Improved process for the preparation of dimethyl-2,3-dihydro-1H-indene derivatives

Abstract

The present invention provides an improved method for producing a dimethyl-2,3-dihydro-1H-indene derivative or a pharmaceutically acceptable salt thereof. The present invention also provides novel intermediates useful in the production method. When the compound of formula 1 or its stereoisomer is produced via the novel intermediate of the present invention, it is possible to minimize the amount of heavy metal (Pd) remaining in the final product, i.e., the compound of formula 1 or its stereoisomer. Furthermore, the method of the present invention makes it possible to produce the stereoisomer of the compound of formula 1 or its pharmaceutically acceptable salt with high optical purity.

Description

[Technical Field]

[0001] The present invention relates to an improved process for preparing dimethyl-2,3-dihydro-1H-indene derivatives or pharmaceutically acceptable salts thereof, and to novel intermediates useful in said process. [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> JPEG2025534728000001.jpg45137

[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> JPEG2025534728000002.jpg84163

[0004] The method according to Reaction Scheme 1 includes, in the final step, a Suzuki coupling reaction 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 substituted with X1, X2, X3, or X4 (e.g., 3-chloro-4-isopropoxyphenylboronic acid) to produce a product (e.g., a compound of Formula 1 in the form of a free base). The Suzuki coupling reaction involves the use of a palladium catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2). However, the Suzuki coupling reaction performed in the final step carries a high risk of heavy metals such as palladium, ligands used for the Suzuki coupling reaction, and by-products thereof remaining in the product (e.g., a compound of Formula 1 in the form of a free base). Summary of the Invention [Problem to be solved by the invention]

[0005] The present inventors have conducted various studies to develop an improved method for producing the compound of formula 1 or a pharmaceutically acceptable salt thereof. The present inventors have found that when the compound of formula 1 or a stereoisomer thereof is produced via a novel intermediate, the amount of heavy metal (Pd) and by-products remaining in the final product (i.e., the compound of formula 1 or a stereoisomer thereof) can be minimized.

[0006] Furthermore, the present inventors have developed a method for converting one of the intermediates (i.e., 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine) into (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine with high optical purity. Furthermore, the present inventors have found that when the compound of formula 1 is produced using the obtained (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine and the intermediate, the stereoisomer of the compound of formula 1 can be produced with high optical purity.

[0007] Thus, the present invention provides an improved process for preparing a compound of formula 1, or a pharmaceutically acceptable salt thereof, which process involves the use of a novel intermediate.

[0008] The present invention also provides the novel intermediate.

[0009] Furthermore, the present invention provides a method for producing (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine having high optical purity. [Means for solving the problem]

[0010] According to one aspect of the present invention, there is provided a method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof, said method comprising: (a) reacting a compound of formula 4 with 3-chloro-4-isopropoxyphenylboronic acid, followed by reaction with D-tartaric acid to produce a compound of formula 3; (b) reacting a compound of formula 3 with a base to produce a compound of formula 2; and (c) reacting the compound of formula 2 with (S)-4-nitrophenyl quinuclidin-3-yl carbonate to produce the compound of formula 1. A method of manufacturing is provided, comprising: <Expression 1> JPEG2025534728000003.jpg45137<Expression 2> JPEG2025534728000004.jpg35139<expression 3> JPEG2025534728000005.jpg44146<expression 4> JPEG2025534728000006.jpg19145

[0011] According to another aspect of the present invention, there is provided a method for preparing a compound of formula 1a, or a pharmaceutically acceptable salt thereof, said method comprising: (a') reacting the compound of formula 4a with 3-chloro-4-isopropoxyphenylboronic acid, followed by reaction with D-tartaric acid to produce the compound of formula 3a; (b') reacting a compound of formula 3a with a base to produce a compound of formula 2a; and (c') reacting the compound of formula 2a with (S)-4-nitrophenyl quinuclidin-3-yl carbonate to produce the compound of formula 1a. A method of manufacturing is provided, comprising: <Formula 1a> JPEG2025534728000007.jpg45146<Formula 2a> JPEG2025534728000008.jpg35142<Formula 3a> JPEG2025534728000009.jpg43152<Formula 4a> JPEG2025534728000010.jpg20135

[0012] According to yet another aspect of the present invention, there is provided a method for preparing a compound of formula 4a, comprising the steps of: (i) reacting a compound of formula 4 with N-acetyl-D-leucine in a water-miscible organic solvent or a mixture of water and a water-miscible organic solvent to obtain a compound of formula 5; and <Expression 4> JPEG2025534728000011.jpg19145<Formula 5> JPEG2025534728000012.jpg25149(ii) reacting the compound of formula 5 with a base to obtain the compound of formula 4a. <Formula 4a> JPEG2025534728000013.jpg20135

[0013] According to yet another aspect of the present invention, there is provided a method for preparing a compound of formula 4a, comprising the steps of: (p) reacting the compound of formula 9 with iodomethane to produce the compound of formula 8; <Formula 8> JPEG2025534728000014.jpg19140<Formula 9> JPEG2025534728000015.jpg19142(q) reacting the compound of formula 8 with (S)-(-)-methyl-2-propanesulfinamide to produce the compound of formula 7; <Formula 7> JPEG2025534728000016.jpg29148(r) reducing the compound of formula 7 to produce a mixture of the compound of formula 6a and the compound of formula 6b; <Formula 6a> JPEG2025534728000017.jpg29140<Formula 6b> JPEG2025534728000018.jpg30154

[0014] (s) reacting a mixture of the compound of formula 6a and the compound of formula 6b with an acid to produce a mixture of the compound of formula 4a and the compound of formula 4b, reacting the mixture of the compound of formula 4a and the compound of formula 4b with N-acetyl-D-leucine in a water-miscible organic solvent or a mixture of water and a water-miscible organic solvent, and then isolating the compound of formula 5; and <Formula 4a> JPEG2025534728000019.jpg20135<Expression 4b> JPEG2025534728000020.jpg21138<Formula 5> JPEG2025534728000021.jpg25149(t) reacting the compound of formula 5 with a base to obtain the compound of formula 4a. <Formula 4a> JPEG2025534728000022.jpg20135

[0015] Yet another aspect of the present invention provides intermediates useful in the preparation of compounds of formula 1, namely compounds of formula 2: <Expression 2> JPEG2025534728000023.jpg35139

[0016] Yet another aspect of the present invention provides an intermediate useful in the preparation of compounds of formula 1a, namely compounds of formula 2a. <Formula 2a> JPEG2025534728000024.jpg35142

[0017] Yet another aspect of the present invention provides intermediates useful in the preparation of compounds of formula 1, namely compounds of formula 3: <Expression 3> JPEG2025534728000025.jpg44146

[0018] Yet another aspect of the present invention provides an intermediate useful in the preparation of compounds of formula 1a, namely compounds of formula 3a. <Formula 3a> JPEG2025534728000026.jpg43152

[0019] Yet another aspect of the present invention provides an intermediate useful in the preparation of compounds of formula 1a, namely compounds of formula 5: <Formula 5> JPEG2025534728000027.jpg25149 [Effects of the Invention]

[0020] When the compound of formula 1 or its stereoisomer is produced via a novel intermediate according to the present invention, it is possible to minimize the amount of heavy metal (Pd) remaining in the final product (i.e., the compound of formula 1 or its stereoisomer).In addition, when the compound of formula 1 is produced by converting 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine to (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine and then producing the compound of formula 1a via the novel intermediate according to the present invention, it is possible to produce the stereoisomer of the compound of formula 1 or its pharmaceutically acceptable salt with high optical purity. DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention provides an improved process for preparing (S)-quinuclidin-3-yl(5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, i.e., a compound of formula 1, or a pharmaceutically acceptable salt thereof. That is, the present invention provides a process for preparing a compound of formula 1, or a pharmaceutically acceptable salt thereof, comprising: (a) reacting a compound of formula 4 with 3-chloro-4-isopropoxyphenylboronic acid, followed by reaction with D-tartaric acid to produce a compound of formula 3; (b) reacting a compound of formula 3 with a base to produce a compound of formula 2; and (c) reacting a compound of formula 2 with (S)-4-nitrophenyl quinuclidin-3-yl carbonate to produce a compound of formula 1. <Expression 1> JPEG2025534728000028.jpg45137<Formula 2> JPEG2025534728000029.jpg35139<expression 3> JPEG2025534728000030.jpg44146<expression 4> JPEG2025534728000031.jpg19145

[0022] The present invention also provides an improved process for preparing the stereoisomer of the compound of formula 1, i.e., (S)-quinuclidin-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, or a pharmaceutically acceptable salt thereof. That is, the present invention provides a process for preparing a compound of formula 1a, or a pharmaceutically acceptable salt thereof, comprising: (a') reacting the compound of formula 4a with 3-chloro-4-isopropoxyphenylboronic acid, followed by reaction with D-tartaric acid to produce the compound of formula 3a; (b') reacting a compound of formula 3a with a base to produce a compound of formula 2a; and (c') reacting a compound of formula 2a with (S)-4-nitrophenyl quinuclidin-3-yl carbonate to produce a compound of formula 1a. <Formula 1a> JPEG2025534728000032.jpg45146<Formula 2a> JPEG2025534728000033.jpg35142<Formula 3a> JPEG2025534728000034.jpg43152<Expression 4a> JPEG2025534728000035.jpg20135

[0023] In the process of the present invention, the compound of formula 4 (i.e., 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine) is a known compound and therefore may be purchased commercially or synthesized according to the literature.

