixture was filtered under reduced pressure, the obtained wet cake was washed with 2-propanol (1.5 mL). The obtained solid was vacuum dried to obtain 0.51 g of the title compound. (Yield: 69%)

[0057] Example 9: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0058] (1) Concentrated residue of (S)-quinuclidine-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate

[0059] 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. (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (10.0 g, 0.03 mol) and tetrahydrofuran (30 mL) were added to the reaction mixture. The reaction mixture was refluxed for about 15 hours under stirring and then cooled to room temperature. Pure 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 thereto. The reaction mixture was stirred at room temperature for about 4 hours and then concentrated under reduced pressure. Pure 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 obtain 13.5 g of (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate as a concentrated residue (yield: 92%).

[0060] (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]heptane-1-yl) methanesulfonate

[0061] The concentrated residue (13.5 g, 27.9 mmol) obtained in (1) was dissolved in ethyl acetate (20 mL), and (1S)-(+)-10-camphorsulfonic acid (6.5 g, 27.9 mmol) was added thereto. The reaction mixture was stirred at about 50° C. for about 1 hour, cooled to 25° C., and then stirred for about 1 hour. After the reaction mixture was filtered under reduced pressure, the wet cake was washed with ethyl acetate (30 mL). The obtained solid was vacuum dried to obtain 18.3 g of the title compound. (Yield: 92%)

[0062] Example 10: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0063] (S)-quinuclidine-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. To the above solution was added (1S)-(+)-10-camphorsulfonic acid (0.48 g, 2.07 mmol) dissolved in pure water (0.2 mL). 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. After the reaction mixture was filtered under reduced pressure, the resulting wet cake was washed with ethyl acetate (3 mL). The resulting solid was vacuum dried to obtain 1.19 g of the title compound. (Yield: 80%)

[0064] Example 11: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0065] (S)-quinuclidine-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. After the reaction mixture was filtered under reduced pressure, the resulting wet cake was washed with ethyl acetate (30 mL). The resulting solid was vacuum dried to obtain 3.5 g of the title compound. (Yield: 82%)

[0066] Example 12: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0067] (S)-quinuclidine-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. To the above solution was added (1S)-(+)-10-camphorsulfonic acid (0.48 g, 2.07 mmol) dissolved in pure water (0.2 mL). 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. After the reaction mixture was filtered under reduced pressure, the resulting wet cake was washed with isopropyl acetate (3 mL). The resulting solid was vacuum dried to obtain 1.29 g of the title compound. (Yield: 87%)

[0068] Example 13: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0069] (S)-quinuclidine-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. To the above solution was added (1S)-(+)-10-camphorsulfonic acid (0.48 g, 2.07 mmol) dissolved in pure water (0.2 mL). 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. After the reaction mixture was filtered under reduced pressure, the resulting wet cake was washed with methyl ethyl ketone (3 mL). The resulting solid was vacuum dried to obtain 1.19 g of the title compound. (Yield: 80%)

[0070] Example 14: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0071] (S)-quinuclidine-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 about 0.1 M. A solution obtained by dissolving (1S)-(+)-10-camphorsulfonic acid in methanol (232 mg, 1 mL) at a concentration of about 0.1 M was added to the above solution. After the reaction mixture was stirred at room temperature for 1 hour, the solvent was evaporated at about 20° C. for 24 hours to obtain about 715 mg of the title compound. (Yield: 100%)

[0072] Example 15: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0073] (S)-quinuclidine-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 about 0.1 M. A solution obtained by dissolving (1S)-(+)-10-camphorsulfonic acid in methanol (348 mg, 1.5 mL) at a concentration of about 1 M was added to the above solution. After the reaction mixture was stirred at room temperature for 1 hour, diisopropyl ether (20 mL) was added thereto. The resulting precipitate was filtered and then dried at room temperature to obtain about 600 mg of the title compound. (Yield: 84%)

[0074] Example 16: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0075] (S)-quinuclidine-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 about 0.1 M. A solution obtained by dissolving (1S)-(+)-10-camphorsulfonic acid in methanol (232 mg, 1 mL) at a concentration of about 1 M was added to the above solution. After the reaction mixture was stirred at room temperature for 1 hour, methyl tert-butyl ether (30 mL) was added thereto. The reaction mixture was stirred at room temperature for 12 hours and then filtered under reduced pressure. The resulting substance was washed with methyl tert-butyl ether and then vacuum dried at 40° C. to obtain about 610 mg of the title compound. (Yield: 85%)

[0076] Example 17: Preparation of (S)-quinuclidine-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]heptane-1-yl) methanesulfonate