[0024] It has been found in accordance with the present invention that when the compound of formula 4 is resolved using a specific optical resolution agent (i.e., N-acetyl-D-leucine), (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine can be prepared in high optical purity.

[0025] In one embodiment, the compound of formula 4a may be prepared by a process comprising the steps of: (i) reacting a compound of formula 4 with N-acetyl-D-leucine in a water-miscible organic solvent or a mixture of water and a water-miscible organic solvent to obtain a compound of formula 5; and <Expression 4> JPEG2025534728000036.jpg19145<Formula 5> JPEG2025534728000037.jpg25149(ii) reacting the compound of formula 5 with a base to obtain a compound of formula 4a.

[0026] In step (i), the resolving agent, i.e., N-acetyl-D-leucine, may be used in a ratio of 0.3 to 10 equivalents per equivalent of the compound of formula 4, but is not limited thereto. The water-miscible organic solvent may be one or more selected from the group consisting of acetone, acetonitrile, C1-C5 alcohols, tetrahydrofuran, methyl ethyl ketone, isopropyl acetate, ethyl acetate, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran, and dichloromethane, preferably acetone or acetonitrile. The volume ratio of the water-miscible organic solvent to water in the mixed solvent may be in the range of 3:1 to 20:1, for example, about 9:1. The reaction in step (i) may be carried out at a temperature of 0°C to 70°C (e.g., about 35°C) for 1 to 24 hours. The solid produced in step (i), i.e., (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine acetyl-D-leucinate of formula 5, may be isolated according to conventional methods such as filtration and drying (e.g., vacuum drying).

[0027] In step (ii), the base may be one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, calcium hydroxide, sodium bicarbonate, and potassium phosphate. For example, sodium hydroxide may be used. The base may be used in a ratio of 1 to 3 equivalents per equivalent of the compound of formula 5, but is not limited thereto. The reaction in step (ii) may be carried out in a mixed solvent of water and an organic solvent such as isopropyl acetate, ethyl acetate, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran, or dichloromethane. The volume ratio of the organic solvent to water in the mixed solvent may be, but is not limited to, 1:1 to 10:1. The product, i.e., (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine, may be isolated by conventional methods such as washing, drying, and concentration.

[0028] In another embodiment, the compound of formula 4a may be prepared by a process comprising the steps of: (p) reacting the compound of formula 9 with iodomethane to produce the compound of formula 8; <Formula 8> JPEG2025534728000038.jpg19140<Formula 9> JPEG2025534728000039.jpg19142(q) reacting the compound of formula 8 with (S)-(-)-methyl-2-propanesulfinamide to produce the compound of formula 7; <Formula 7> JPEG2025534728000040.jpg29148(r) reducing the compound of formula 7 to produce a mixture of the compound of formula 6a and the compound of formula 6b; <Formula 6a> JPEG2025534728000041.jpg29140<Formula 6b> JPEG2025534728000042.jpg30154(s) reacting a mixture of the compound of formula 6a and the compound of formula 6b with an acid to produce a mixture of the compound of formula 4a and the compound of formula 4b, reacting the mixture of the compound of formula 4a and the compound of formula 4b with N-acetyl-D-leucine in a water-miscible organic solvent or a mixed solvent of water and a water-miscible organic solvent, and then isolating the compound of formula 5; and <Formula 4a> JPEG2025534728000043.jpg20135<Expression 4b> JPEG2025534728000044.jpg21138<expression 5> JPEG2025534728000045.jpg25149(t) reacting the compound of formula 5 with a base to obtain the compound of formula 4a. <Formula 4a> JPEG2025534728000046.jpg20135

[0029] In step (p), iodomethane may be used in a ratio of 2.0 to 3.0 equivalents per equivalent of the compound of formula 9 (5-bromo-2,3-dihydro-1H-inden-1-one), but is not limited thereto. The reaction in step (p) may be carried out in a water-miscible organic solvent or a mixed solvent of water and a water-miscible organic solvent in the presence of a base. The water-miscible organic solvent may be one or more selected from the group consisting of N-methyl-2-pyrrolidone, acetonitrile, tetrahydrofuran, and dimethylformamide. The volume ratio of the water-miscible organic solvent to water in the mixed solvent may be in the range of 1:1 to 10:1, for example, about 6:1. The base may be selected from the group consisting of cesium carbonate (CsCO), sodium carbonate (NaCO), potassium carbonate (KCO), potassium phosphate (KPO), triethylamine, diisopropylamine, potassium hydroxide, potassium acetate, potassium t-butoxide, sodium hydroxide, sodium hydride, sodium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, and diisopropylethylamine. The base may be used in a ratio of 2.0 to 3.0 equivalents per equivalent of the compound of Formula 9, but is not limited thereto. The reaction in step (p) may be carried out at a temperature of 0°C to 40°C for 1 to 20 hours. The product of step (p), ie, 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one of formula 8, may be isolated according to conventional methods such as extraction, filtration, concentration, and the like.

[0030] In step (q), (S)-(-)-methyl-2-propanesulfinamide may be used in a ratio of 1.0 to 2.0 equivalents per equivalent of the compound of formula 8, but is not limited thereto. The reaction in step (q) is preferably carried out in the presence of a titanium catalyst such as titanium ethoxide or titanium isopropoxide. The titanium catalyst may be used in a ratio of 2.0 to 3.0 equivalents per equivalent of the compound of formula 8, but is not limited thereto. The reaction in step (q) may be carried out in the presence or absence of a solvent. When the reaction is carried out in the presence of a solvent, the solvent may be toluene, C1-C10 The solvent may be one or more selected from the group consisting of alcohol, dichloromethane, tetrahydrofuran, acetonitrile, isopropyl acetate, dimethylformamide, dimethylacetamide, 2-methyltetrahydrofuran, ethyl acetate, and 1,4-dioxane. According to the present invention, it has been found that the reaction in step (q) may be particularly preferably carried out under a nitrogen atmosphere at a high temperature. Therefore, the reaction in step (q) may be preferably carried out under a nitrogen atmosphere (e.g., while purging with nitrogen gas) at a temperature of 70°C to 100°C. The product of step (q), i.e., (S,Z)-N-(5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide of Formula 7, may be isolated by a conventional method such as concentration, or the residue obtained by concentration may be used in the next reaction without isolation.

[0031] In step (r), the reduction may be carried out using a reducing agent. The reducing agent may be one or more selected from the group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride. The reducing agent may be used in a ratio of 1.0 to 2.0 equivalents per equivalent of the compound of formula 7, but is not limited thereto. The reaction in step (r) may be carried out using a solvent such as tetrahydrofuran, toluene, C1 to C6 toluene, or the like. 10 The reaction may be carried out in an organic solvent such as alcohol, dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, 2-methyltetrahydrofuran, or 1,4-dioxane at a temperature of 0° C. to 50° C. The product of step (r), i.e., a mixture of (S)—N—((R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide of formula 6a and (S)—N—((S)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide of formula 6b, may be obtained by conventional methods such as extraction and concentration, and the resulting residue may be used in the next reaction without isolation.

[0032] In step (s), the acid may be an inorganic acid such as hydrochloric acid, sulfuric acid, or nitric acid. The acid may be used in a ratio of 2.0 to 10.0 equivalents per equivalent of the compound of formula 6. The reaction of the mixture of the compound of formula 6a and the compound of formula 6b with the acid may be carried out using ethyl acetate, toluene, C1 to C6 10 The reaction may be carried out in an organic solvent such as alcohol, dichloromethane, tetrahydrofuran, acetonitrile, isopropyl acetate, dimethylformamide, dimethylacetamide, or 2-methyltetrahydrofuran at a temperature of 0°C to 50°C. The reaction of a mixture of the compound of formula 6a and the compound of formula 6b with an acid produces a mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine of formula 4a and (S)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine of formula 4b, preferably in a weight ratio of 7:3 to 6:4. The resulting mixture may be isolated by conventional methods such as neutralization, extraction, or concentration, or the residue obtained by concentration may be used in the next reaction without isolation. The reaction of a mixture of the compound of formula 4a and the compound of formula 4b with N-acetyl-D-leucine may be carried out in the same manner as in step (i).

[0033] The reaction in step (t) may be carried out in the same manner as in step (ii).

[0034] For example, a method for preparing a stereoisomer of a compound of formula 1 or a pharmaceutically acceptable salt thereof can be shown in Scheme 2 or Scheme 3 below. <Reaction Scheme 2> TIFF2025534728000047.tif59168<Reaction Scheme 3> TIFF2025534728000048.tif82167

[0035] The method of the present invention includes a step [step (a) or step (a')] of reacting a compound of formula 4 or a compound of formula 4a with 3-chloro-4-isopropoxyphenylboronic acid and subsequently with D-tartaric acid to produce a compound of formula 3 or a compound of formula 3a.

[0036] The reaction of the compound of formula 4 or the compound of formula 4a with 3-chloro-4-isopropoxyphenylboronic acid may be carried out by Suzuki reaction. That is, the reaction of the compound of formula 4 or the compound of formula 4a with 3-chloro-4-isopropoxyphenylboronic acid may be carried out in the presence of a metal catalyst and a base. Alternatively, the reaction of the compound of formula 4 or the compound of formula 4a with 3-chloro-4-isopropoxyphenylboronic acid may be carried out in the presence of a ligand in addition to the metal catalyst and a base.

[0037] The metal catalyst may be one or more selected from the group consisting of palladium, copper, iron, cadmium, zinc, and nickel, and preferably one or more selected from the group consisting of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), palladium(II) acetate (Pd(OAc)2), bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3).

[0038] The base may be selected from the group consisting of cesium carbonate (CsCO), sodium carbonate (NaCO), potassium carbonate (KCO), potassium phosphate (KPO), triethylamine, diisopropylamine, potassium hydroxide, potassium acetate, potassium t-butoxide, sodium hydroxide, sodium hydride, sodium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, and diisopropylethylamine.

[0039] The ligand may be one or more selected from the group consisting of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), and 1,1'-bis(diphenylphosphino)ferrocene (DPPF).

[0040] The reaction of a compound of formula 4 or a compound of formula 4a with 3-chloro-4-isopropoxyphenylboronic acid may be carried out in the presence of water, C1-C 10 The reaction may be carried out in the presence of one or more solvents selected from the group consisting of alcohol, dichloromethane, tetrahydrofuran, acetone, acetonitrile, isopropyl acetate, dimethylformamide, dimethylacetamide, toluene, 2-methyltetrahydrofuran, ethyl acetate, and 1,4-dioxane. In one embodiment, the reaction is carried out in the presence of water and a C1-C 10 The reaction may be carried out in a mixed solvent with an organic solvent such as alcohol, dichloromethane, tetrahydrofuran, acetone, acetonitrile, toluene, or 2-methyltetrahydrofuran. The volume ratio of the organic solvent to water in the mixed solvent may be, but is not limited to, 1:1 to 20:1. The reaction may be carried out at a temperature ranging from 50°C to the reflux temperature of the solvent used. Other reaction conditions, including the amounts of the palladium catalyst, ligand, and base used, may be determined according to known methods for the Suzuki reaction.

[0041] The product obtained by the Suzuki reaction is crystallized in the form of the compound of formula 3 or the compound of formula 3a by reaction with D-tartaric acid. The compound of formula 3 or the compound of formula 3a is suitable for mass production due to its excellent filterability, and is easy to scale up. D-tartaric acid may be used in a ratio of 0.4 to 2.0 equivalents per equivalent of the compound of formula 4 or the compound of formula 4a. The reaction is carried out in a solvent containing water, acetone, C1 to C6 10The reaction may be carried out in a mixed solvent with an organic solvent such as alcohol, dichloromethane, tetrahydrofuran, acetonitrile, isopropyl acetate, toluene, 2-methyltetrahydrofuran, or ethyl acetate, or in an organic solvent such as acetone, at 0°C to 70°C (e.g., about 50°C) for 0 to 3 hours (e.g., about 30 minutes). The volume ratio of the organic solvent to water in the mixed solvent may be, but is not limited to, a range of 5:1 to 30:1. The product, i.e., the compound of Formula 3 or the compound of Formula 3a, may be isolated by a conventional method such as filtration or drying (e.g., vacuum drying).

[0042] The method of the present invention includes a step [step (b) or step (b')] of reacting a compound of formula 3 or a compound of formula 3a with a base to produce a compound of formula 2 or a compound of formula 2a.

[0043] The base used in step (b) or step (b') may be one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, and sodium phosphate. The base may be used in a ratio of 1 to 5 equivalents per equivalent of the compound of formula 3 or the compound of formula 3a, but is not limited thereto. The reaction of the compound of formula 3 or the compound of formula 3a with the base may be carried out in a mixed solvent of water and an organic solvent such as isopropyl acetate, ethyl acetate, dichloromethane, toluene, or 2-methyltetrahydrofuran. The volume ratio of the organic solvent to water in the mixed solvent may be in the range of 1:1 to 10:1, but is not limited thereto. The product, i.e., the compound of formula 2 or the compound of formula 2a, may be isolated by a conventional method such as washing or concentration (e.g., concentration under reduced pressure).

[0044] The method of the present invention includes a step [step (c) or step (c')] of reacting a compound of formula 2 or a compound of formula 2a with (S)-4-nitrophenyl quinuclidin-3-yl carbonate to produce a compound of formula 1 or a compound of formula 1a.

[0045] (S)-4-nitrophenyl quinuclidin-3-yl carbonate may be prepared according to known methods (e.g., WO 2021 / 096238). For example, (S)-4-nitrophenyl quinuclidin-3-yl carbonate may be prepared by reacting (S)-(+)-3-quinuclidinol with bis(4-nitrophenyl) carbonate in the presence or absence of a base. When the reaction is carried out in the presence of a base, the base may be one or more bases selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, sodium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, triethylamine, diisopropylamine, and diisopropylethylamine. The base may be used in a ratio of 1 to 3 equivalents per equivalent of (S)-(+)-3-quinuclidinol, but is not limited thereto.

[0046] It has been found in accordance with the present invention that the reaction of (S)-(+)-3-quinuclidinol with bis(4-nitrophenyl) carbonate and the reaction of the compound of formula 2 or 2a with (S)-4-nitrophenyl quinuclidin-3-yl carbonate can be carried out in a one-pot reaction. Thus, the reaction of (S)-(+)-3-quinuclidinol with bis(4-nitrophenyl) carbonate and the reaction of the compound of formula 2 or 2a with (S)-4-nitrophenyl quinuclidin-3-yl carbonate may preferably be carried out in a one-pot reaction.

[0047] The reaction of the compound of Formula 2 or the compound of Formula 2a with (S)-4-nitrophenyl quinuclidin-3-yl carbonate may be carried out in the presence or absence of a base. When the reaction is carried out in the presence of a base, the base may be one or more bases selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, sodium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, triethylamine, diisopropylamine, and diisopropylethylamine. The base may be used in a ratio of 1 to 3 equivalents per equivalent of the compound of Formula 2 or the compound of Formula 2a, but is not limited thereto. Alternatively, the reaction of the compound of formula 2 or 2a with (S)-4-nitrophenyl quinuclidin-3-yl carbonate may be carried out in one or more solvents selected from the group consisting of dimethylacetamide, dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile, isopropyl acetate, 2-methyltetrahydrofuran, and ethyl acetate. If necessary, the resulting compound of formula 1 or 1a may be isolated in the form of a pharmaceutically acceptable salt thereof, for example, a camphorsulfonate salt.

[0048] The present invention includes within its scope a process for the preparation of a compound of formula 4a which is used as a starting material in the preparation of a compound of formula 1a, or a pharmaceutically acceptable salt thereof.

[0049] In one embodiment, the present invention includes a method for preparing a compound of formula 4a, comprising the steps of: (i) reacting a compound of formula 4 with N-acetyl-D-leucine in a water-miscible organic solvent or a mixture of water and a water-miscible organic solvent to obtain a compound of formula 5; and <Expression 4> JPEG2025534728000049.jpg19145<Formula 5> JPEG2025534728000050.jpg25149(ii) reacting the compound of formula 5 with a base to obtain the compound of formula 4a. <Formula 4a> JPEG2025534728000051.jpg20135The reactions in step (i) and step (ii) may be carried out in the same manner as described above.

[0050] In another embodiment, the present invention includes a method for preparing a compound of formula 4a, comprising the steps of: (p) reacting the compound of formula 9 with iodomethane to produce the compound of formula 8; <Formula 8> JPEG2025534728000052.jpg19140<Formula 9> JPEG2025534728000053.jpg19142(q) reacting the compound of formula 8 with (S)-(-)-methyl-2-propanesulfinamide to produce the compound of formula 7; <Formula 7> JPEG2025534728000054.jpg29148(r) reducing the compound of formula 7 to produce a mixture of the compound of formula 6a and the compound of formula 6b; <Formula 6a> JPEG2025534728000055.jpg29140<Formula 6b> JPEG2025534728000056.jpg30154(s) reacting a mixture of the compound of formula 6a and the compound of formula 6b with an acid to produce a mixture of the compound of formula 4a and the compound of formula 4b, reacting the mixture of the compound of formula 4a and the compound of formula 4b with N-acetyl-D-leucine in a water-miscible organic solvent or a mixed solvent of water and a water-miscible organic solvent, and then isolating the compound of formula 5; and <Formula 4a> JPEG2025534728000057.jpg20135<Formula 4b> JPEG2025534728000058.jpg21138<expression 5> JPEG2025534728000059.jpg25149(t) reacting the compound of formula 5 with a base to obtain the compound of formula 4a. <Formula 4a> JPEG2025534728000060.jpg20135The reactions in steps (p) to (t) may be carried out in the same manner as described above.

[0051] The present invention also includes within its scope novel intermediates useful in the preparation of compounds of formula 1 or 1a, or pharmaceutically acceptable salts thereof.