[0077] (S)-quinuclidine-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 about 0.1 M. A solution obtained by dissolving (1S)-(+)-10-camphorsulfonic acid in methanol (232 mg, 1 mL) at a concentration of about 1 M was added to the above solution. After the reaction mixture was stirred at room temperature for 1 hour, methyl tert-butyl ether (20 mL) was added thereto. The reaction mixture was stirred at about 5° C. for about 12 hours and then filtered under reduced pressure while maintaining the temperature at about 5° C. The resulting substance was washed with methyl tert-butyl ether and then dried in vacuo at room temperature to obtain about 600 mg of the title compound. (Yield: 84%)

[0078] Comparative Example 1: Preparation of HCl salt of (S)-quinuclidine-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate

[0079] (S)-quinuclidine-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 about 0.1 M. 1 M hydrochloric acid solution (36 mg, 1 mL) was added to the above solution. After the reaction mixture was stirred at room temperature for 1 hour, methyl tert-butyl ether (40 mL) was added thereto. The reaction mixture was stirred for about 5 hours and then filtered under reduced pressure. The resulting substance (solid) was vacuum dried at room temperature to obtain 450 mg of the title compound. (Yield: 87%)

[0080] Comparative Example 2: Preparation of tartrate salt of (S)-quinuclidine-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate

[0081] (S)-quinuclidine-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 about 0.1 M. 1 M tartaric acid solution (150 mg, 1 mL) was added to the above solution. After the reaction mixture was stirred at room temperature for 1 hour, methyl tert-butyl ether (40 mL) was added thereto. The reaction mixture was stirred for about 5 hours and then filtered under reduced pressure. The resulting substance (solid) was vacuum dried at room temperature to obtain 505 mg of the title compound. (Yield: 80%)

[0082] Comparative Example 3: Preparation of Citrate Salt of (S)-quinuclidine-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate

[0083] (S)-quinuclidine-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) at a concentration of about 1 M. 1 M citric acid solution (192 mg, 1 mL) was added to the above solution. After the reaction mixture was stirred at room temperature for 1 hour, methyl tert-butyl ether (20 mL) was added thereto. The reaction mixture was stirred for about 5 hours and then filtered under reduced pressure. The resulting substance (solid) was vacuum dried at room temperature to obtain 530 mg of the title compound. (Yield: 79%)

[0084] Test Case 1: Features

[0085] (1) XRD analysis

[0086] X-ray diffraction (XRD) analysis was performed using a Bruker D8 Advance X-ray powder diffractometer. CuK generated at 40 mA and 40 kV was used. α1 Radiation (λ α1 = 1.54060 Å), with a scan rate of 0.1 s per step over a range of 4° to 40° 2θ values.

[0087] The XRD analysis results of (S)-quinuclidine-3-yl(5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ('compound of WO2021 / 096238', free base form) prepared according to the method disclosed in WO2021 / 096238 are as follows Figure 1 As shown. Figure 1 It can be seen from the results that the free base prepared according to the method disclosed in WO2021 / 096238 is in an amorphous form.

[0088] The XRD analysis results of the compound obtained in Example 1 are as follows: Figure 2 As shown. Figure 2 From the results, it can be seen that the compound obtained in Example 1 is in crystalline form. The main XRD peaks (2θ) of the compound obtained in Example 1 were 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.

[0089] And the XRD analysis results of the compounds obtained in Comparative Examples 1 to 3 are as follows: Figure 3 As shown. Figure 3 As can be seen from the results, the compounds in the form of HCl salt (hydrochloride), tartrate and citrate were obtained in an amorphous form.

[0090] (2) Differential Scanning Calorimetry (DSC) Thermal Spectrum Analysis

[0091] Differential Scanning Calorimetry (DSC) analysis was performed using a Mettler Toledo DSC1 differential scanning calorimeter under the following conditions: starting temperature 30°C, final temperature 300°C, heating rate 10°C / min, nitrogen flow rate 50 mL / min.

[0092] The DSC analysis results of the compound obtained in Example 1 are as follows: Figure 4 As shown. Figure 4 From the results, it can be seen that the compound obtained in Example 1 exhibits an endothermic peak at 229±2°C.

[0093] (3) Water content analysis

[0094] As a result of measuring the water content of the compound obtained in Example 1 by Karl Fischer titration, it was determined that the water content of the compound obtained in Example 1 was in the range of about 0.3% to 0.5%.