[0052] In one embodiment, the present invention comprises compounds of formula 2 that are useful in the preparation of compounds of formula 1 or pharmaceutically acceptable salts thereof. <Expression 2> JPEG2025534728000061.jpg35139

[0053] In another embodiment, the present invention encompasses compounds of formula 2a that are useful in the preparation of compounds of formula 1a or pharmaceutically acceptable salts thereof. <Formula 2a> JPEG2025534728000062.jpg35142

[0054] In yet another embodiment, the present invention encompasses compounds of formula 3 that are useful in the preparation of compounds of formula 1 or pharmaceutically acceptable salts thereof. <Expression 3> JPEG2025534728000063.jpg44146

[0055] In yet another embodiment, the present invention encompasses compounds of formula 3a that are useful in the preparation of compounds of formula 1a, or pharmaceutically acceptable salts thereof. <Formula 3a> JPEG2025534728000064.jpg43152

[0056] In yet another embodiment, the present invention includes compounds of formula 5 that are useful in the preparation of compounds of formula 1a. <Formula 5> JPEG2025534728000065.jpg25149

[0057] 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]

[0058] Example 1: (R)-5-Bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine acetyl-D-leucinate (Compound 5) 5-Bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (44 g, 183.2 mmol) was dissolved in a mixed solvent of acetone (792 mL) and purified water (88 mL) at room temperature, and then N-acetyl-D-leucine (14.3 g, 82.4 mmol) was added. The reaction mixture was stirred at 35°C for approximately 19 hours. The resulting solid was filtered and dried under vacuum to obtain 24.0 g of the title compound. (Yield: 31.7%, Optical purity: 99.5%)

[0059] Example 2: (R)-5-Bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine acetyl-D-leucinate (Compound 5) 5-Bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (3 g, 12.5 mmol) was dissolved in a mixed solvent of acetonitrile (54 mL) and purified water (6 mL) at room temperature, and then N-acetyl-D-leucine (1.0 g, 5.6 mmol) was added. The reaction mixture was stirred at 25°C for approximately 20 hours. The resulting solid was filtered and dried under vacuum to obtain 1.9 g of the title compound. (Yield: 36.8%, Optical purity: 93.0%)

[0060] Example 3: (R)-5-Bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (Compound 4a) (R)-5-Bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine. A mixture of acetyl-D-leucinate (44 g, 0.106 mol), isopropyl acetate (220 mL), and purified water (220 mL) was stirred at room temperature while 50% sodium hydroxide (14.5 g, 0.181 mol) was added. The reaction mixture was stirred for 20 minutes, and then the layers were separated. The aqueous layer was extracted with isopropyl acetate (132 mL). The combined organic layers were washed with purified water (88 mL), dried over magnesium sulfate (22 g), and concentrated under reduced pressure to give 25.5 g of the title compound. (Yield: 100%, Optical purity: 99.5%)

[0061] Example 4: 5-Bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (Compound 8) A solution of 85% potassium hydroxide (3.9 g, 59.2 mmol) in purified water (5 mL) was cooled to 0-5°C. A mixture of 5-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.7 mmol), N-methyl-2-pyrrolidone (30 mL), and iodomethane (7.1 g, 49.8 mmol) was added to the potassium hydroxide solution while maintaining the temperature below 30°C. The reaction mixture was stirred at room temperature for approximately 4 hours. Isopropyl acetate (20 mL) and toluene (10 mL) were added to the reaction mixture, followed by stirring. After separating the organic layer, the resulting aqueous layer was extracted with isopropyl acetate (30 mL). The combined organic layers were washed with purified water (30 mL) and concentrated to give 4.8 g of the title compound. (Yield: 84.7%) 1 H-NMR (400 MHz, CDCl3) δ 7.64 (d, 2H), 7.28 (d, 1H), 2.99 (s, 2H), 1.25 (s, 6H)

[0062] Example 5: 5-Bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (Compound 8) A solution of 85% potassium hydroxide (23.5 g, 355.4 mmol) in purified water (30 mL) was cooled to 0-5°C. A mixture of 5-bromo-2,3-dihydro-1H-inden-1-one (30 g, 142.1 mmol), N-methyl-2-pyrrolidone (180 mL), and iodomethane (44.4 g, 312.8 mmol) was added to the potassium hydroxide solution while maintaining the temperature below 30°C. The reaction mixture was stirred at room temperature for approximately 4 hours. Purified water (450 mL) was slowly added to the reaction mixture, followed by toluene (300 mL). The reaction mixture was stirred and then filtered through a Celite pad. The organic layer was separated from the filtrate, and the resulting aqueous layer was extracted with toluene (300 mL). The combined organic layers were washed with 10% sodium chloride solution and concentrated to give 30.8 g of the title compound. (Yield: 90.6%) 1 H-NMR (400 MHz, CDCl3) δ 7.64 (d, 2H), 7.28 (d, 1H), 2.99 (s, 2H), 1.25 (s, 6H)

[0063] Example 6: (S,Z)—N-(5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide (Compound 7) A mixture of 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (10 g, 41.8 mmol), titanium(IV) ethoxide (19.1 g, 83.6 mmol), and toluene (100 mL) was stirred at room temperature. (S)-(-)-2-methylpropanesulfinamide (10.1 g, 83.6 mmol) was added to the mixture, and the mixture was stirred at 85°C for approximately 19 hours under a nitrogen gas stream. The reaction mixture was concentrated, and the resulting residue was used in the next reaction without further purification. 1 H-NMR (400 MHz, DMSO-d6) δ 8.2 (s, 1H), 7.7 (s, 1H), 7.6 (d, 1H), 3.0 (s, 2H), 1.2 (s, 9H), 1.0 (s, 6H)

[0064] Example 7: (S,Z)—N-(5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide (Compound 7) A mixture of 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (27 g, 112.9 mmol) and titanium(IV) ethoxide (51.5 g, 225.8 mmol) was stirred at room temperature. (S)-(-)-2-methylpropanesulfinamide (27.4 g, 225.8 mmol) was added to the mixture, and the mixture was stirred at 85°C under a nitrogen gas stream for 6 hours. The reaction mixture was concentrated, and the resulting residue was used in the next reaction without further purification. 1 H-NMR (400 MHz, DMSO-d6) δ 8.2 (s, 1H), 7.7 (s, 1H), 7.6 (d, 1H), 3.0 (s, 2H), 1.2 (s, 9H), 1.0 (s, 6H)

[0065] Example 8: Mixture of (S)—N—((R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (Compound 6a) and (S)—N—((S)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (Compound 6b) A mixture of (S,Z)-N-(5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide (192.8 g, 563.3 mmol) and tetrahydrofuran (1.35 L) was cooled to -10 °C. Sodium borohydride (23.4 g, 619.6 mmol) was added to the reaction mixture, and the mixture was stirred while the temperature was slowly raised to room temperature. After the reaction was completed, the reaction mixture was cooled to 0 °C, and citric acid solution (2.9 L) was slowly added. The reaction mixture was extracted with ethyl acetate (965 mL). The resulting organic layer was washed with 10% sodium chloride solution (965 mL) and then concentrated. The resulting residue was used in the next reaction without further purification.

[0066] The residue was identified as a mixture of the compound of formula 6a and the compound of formula 6b. After separation by silica gel column chromatography (eluent: hexane / ethyl acetate), the NMR data measured are as follows: <Compound of Formula 6a> 1 H-NMR (400 MHz, CDCl3) δ 7.3 (m, 2H), 7.1 (d, 1H), 4.4 (d, 1H), 3.5 (d, 1H), 2.8 (q, 2H), 1.4 (s, 3H), 1.3 (s, 9H), 0.96 (s, 3H) <Compound of Formula 6b> 1 H-NMR (400 MHz, CDCl3) δ 7.5 (d, 1H), 7.3 (m, 2H), 4.4 (d, 1H), 3.3 (d, 1H), 2.8 (q, 2H), 1.3 (s, 9H), 1.2 (s, 3H), 0.90 (s, 3H)

[0067] Example 9: (R)-5-Bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine acetyl-D-leucinate (Compound 5) A mixture of the residue obtained in Example 8 (i.e., a mixture of the compound of formula 6a and the compound of formula 6b) (181.4 g, 526.8 mmol) and ethyl acetate (1.8 L) was cooled to 0°C and stirred. Concentrated hydrochloric acid (35%) (183 mL) was added to the reaction mixture, and the mixture was warmed to room temperature and stirred for 4 hours. Purified water (907 mL) was added to the reaction mixture, and the mixture was cooled to 0°C. The pH was adjusted to 9-11 with 50% sodium hydroxide. The separated organic layer was washed with 10% sodium chloride solution (907 mL) and then concentrated under reduced pressure. Acetone (907 mL) was added to the resulting residue, and the mixture was re-concentrated. Acetone (2.27 L) and purified water (253 mL) were added to the resulting concentrated residue, and the mixture was stirred at room temperature. N-acetyl-D-leucine (68.4 g, 395.1 mmol) was added to the reaction mixture, and the mixture was stirred at 35°C for approximately 16 hours. The resulting solid was filtered and then dried under vacuum to give 84.3 g of the title compound (yield: 38.7% (three-step yield from the compound of formula 8), optical purity: 99.2%). 1H-NMR (400 MHz, DMSO-d6) δ 7.9 (d, 1H), 7.4 (d, 2H), 7.3 (d, 1H), 4.1 (q, 1H), 3.9 (s, 1H), 2.7 (q, 2H), 1.8 (s, 3H), 1.6 (m, 1H), 1.5 (m, 2H), 1.2 (s, 3H), 0.9 (d, 3H), 0.8 (d, 6H)

[0068] Example 10: (R)-5-Bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (Compound 4a) A mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine acetyl-D-leucinate (7.5 g, 18.1 mmol), isopropyl acetate (37 mL), and purified water (37 mL) was stirred at room temperature. 50% sodium hydroxide (2.5 g, 53.0 mmol) was added with stirring. After layer separation, the aqueous layer was extracted with isopropyl acetate (23 mL). The combined organic layer was washed with purified water (20 mL), dried over magnesium sulfate (3.8 g), and then concentrated under reduced pressure to give 4.5 g of the title compound. (Yield: 100%, optical purity: 97.5%) 1 H-NMR (400 MHz, CDCl3) δ 7.3 (m, 2H), 7.2 (d, 1H), 3.8 (s, 1H), 2.7 (t, 1H), 1.2 (s,3H), 0.88 (s, 3H)

[0069] Example 11: 5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (Compound 3) A mixture of 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (5.0 g, 0.0208 mol), 3-chloro-4-isopropoxyphenylboronic acid (5.1 g, 0.0238 mol), potassium carbonate (5.8 g, 0.042 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.3 g, 0.41 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.4 g, 0.84 mmol), tetrahydrofuran (45 mL), and purified water (10 mL) was refluxed with stirring for 7 h. The reaction mixture was concentrated under reduced pressure and extracted with purified water (15 mL), ethyl acetate (35 mL), and dichloromethane (25 mL). The separated organic layer was washed with purified water (25 mL) and then concentrated under reduced pressure. Acetone (45 mL) was added to the resulting concentrated residue, followed by a solution of D-tartaric acid (1.56 g, 0.0104 mol) in purified water (5 mL). The reaction mixture was heated to 50°C, stirred for 30 minutes, and then cooled to room temperature. The resulting solid was filtered and dried under vacuum to obtain 7.9 g of the title compound. (Yield: 93.7%, Purity: 94.8%) 1 H-NMR (400 MHz, DMSO) δ 7.70 (s, 1H), 7.69-7.43 (m, 4H), 7.23 (d, 1H), 4.05 (s, 1H), 3.80 (s, 1H), 2.76 (q, 2H), 1.32 (d, 6H), 1.20 (s, 3H), 0.95 (s, 3H)

[0070] Example 12: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (Compound 3a) A mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (3.0 g, 0.0125 mol), 3-chloro-4-isopropoxyphenylboronic acid (3.1 g, 0.0144 mol), potassium carbonate (3.5 g, 0.025 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.18 g, 0.25 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.24 g, 0.5 mmol), tetrahydrofuran (27.0 mL), and purified water (6 mL) was stirred at 60 °C for 4 h. Purified water (15 mL) was added to the reaction mixture, which was then concentrated under reduced pressure and extracted with ethyl acetate (15 mL). The resulting extract was washed with purified water (15 mL) and then concentrated under reduced pressure. Acetone (27 mL) was added to the resulting concentrated residue, followed by the addition of D-tartaric acid (0.94 g, 0.006 mol) and purified water (3 mL). The reaction mixture was heated to 50°C, stirred for 30 minutes, and then cooled to room temperature. The resulting solid was filtered and dried under vacuum to obtain 4.4 g of the title compound. (Yield: 87.0%) 1 H-NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.59-7.50 (d, 1H), 7.49-7.47 (d, 3H), 7.14-7.12 (d, 2H), 4.70-4.64 (m, 1H), 4.35 (d, 2H), 3.0 (d, 1H), 2.82 (d, 1H), 1.39 (d, 6H), 1.27-1.23 (d, 6H)

[0071] Example 13: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (Compound 3a) A mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (5.0 g, 0.0208 mol), 3-chloro-4-isopropoxyphenylboronic acid (5.13 g, 0.0239 mol), potassium carbonate (5.76 g, 0.0416 mol), bis(triphenylphosphine)palladium(II) dichloride (0.3 g, 0.416 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.4 g, 0.833 mmol), acetone (35 mL), and purified water (5 mL) was stirred at 60 °C for 4 h. Purified water (25 mL) was added to the reaction mixture, which was then concentrated under reduced pressure and extracted with ethyl acetate (15 mL). The resulting extract was washed with purified water (25 mL) and then concentrated under reduced pressure. Acetone (45 mL) was added to the resulting concentrated residue, followed by the addition of D-tartaric acid (1.56 g, 10.41 mmol) and purified water (5 mL). The reaction mixture was heated to 50°C, stirred for 30 minutes, and then cooled to room temperature. The resulting solid was filtered and dried under vacuum to give 6.7 g of the title compound. (Yield: 79.5%) 1 H-NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.59-7.50 (d, 1H), 7.49-7.47 (d, 3H), 7.14-7.12 (d, 2H), 4.70-4.64 (m, 1H), 4.35 (d, 2H), 3.0 (d, 1H), 2.82 (d, 1H), 1.39 (d, 6H), 1.27-1.23 (d, 6H)

[0072] Example 14: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (Compound 3a) A mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (50.0 g, 0.208 mol), 3-chloro-4-isopropoxyphenylboronic acid (43.8 g, 0.204 mol), potassium carbonate (57.6 g, 0.416 mol), bis(triphenylphosphine)palladium(II) dichloride (3.0 g, 4.164 mmol), ethanol (225 mL), and purified water (150 mL) was refluxed with stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, and methyl tert-butyl ether (500 mL) and 3N hydrochloric acid solution (500 mL) were slowly added. Purified water (250 mL) was added to the separated organic layer. The reaction mixture was neutralized with 50% sodium hydroxide solution. The separated organic layer was washed with purified water and then concentrated under reduced pressure. Acetone (250 mL) was added to the resulting concentrated residue, followed by concentration under reduced pressure. Acetone (450 mL) was added again to the resulting concentrated residue, followed by addition of a solution of D-tartaric acid (15.6 g, 0.104 mol) in acetone (250 mL). The reaction mixture was refluxed with stirring for 30 minutes and then cooled to room temperature. The resulting solid was filtered and dried under vacuum to obtain 71.3 g of the title compound. (Yield: 84.6%) 1 H-NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.59-7.50 (d, 1H), 7.49-7.47 (d, 3H), 7.14-7.12 (d, 2H), 4.70-4.64 (m, 1H), 4.35 (d, 2H), 3.0 (d, 1H), 2.82 (d, 1H), 1.39 (d, 6H), 1.27-1.23 (d, 6H)

[0073] Example 15: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (Compound 3a) A mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (10.0 g, 0.0416 mol), 3-chloro-4-isopropoxyphenylboronic acid (10.3 g, 0.0479 mol), potassium carbonate (11.51 g, 0.0833 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.61 g, 0.0008 mol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.79 g, 0.002 mol), tetrahydrofuran (90.0 mL), and purified water (20 mL) was refluxed with stirring for 3 h. Purified water (50 mL) was added to the reaction mixture, which was concentrated under reduced pressure and then extracted with ethyl acetate (50 mL). The resulting extract was washed with purified water (50 mL) and then concentrated under reduced pressure. Acetone (90 mL) was added to the resulting concentrated residue, followed by the addition of D-tartaric acid (3.13 g, 0.021 mol) and purified water (10 mL). The reaction mixture was heated to 50°C, stirred for 30 minutes, and then cooled to room temperature. The resulting solid was filtered and dried under vacuum to obtain 13.95 g of the title compound. (Yield: 82.7%) 1 H-NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.59-7.5 (d, 1H), 7.49-7.47 (d, 3H), 7.14-7.12 (d, 2H), 4.70-4.64 (m, 1H), 4.35 (d, 2H), 3.0 (d, 1H), 2.82 (d, 1H), 1.39 (d, 6H), 1.27-1.23 (d, 6H)

[0074] Example 16: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (Compound 3a) A mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (3.0 g, 0.0125 mol), 3-chloro-4-isopropoxyphenylboronic acid (3.1 g, 0.0144 mol), potassium carbonate (3.5 g, 0.025 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.18 g, 0.003 mol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.24 g, 0.005 mol), tetrahydrofuran (27.0 mL), and purified water (4.8 mL) was refluxed with stirring for 4 hours. Purified water (15 mL) was added to the reaction mixture, which was concentrated under reduced pressure and then extracted with ethyl acetate (15 mL). The resulting extract was washed with purified water (15 mL) and then concentrated under reduced pressure. Acetone (27 mL) was added to the resulting concentrated residue, followed by the addition of D-tartaric acid (0.94 g, 0.006 mol) and purified water (3 mL). The reaction mixture was heated to 50°C, stirred for 30 minutes, and then cooled to room temperature. The resulting solid was filtered and dried under vacuum to give 4.3 g of the title compound. (Yield: 85.0%) 1 H-NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.59-7.5 (d, 1H), 7.49-7.47 (d, 3H), 7.14-7.12 (d, 2H), 4.70-4.64 (m, 1H), 4.35 (d, 2H), 3.0 (d, 1H), 2.82 (d, 1H), 1.39 (d, 6H), 1.27-1.23 (d, 6H)