[0095] Test Example 2: Stability Evaluation

[0096] (1) Stability test (accelerated conditions)

[0097] The stability test was carried out under accelerated conditions (40 ± 2 ° C, 75 ± 5% RH) for 0, 1 month and 3 months when the compound obtained in Example 1 was stored in a stability test room (CARON). The results obtained by measuring purity (HPLC purity) and water content (by Karl Fischer titration) are shown in Table 1 below.

[0098] [Table 1]

[0099] The compound of Example 1 ((1S)-(+)-10-camphorsulfonate)

[0100]

[0101] From the results in Table 1, it can be seen that the compound obtained in the form of (1S)-(+)-10-camphorsulfonate according to the present invention maintains a stable state under accelerated conditions, and its purity does not change. It can also be seen that under accelerated conditions, its water content has no significant difference (within 1.0%).

[0102] In addition, the XRD analysis results (measured by the same method as in Test Example 1) and the appearance of the compound obtained according to Example 1 under the accelerated conditions as described above are respectively as follows: Figure 5 and Figure 6 As shown. Figure 5 and Figure 6 The results confirmed that the compound in the form of (1S)-(+)-10-camphorsulfonate obtained according to the present invention has excellent stability under accelerated conditions.

[0103] (2) Photostability test

[0104] The photostability test was performed according to ICH Guideline Q1B. That is, the compounds obtained in Example 1 were exposed to ultraviolet light (20 W / m 2 The photostability test was performed by exposure to light (10000 lux) for 10 hours and visible light (30000 lux) for 40 hours. The results obtained by measuring the purity (HPLC purity) and water content (by Karl Fischer titration) are shown in Table 2 below.

[0105] [Table 2]

[0106] The compound of Example 1 ((1S)-(+)-10-camphorsulfonate)

[0107]

[0108] As can be seen from the results in Table 2, the compound in the form of (1S)-(+)-10-camphorsulfonate obtained according to the present invention has excellent photostability.

[0109] Test Example 3: Hygroscopicity evaluation

[0110] The hygroscopicity of the compound obtained in Example 1 and the compounds obtained in Comparative Examples 1 to 3 was measured using a moisture adsorption analyzer (dynamic vapor adsorption, DVS). Specifically, at room temperature (about 25°C) and RH80%, the compound of WO2021 / 096238, the compound obtained in Example 1, and the compounds obtained in Comparative Examples 1 to 3 were exposed to a moisture adsorption analyzer (Surface Measurement System, DVSintrinsic) for 24 hours; then the weight changes were measured. The results are shown in Table 3 below.

[0111] [Table 3]

[0112]

[0113] As can be seen from the results in Table 3, the compound in the form of (1S)-(+)-10-camphorsulfonate obtained according to the present invention exhibits significantly low hygroscopicity.

[0114] Comparative Example 4: Water Solubility Evaluation

[0115] The water solubility of (S)-quinuclidine-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl) carbamate ('compound of WO2021 / 096238', free base form) prepared according to the method disclosed in WO2021 / 096238 and the compound obtained in Example 1 was measured at 20°C. The results are shown in Table 4 below.

[0116] [Table 4]

[0117]

[0118] As can be seen from the results in Table 4, the compound in the form of (1S)-(+)-10-camphorsulfonate obtained according to the present invention exhibits remarkably high water solubility.

Claims

1. A (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.

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, which is in crystalline form.

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

4. 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 3, wherein the crystalline form has the XRD pattern of Figure 2.

5. The (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 according to claim 2, wherein the crystalline form has a differential scanning calorimetry (DSC) thermogram showing an endothermic peak at 220°C 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 according to claim 5, wherein the crystalline form has a differential scanning calorimetry (DSC) thermogram of Figure 4.

7. A method for preparing a (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, 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.

8. The method according to claim 7, wherein step (a) is performed at a temperature of 35°C to 70°C.

9. The method of claim 7, wherein step (a) is performed at a temperature of 40°C to 60°C.

10. The method according to claim 7, wherein the solvent is an organic solvent selected from the group consisting of acetone, methyl ethyl ketone, C1-C5 alcohols, 2-methyltetrahydrofuran, isopropyl acetate, methyl tert-butyl ether and ethyl acetate.

11. 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 according to claim 7, wherein cooling is performed at a temperature of 0°C to 30°C.

14. The method according to claim 7, wherein cooling is performed at a temperature of 5°C to 25°C.

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

16. A method for preparing a (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, 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 anti-solvent to the solution obtained in step (i) to form a precipitate.

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

18. The method of claim 16, wherein the anti-solvent is selected from the group consisting of diisopropyl ether, methyl tert-butyl ether, diethyl ether and heptane.

19. A method for preparing a (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, 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).

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

Images