[0075] Example 17: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (Compound 3a) A mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (3.0 g, 0.0125 mol), 3-chloro-4-isopropoxyphenylboronic acid (3.1 g, 0.0144 mol), potassium carbonate (3.5 g, 0.025 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.18 g, 0.003 mol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.24 g, 0.005 mol), tetrahydrofuran (27.0 mL), and purified water (3.9 mL) was refluxed with stirring for 4 hours. Purified water (15 mL) was added to the reaction mixture, which was concentrated under reduced pressure and then extracted with ethyl acetate (15 mL). The resulting extract was washed with purified water (15 mL) and then concentrated under reduced pressure. Acetone (27 mL) was added to the resulting concentrated residue, followed by the addition of D-tartaric acid (0.94 g, 0.006 mol) and purified water (3 mL). The reaction mixture was heated to 50°C, stirred for 30 minutes, and then cooled to room temperature. The resulting solid was filtered and dried under vacuum to give 4.3 g of the title compound. (Yield: 85.0%) 1 H-NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.59-7.5 (d, 1H), 7.49-7.47 (d, 3H), 7.14-7.12 (d, 2H), 4.70-4.64 (m, 1H), 4.35 (d, 2H), 3.0 (d, 1H), 2.82 (d, 1H), 1.39 (d, 6H), 1.27-1.23 (d, 6H)

[0076] Example 18: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (Compound 3a) A mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (3.0 g, 0.0125 mol), 3-chloro-4-isopropoxyphenylboronic acid (3.1 g, 0.0144 mol), potassium carbonate (3.5 g, 0.025 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.18 g, 0.003 mol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.24 g, 0.005 mol), tetrahydrofuran (27.0 mL), and purified water (3.0 mL) was refluxed with stirring for 2 hours. Purified water (15 mL) was added to the reaction mixture, which was concentrated under reduced pressure and then extracted with ethyl acetate (15 mL). The resulting extract was washed with purified water (15 mL) and then concentrated under reduced pressure. Acetone (27 mL) was added to the resulting concentrated residue, followed by the addition of D-tartaric acid (0.94 g, 0.006 mol) and purified water (3 mL). The reaction mixture was heated to 50°C, stirred for 30 minutes, and then cooled to room temperature. The resulting solid was filtered and dried under vacuum to give 4.2 g of the title compound. (Yield: 83.0%) 1 H-NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.59-7.5 (d, 1H), 7.49-7.47 (d, 3H), 7.14-7.12 (d, 2H), 4.70-4.64 (m, 1H), 4.35 (d, 2H), 3.0 (d, 1H), 2.82 (d, 1H), 1.39 (d, 6H), 1.27-1.23 (d, 6H)

[0077] Example 19: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (Compound 3a) A mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (3.0 g, 0.0125 mol), 3-chloro-4-isopropoxyphenylboronic acid (3.1 g, 0.0144 mol), potassium carbonate (3.5 g, 0.025 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.18 g, 0.003 mol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.24 g, 0.005 mol), tetrahydrofuran (27.0 mL), and purified water (2.1 mL) was refluxed with stirring for 2 hours. Purified water (15 mL) was added to the reaction mixture, which was concentrated under reduced pressure and then extracted with ethyl acetate (15 mL). The resulting extract was washed with purified water (15 mL) and then concentrated under reduced pressure. Acetone (27 mL) was added to the resulting concentrated residue, followed by the addition of D-tartaric acid (0.94 g, 0.006 mol) and purified water (3 mL). The reaction mixture was heated to 50°C, stirred for 30 minutes, and then cooled to room temperature. The resulting solid was filtered and dried under vacuum to give 4.4 g of the title compound. (Yield: 87.0%) 1 H-NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.59-7.5 (d, 1H), 7.49-7.47 (d, 3H), 7.14-7.12 (d, 2H), 4.70-4.64 (m, 1H), 4.35 (d, 2H), 3.0 (d, 1H), 2.82 (d, 1H), 1.39 (d, 6H), 1.27-1.23 (d, 6H)

[0078] Example 20: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (Compound 3a) A mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (10.0 g, 0.0416 mol), 3-chloro-4-isopropoxyphenylboronic acid (10.3 g, 0.0479 mol), potassium carbonate (11.51 g, 0.0833 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.61 g, 0.0008 mol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.79 g, 0.002 mol), tetrahydrofuran (90.0 mL), and purified water (20 mL) was stirred at 55 °C for 4 h. Purified water (50 mL) was added to the reaction mixture, which was then concentrated under reduced pressure and extracted with ethyl acetate (50 mL). The resulting extract was washed with purified water (50 mL) and then concentrated under reduced pressure. Acetone (90 mL) was added to the resulting concentrated residue, followed by the addition of D-tartaric acid (3.13 g, 0.021 mol) and purified water (10 mL). The reaction mixture was heated to 50°C, stirred for 30 minutes, and then cooled to room temperature. The resulting solid was filtered and dried under vacuum to obtain 13.95 g of the title compound. (Yield: 82.7%) 1 H-NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.59-7.5 (d, 1H), 7.49-7.47 (d, 3H), 7.14-7.12 (d, 2H), 4.70-4.64 (m, 1H), 4.35 (d, 2H), 3.0 (d, 1H), 2.82 (d, 1H), 1.39 (d, 6H), 1.27-1.23 (d, 6H)

[0079] Example 21: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (Compound 3a) A mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (3.0 g, 0.0125 mol), 3-chloro-4-isopropoxyphenylboronic acid (3.1 g, 0.0144 mol), potassium carbonate (3.5 g, 0.025 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.18 g, 0.003 mol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.24 g, 0.005 mol), acetone (27.0 mL), and purified water (3 mL) was refluxed with stirring for 7 h. Purified water (15 mL) was added to the reaction mixture, which was concentrated under reduced pressure and then extracted with ethyl acetate (15 mL). The resulting extract was washed with purified water (15 mL) and then concentrated under reduced pressure. Acetone (27 mL) was added to the resulting concentrated residue, followed by the addition of D-tartaric acid (0.94 g, 0.006 mol) and purified water (3 mL). The reaction mixture was heated to 50°C, stirred for 30 minutes, and then cooled to room temperature. The resulting solid was filtered and dried under vacuum to obtain 4.1 g of the title compound. (Yield: 81.1%) 1 H-NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.59-7.5 (d, 1H), 7.49-7.47 (d, 3H), 7.14-7.12 (d, 2H), 4.70-4.64 (m, 1H), 4.35 (d, 2H), 3.0 (d, 1H), 2.82 (d, 1H), 1.39 (d, 6H), 1.27-1.23 (d, 6H)

[0080] Example 22: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (Compound 3a) A mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (5.0 g, 0.0208 mol), 3-chloro-4-isopropoxyphenylboronic acid (5.13 g, 0.0239 mol), potassium carbonate (5.76 g, 0.0416 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.29 g, 0.0004 mol), acetone (27.0 mL), and purified water (6 mL) was refluxed with stirring for 24 hours. Purified water (25 mL) was added to the reaction mixture, which was then concentrated under reduced pressure and extracted with ethyl acetate (25 mL). The resulting extract was washed with purified water (25 mL) and then concentrated under reduced pressure. Acetone (45 mL) was added to the resulting concentrated residue, followed by D-tartaric acid (1.56 g, 0.0104 mol) and purified water (3 mL). The reaction mixture was heated to 50°C, stirred for 30 minutes, and then cooled to room temperature. The resulting solid was filtered and dried in vacuo to give 7.0 g of the title compound. (Yield: 83.0%) 1 H-NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.59-7.5 (d, 1H), 7.49-7.47 (d, 3H), 7.14-7.12 (d, 2H), 4.70-4.64 (m, 1H), 4.35 (d, 2H), 3.0 (d, 1H), 2.82 (d, 1H), 1.39 (d, 6H), 1.27-1.23 (d, 6H)

[0081] Example 23: 5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (Compound 2) To a mixture of 5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (7.3 g, 0.018 mol), dichloromethane (73 mL), and purified water (51 mL), 50% sodium hydroxide (1.7 g, 0.022 mol) was added with stirring. The reaction mixture was stirred at room temperature for approximately 30 minutes, and then the layers were separated. The organic layer was washed with purified water (37 mL) and then concentrated under reduced pressure to give 6.0 g of the title compound. (Yield: 100.0%) 1 H NMR (400 MHz, CDCl3) 7.60 (s, 1H), 7.41-7.33 (m, 4H), 7.00 (d, 1H), 4.59 (m, 1H), 3.94 (s, 1H), 2.74 (s, 2H), 1.41 (d, 6H), 1.24 (s, 3H), 0.91 (s, 3H)

[0082] Example 24: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (Compound 2a) To a mixture of (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (2S,3S)-2,3-dihydroxysuccinate (20.0 g, 0.049 mol), dichloromethane (200 mL), and purified water (140 mL), 50% sodium hydroxide (4.8 g, 0.059 mol) was added with stirring. The reaction mixture was stirred at room temperature for approximately 30 minutes, and then the layers were separated. The organic layer was washed with purified water (75 mL) and then concentrated under reduced pressure to give 16.3 g of the title compound. (Yield: 100.0%) 1 H NMR (400 MHz, CDCl3) 7.60 (s, 1H), 7.41-7.33 (m, 4H), 7.00 (d, 1H), 4.59 (m, 1H), 3.94 (s, 1H), 2.74 (s, 2H), 1.41 (d, 6H), 1.24 (s, 3H), 0.91 (s, 3H)

[0083] Example 25: (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound 1a) A mixture of (S)-3-quinuclidinol (50.9 g, 0.400 mol), tetrahydrofuran (1320 mL), and bis(4-nitrophenyl) carbonate (126.8 g, 0.417 mol) was stirred at 40-45 °C for 21 hours. To the reaction mixture, (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (110.0 g, 0.335 mol) and tetrahydrofuran (330 mL) were added. The reaction mixture was refluxed with stirring for approximately 15 hours and then cooled to room temperature. Purified water (880 mL) was added to the reaction mixture, and the reaction mixture was cooled to 15 °C. 50% sodium hydroxide (66.7 g, 0.834 mol) was added to the reaction mixture, which was then concentrated under reduced pressure. To the resulting residue, purified water (1320 mL) and isopropyl acetate (1650 mL) were added. The separated organic layer was washed with 2N sodium hydroxide solution (1100 mL) and purified water (550 mL), and concentrated under reduced pressure to give 148.5 g of the title compound. (Yield: 92.2%) 1 H-NMR (400MHz, CDCl3) δ 7.59(s, 1H), 7.41(m, 2H), 7.34(s, 1H), 7.29(m, 1H), 7.00(d, 1H), 4.98(d, 1H), 4.84-4.67(m, 2H), 4.58(m, 1H), 3.30(m, 1H) , 2.90-2.73(m, 7H), 2.09(m, 1H), 1.85(m, 1H), 1.70(m, 1H), 1.60(m, 1H), 1.42(m, 1H), 1.41(d, 6H), 1.30(s, 3H), 0.98(s, 3H)

[0084] Example 26: (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound 1a) A mixture of (S)-3-quinuclidinol (1.39 g, 10.91 mmol), acetonitrile (36 mL), and bis(4-nitrophenyl)carbonate (3.32 g, 10.91 mmol) was stirred at 40 °C for 6 hours. To the reaction mixture, (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (3.0 g, 9.09 mmol) and acetonitrile (9 mL) were added. The reaction mixture was stirred at 70 °C for approximately 15 hours and then cooled to room temperature. Purified water (24 mL) and 50% sodium hydroxide were added to the reaction mixture, which was then stirred at room temperature for approximately 1 hour. Purified water (12 mL) was added to the reaction mixture, which was then concentrated under reduced pressure. Ethyl acetate (51 mL) was added to the resulting residue. The separated organic layer was washed with 5% aqueous sodium bicarbonate, dried over magnesium sulfate, and then concentrated under reduced pressure to give 3.8 g of the title compound (yield: 86.5%). 1 H-NMR (400MHz, CDCl3) δ 7.59(s, 1H), 7.41(m, 2H), 7.34(s, 1H), 7.29(m, 1H), 7.00(d, 1H), 4.98(d, 1H), 4.84-4.67(m, 2H), 4.58(m, 1H), 3.30(m, 1H) , 2.90-2.73(m, 7H), 2.09(m, 1H), 1.85(m, 1H), 1.70(m, 1H), 1.60(m, 1H), 1.42(m, 1H), 1.41(d, 6H), 1.30(s, 3H), 0.98(s, 3H)

[0085] Example 27: (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound 1a) A mixture of (S)-3-quinuclidinol (4.6 g, 0.036 mol), acetonitrile (120 mL), diisopropylethylamine (7.8 g, 0.06 mol), and bis(4-nitrophenyl)carbonate (11.5 g, 0.038 mol) was stirred at 40 °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 acetonitrile (30 mL) were added. The reaction mixture was refluxed with stirring for approximately 15 hours and then cooled to room temperature. Purified water (80 mL) was added to the reaction mixture, which was then concentrated under reduced pressure. 50% sodium hydroxide (6.1 g, 0.076 mol) was added to the reaction mixture, which was stirred at room temperature for approximately 1 hour and then concentrated under reduced pressure. To the resulting residue, purified water (120 mL) and isopropyl acetate (150 mL) were added. The separated organic layer was washed with 2N sodium hydroxide solution (100 mL) and then purified water (50 mL), and then concentrated under reduced pressure to give 13.0 g of the title compound. (Yield: 88.8%) 1 H-NMR (400MHz, CDCl3) δ 7.59(s, 1H), 7.41(m, 2H), 7.34(s, 1H), 7.29(m, 1H), 7.00(d, 1H), 4.98(d, 1H), 4.84-4.67(m, 2H), 4.58(m, 1H), 3.30(m, 1H) , 2.90-2.73(m, 7H), 2.09(m, 1H), 1.85(m, 1H), 1.70(m, 1H), 1.60(m, 1H), 1.42(m, 1H), 1.41(d, 6H), 1.30(s, 3H), 0.98(s, 3H)

[0086] Example 28: (S)-quinuclidin-3-yl (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 ((1S)-(+)-10-camphorsulfonate of Compound 1) A mixture of (S)-3-quinuclidinol (2.8 g, 0.022 mol), tetrahydrofuran (72 mL), and bis(4-nitrophenyl)carbonate (6.9 g, 0.023 mol) was stirred at 40-45°C for 2 hours. 5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (6.0 g, 0.018 mol) and tetrahydrofuran (18 mL) were added to the reaction mixture. The reaction mixture was refluxed with stirring for approximately 15 hours and then cooled to room temperature. Purified water (48 mL) was added to the reaction mixture. 50% sodium hydroxide (3.6 g, 0.045 mol) was added to the reaction mixture, which was then concentrated under reduced pressure. Purified water (72 mL) and isopropyl acetate (105 mL) were added to the resulting residue. The separated organic layer was washed successively with 2N sodium hydroxide solution (60 mL) and purified water (30 mL), and then concentrated under reduced pressure. The resulting residue was dissolved in methyl ethyl ketone (78 mL). The resulting solution was heated to 50°C, and (1S)-(+)-10-camphorsulfonic acid (4.2 g, 0.018 mol) was added. 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 (18 mL). The resulting solid was dried in vacuo to give 4.0 g of the title compound. (Yield: 30.7%, Purity: 93.6%) 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)

[0087] Example 29: (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 ((1S)-(+)-10-camphorsulfonate of Compound 1a) (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (148.5 g, 0.307 mol) was dissolved in methyl ethyl ketone (1430 mL). The reaction mixture was heated to 50°C, and (1S)-(+)-10-camphorsulfonic acid (77.5 g, 0.334 mol) dissolved in purified water (33 mL) was added. The reaction mixture was cooled to approximately 25°C and stirred for approximately 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with methyl ethyl ketone (330 mL). The resulting solid was dried under vacuum to give 178.0 g of the title compound. (Yield: 80.9%, Purity: 99.5%) 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)

[0088] Comparative Example: (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound 1a) A mixture of (S)-quinuclidin-3-yl((R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (20.0 g, 0.050 mol), cesium carbonate (33.1 g, 0.102 mol), 3-chloro-4-isopropoxyphenylboronic acid (12.0 g, 0.0056 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.86 g, 0.0025 mol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (2.42 g, 0.0051 mol), tetrahydrofuran (180 mL), and purified water (20 mL) was stirred at 60 °C for 5 hours. The reaction mixture was concentrated under reduced pressure, and purified water (100 mL) and ethyl acetate (200 mL) were added. Purified water (100 mL) was added to the separated organic layer, and the pH was adjusted to 1-2 with concentrated hydrochloric acid. The separated organic layer was concentrated under reduced pressure to obtain 20.0 g of the title compound. (Yield: 81.4%) 1 H-NMR (400MHz, CDCl3) δ 7.59(s, 1H), 7.41(m, 2H), 7.34(s, 1H), 7.29(m, 1H), 7.00(d, 1H), 4.98(d, 1H), 4.84-4.67(m, 2H), 4.58(m, 1H), 3.30(m, 1H) , 2.90-2.73(m, 7H), 2.09(m, 1H), 1.85(m, 1H), 1.70(m, 1H), 1.60(m, 1H), 1.42(m, 1H), 1.41(d, 6H), 1.30(s, 3H), 0.98(s, 3H)

[0089] Test example: Measurement of residual palladium The residual amount of palladium in the products produced in the Comparative Example, Example 25, and Example 29 was measured. Specifically, an ORS (Octopole Reaction System) was used to reduce interference caused by collisions of injected helium gas with ionized atoms. The Agilent 7800 ICP-MS model was used. A calibration curve was created using a multi-element stock solution (Agilent), and samples pretreated with dilute hydrochloric acid solution were quantitatively analyzed to measure the residual amount of palladium. The results are shown in Table 1 below. [Table 1]

[0090] As can be seen from the results in Table 1, when compound 1 is produced according to the present invention, the amount of residual palladium in the product can be significantly reduced.

Claims

1. A method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof, said method comprising: (a) reacting a compound of formula 4 with 3-chloro-4-isopropoxyphenylboronic acid, followed by reaction with D-tartaric acid to produce a compound of formula 3; (b) reacting a compound of formula 3 with a base to produce a compound of formula 2; and (c) reacting the compound of formula 2 with (S)-4-nitrophenyl quinuclidin-3-yl carbonate to produce the compound of formula 1. A manufacturing method comprising: <Formula 1> <Formula 2> <Formula 3> <Formula 4>

2. A method for preparing a compound of formula 1a or a pharmaceutically acceptable salt thereof, said method comprising: (a') reacting the compound of formula 4a with 3-chloro-4-isopropoxyphenylboronic acid, followed by reaction with D-tartaric acid to produce the compound of formula 3a; (b') reacting the compound of formula 3a with a base to produce a compound of formula 2a; and (c') reacting the compound of formula 2a with (S)-4-nitrophenyl quinuclidin-3-yl carbonate to produce the compound of formula 1a. A manufacturing method comprising: <Formula 1a> <Formula 2a> <Formula 3a> <Formula 4a>

3. 3. The process according to claim 2, wherein the compound of formula 4a is obtained by a process comprising the steps of: (i) reacting a compound of formula 4 with N-acetyl-D-leucine in a water-miscible organic solvent or a mixture of water and a water-miscible organic solvent to obtain a compound of formula 5; and <Formula 4> <Formula 5> (ii) reacting a compound of formula 5 with a base to give a compound of formula 4a.

4. The water-miscible organic solvent is acetone, acetonitrile, C １ ~C ５ The method according to claim 3, wherein the solvent is at least one selected from the group consisting of alcohol, tetrahydrofuran, methyl ethyl ketone, isopropyl acetate, ethyl acetate, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran, and dichloromethane.

5. 4. The method according to claim 3, wherein the base is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, calcium hydroxide, sodium bicarbonate, and potassium phosphate.

6. 3. The process according to claim 2, wherein the compound of formula 4a is obtained by a process comprising the steps of: (p) reacting the compound of formula 9 with iodomethane to produce the compound of formula 8; <Formula 8> <Formula 9> (q) reacting the compound of formula 8 with (S)-(-)-methyl-2-propanesulfinamide to produce the compound of formula 7; <Formula 7> (r) reducing the compound of formula 7 to produce a mixture of compounds of formula 6a and formula 6b; <Formula 6a> <Formula 6b> (s) reacting the mixture of the compound of formula 6a and the compound of formula 6b with an acid to produce a mixture of the compound of formula 4a and the compound of formula 4b, reacting the mixture of the compound of formula 4a and the compound of formula 4b with N-acetyl-D-leucine in a water-miscible organic solvent or a mixed solvent of water and a water-miscible organic solvent, and then isolating the compound of formula 5; and <Formula 4a> <Formula 4b> <Formula 5> (t) reacting the compound of formula 5 with a base to obtain the compound of formula 4a. <Formula 4a>

7. The reaction in step (p) is carried out by adding cesium carbonate (Cs ２ CO ３ ), sodium carbonate (Na ２ CO ３ ), potassium carbonate (K ２ CO ３ ), potassium phosphate (K ３ P.O. ４ 7. The process of claim 6, wherein the process is carried out in the presence of a base selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, and diisopropylethylamine.

8. 7. The process of claim 6, wherein the reaction of step (q) is carried out in the presence of a titanium catalyst selected from the group consisting of titanium ethoxide and titanium isopropoxide.

9. 7. The process of claim 6, wherein step (r) is carried out using one or more reducing agents selected from the group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride.

10. 7. The process of claim 6, wherein the acid in step (s) is selected from the group consisting of hydrochloric acid, sulfuric acid, and nitric acid.

11. The water-miscible organic solvent in step (s) is acetone, acetonitrile, C １ ~C ５ 7. The method according to claim 6, wherein the solvent is at least one selected from the group consisting of alcohol, tetrahydrofuran, methyl ethyl ketone, isopropyl acetate, ethyl acetate, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran, and dichloromethane.

12. 7. The method according to claim 6, wherein the base in step (t) is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, calcium hydroxide, sodium bicarbonate, and potassium phosphate.

13. 3. The process according to claim 1, wherein the reaction of the compound of formula 4 or the compound of formula 4a with 3-chloro-4-isopropoxyphenylboronic acid is carried out in the presence of a metal catalyst and a base.

14. The method according to claim 13, wherein the metal catalyst is at least one selected from the group consisting of palladium, copper, iron, cadmium, zinc, and nickel.

15. The base is cesium carbonate (Cs ２ CO ３ ), sodium carbonate (Na ２ CO ３ ), potassium carbonate (K ２ CO ３ ), potassium phosphate (K ３ P.O. ４ ), triethylamine, diisopropylamine, potassium hydroxide, potassium acetate, potassium t-butoxide, sodium hydroxide, sodium hydride, sodium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, and diisopropylethylamine.

16. The process according to claim 13, wherein the reaction is carried out in the presence of one or more ligands selected from the group consisting of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, and 1,1'-bis(diphenylphosphino)ferrocene.

17. The reaction is water, C １ ~C １０ The process according to claim 13, wherein the process is carried out in the presence of one or more solvents selected from the group consisting of alcohol, dichloromethane, tetrahydrofuran, acetone, acetonitrile, isopropyl acetate, dimethylformamide, dimethylacetamide, toluene, 2-methyltetrahydrofuran, ethyl acetate, and 1,4-dioxane.

18. 3. The production method according to claim 1 or 2, wherein the base used in step (b) or step (b') is one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, and sodium phosphate.

19. The method according to claim 1 or 2, wherein (S)-4-nitrophenyl quinuclidin-3-yl carbonate is obtained by reacting (S)-(+)-3-quinuclidinol with bis(4-nitrophenyl)carbonate.

20. The method according to claim 19, wherein the reaction of (S)-(+)-3-quinuclidinol with bis(4-nitrophenyl)carbonate and the reaction of the compound of formula 2 or the compound of formula 2a with (S)-4-nitrophenyl quinuclidin-3-yl carbonate are carried out in a one-pot reaction.

21. The process according to claim 1 or 2, wherein the reaction of the compound of formula 2 or the compound of formula 2a with (S)-4-nitrophenyl quinuclidin-3-yl carbonate is carried out in the absence of a base.

22. The method according to claim 1 or 2, wherein the reaction of the compound of formula 2 or the compound of formula 2a with (S)-4-nitrophenyl quinuclidin-3-yl carbonate is carried out in the presence of one or more bases selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, sodium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, triethylamine, diisopropylamine, and diisopropylethylamine.

23. The method according to claim 1 or 2, wherein the reaction of the compound of formula 2 or the compound of formula 2a with (S)-4-nitrophenyl quinuclidin-3-yl carbonate is carried out in one or more solvents selected from the group consisting of dimethylacetamide, dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile, isopropyl acetate, 2-methyltetrahydrofuran, and ethyl acetate.

24. A method for preparing a compound of formula 4a, comprising the steps of: (i) reacting a compound of formula 4 with N-acetyl-D-leucine in a water-miscible organic solvent or a mixture of water and a water-miscible organic solvent to obtain a compound of formula 5; and <Formula 4> <Formula 5> (ii) reacting a compound of formula 5 with a base to give a compound of formula 4a. <Formula 4a>

25. The water-miscible organic solvent is acetone, acetonitrile, C １ ~C ５ The method according to claim 24, wherein the solvent is at least one selected from the group consisting of alcohol, tetrahydrofuran, methyl ethyl ketone, isopropyl acetate, ethyl acetate, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran, and dichloromethane.

26. 25. The method according to claim 24, wherein the base is one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, calcium hydroxide, sodium bicarbonate, and potassium phosphate.

27. A method for preparing a compound of formula 4a, comprising the steps of: (p) reacting the compound of formula 9 with iodomethane to produce the compound of formula 8; <Formula 8> <Formula 9> (q) reacting the compound of formula 8 with (S)-(-)-methyl-2-propanesulfinamide to produce the compound of formula 7; <Formula 7> (r) reducing the compound of formula 7 to produce a mixture of compounds of formula 6a and formula 6b; <Formula 6a> <Formula 6b> (s) reacting the mixture of the compound of formula 6a and the compound of formula 6b with an acid to produce a mixture of the compound of formula 4a and the compound of formula 4b, reacting the mixture of the compound of formula 4a and the compound of formula 4b with N-acetyl-D-leucine in a water-miscible organic solvent or a mixed solvent of water and a water-miscible organic solvent, and then isolating the compound of formula 5; and <Formula 4a> <Formula 4b> <Formula 5> (t) reacting the compound of formula 5 with a base to obtain the compound of formula 4a. <Formula 4a>

28. The reaction in step (p) is carried out by adding cesium carbonate (Cs ２ CO ３ ), sodium carbonate (Na ２ CO ３ ), potassium carbonate (K ２ CO ３ ), potassium phosphate (K ３ P.O. ４ 28. The process of claim 27, wherein the process is carried out in the presence of a base selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, and diisopropylethylamine.

29. 28. The process of claim 27, wherein the reaction of step (q) is carried out in the presence of a titanium catalyst selected from the group consisting of titanium ethoxide and titanium isopropoxide.

30. 28. The process of claim 27, wherein step (r) is carried out using one or more reducing agents selected from the group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride.

31. 28. The process of claim 27, wherein the acid in step (s) is selected from the group consisting of hydrochloric acid, sulfuric acid, and nitric acid.

32. The water-miscible organic solvent in step (s) is acetone, acetonitrile, C １ ~C ５ The method according to claim 27, wherein the solvent is at least one selected from the group consisting of alcohol, tetrahydrofuran, methyl ethyl ketone, isopropyl acetate, ethyl acetate, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran, and dichloromethane.

33. 28. The method according to claim 27, wherein the base in step (t) is one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, calcium hydroxide, sodium bicarbonate, and potassium phosphate.

34. A compound of formula 2. <Formula 2>

35. A compound of formula 2a. <Formula 2a>

36. A compound of formula 3. <Formula 3>

37. A compound of formula 3a. <Formula 3a>

38. A compound of formula 5. <Formula 5>

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