Improved process for the preparation of dimethyl-2, 3-dihydro-1h-indenders

Abstract

The present invention provides an improved process for the preparation of a dimethyl-2, 3-dihydro-1H-indene derivative, or a pharmaceutically acceptable salt thereof. The present invention also provides novel intermediates used in the process. When a compound of Formula 1 or a stereoisomer thereof is prepared by a novel intermediate according to the present invention, the content of a heavy metal (Pd) remaining in a final product, namely the compound of Formula 1 or a stereoisomer thereof, can be minimized. In addition, the method of the present invention makes it possible to prepare a stereoisomer of the compound of Formula 1 or a pharmaceutically acceptable salt thereof 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. In addition, the present invention relates to novel intermediates useful in the process. Background Art

[0002] It is known that a dimethyl-2,3-dihydro-1H-indene derivative or a pharmaceutically acceptable salt thereof (including a compound of the following formula 1) 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 with 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).

[0009] However, the Suzuki coupling reaction performed in the last step causes a high risk that heavy metals such as palladium, a ligand used to perform the Suzuki coupling reaction, and by-products generated thereby remain in the product (eg, the compound of Formula 1 in the form of a free base). Summary of the invention

[0010] Technical issues

[0011] The present inventors have conducted various studies to develop an improved method for preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The present inventors have found that when a compound of Formula 1 or a stereoisomer thereof is prepared through a novel intermediate, the content of heavy metals (Pd) and by-products remaining in the final product (i.e., the compound of Formula 1 and its stereoisomer) can be minimized.

[0012] In addition, the present inventors have developed a method capable of 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. And the present inventors have found that when the compound of Formula 1 is prepared by using the obtained (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine and the intermediate, the stereoisomers of the compound of Formula 1 can be prepared with high optical purity.

[0013] Thus, the present invention provides an improved process for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, comprising the use of a novel intermediate.

[0014] Furthermore, the present invention provides novel intermediates.

[0015] Furthermore, the present invention provides a method for preparing (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine with high optical purity.

[0016] Technical Solution

[0017] 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, the method comprising:

[0018] (a) reacting a compound of formula 4 with 3-chloro-4-isopropoxyphenylboronic acid and then with D-tartaric acid to prepare a compound of formula 3;

[0019] (b) reacting the compound of formula 3 with a base to prepare a compound of formula 2; and

[0020] (c) reacting the compound of formula 2 with (S)-4-nitrophenylquinuclidine-3-yl carbonate to prepare a compound of formula 1,

[0021] <Formula 1>

[0022]

[0023] <Formula 2>

[0024]

[0025] <Formula 3>

[0026]

[0027] <Formula 4>

[0028] .

[0029] 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, the method comprising:

[0030] (a') reacting a compound of formula 4a with 3-chloro-4-isopropoxyphenylboronic acid and then with D-tartaric acid to prepare a compound of formula 3a;

[0031] (b') reacting the compound of formula 3a with a base to prepare a compound of formula 2a; and

[0032] (c') reacting the compound of formula 2a with (S)-4-nitrophenylquinuclidine-3-yl carbonate to prepare a compound of formula 1a,

[0033] <Formula 1a>

[0034]

[0035] <Formula 2a>

[0036]

[0037] <Formula 3a>

[0038]

[0039] <Formula 4a>

[0040] .

[0041] According to another aspect of the present invention, there is provided a method for preparing a compound of formula 4a, the method comprising:

[0042] (i) reacting the compound of formula 4 with N-acetyl-D-leucine in a water-miscible organic solvent or a mixed solvent of water and a water-miscible organic solvent to obtain a compound of formula 5; and

[0043] <Formula 4>

[0044]

[0045] <Formula 5>

[0046]

[0047] (ii) reacting the compound of formula 5 with a base to obtain a compound of formula 4a,

[0048] <Formula 4a>

[0049] .

[0050] According to another aspect of the present invention, there is provided a method for preparing a compound of formula 4a, the method comprising:

[0051] (p) reacting the compound of formula 9 with methyl iodide to prepare the compound of formula 8;

[0052] <Formula 8>

[0053]

[0054] <Formula 9>

[0055]

[0056] (q) reacting a compound of Formula 8 with (S)-(-)-methyl-2-propanesulfenamide to prepare a compound of Formula 7;

[0057] <Formula 7>

[0058]

[0059] (r) reducing the compound of Formula 7 to prepare a mixture of the compound of Formula 6a and the compound of Formula 6b;

[0060] <Formula 6a>

[0061]

[0062] <Formula 6b>

[0063]

[0064] (s) reacting a mixture of the compound of Formula 6a and the compound of Formula 6b with an acid to prepare 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

[0065] <Formula 4a>

[0066]

[0067] <Formula 4b>

[0068]

[0069] <Formula 5>

[0070]

[0071] (t) reacting the compound of formula 5 with a base to obtain a compound of formula 4a,

[0072] <Formula 4a>

[0073] .

[0074] According to another aspect of the present invention, there is provided an intermediate useful for preparing a compound of formula 1, namely a compound of formula 2:

[0075] <Formula 2>

[0076] .

[0077] According to another aspect of the present invention, there is provided an intermediate useful for preparing a compound of formula 1a, namely a compound of formula 2a:

[0078] <Formula 2a>

[0079] .

[0080] According to another aspect of the present invention, there is provided an intermediate useful for preparing a compound of formula 1, namely a compound of formula 3:

[0081] <Formula 3>

[0082] .

[0083] According to another aspect of the present invention, there is provided an intermediate useful for preparing a compound of formula 1a, namely a compound of formula 3a:

[0084] <Formula 3a>

[0085] .

[0086] According to another aspect of the present invention, there is provided an intermediate useful for preparing a compound of formula 1a, namely a compound of formula 5:

[0087] <Formula 5>

[0088] .

[0089] Beneficial Effects

[0090] When the compound of Formula 1 or its stereoisomer is prepared by the novel intermediate according to the present invention, the content of heavy metal (Pd) remaining in the final product (i.e., the compound of Formula 1 or its stereoisomer) can be minimized. In addition, when the compound of Formula 1 is prepared by converting 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; and then preparing the compound of Formula 1a by the above-mentioned novel intermediate according to the present invention, the stereoisomer of the compound of Formula 1 or its pharmaceutically acceptable salt can be prepared with high optical purity. DETAILED DESCRIPTION

[0091] The present invention provides an improved method for preparing (S)-quinuclidine-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl) carbamate, that is, a compound of formula 1 or a pharmaceutically acceptable salt thereof, that is, the present invention provides a method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, the method comprising:

[0092] (a) reacting a compound of formula 4 with 3-chloro-4-isopropoxyphenylboronic acid and then with D-tartaric acid to prepare a compound of formula 3;

[0093] (b) reacting the compound of formula 3 with a base to prepare a compound of formula 2; and

[0094] (c) reacting the compound of formula 2 with (S)-4-nitrophenylquinuclidine-3-yl carbonate to prepare the compound of formula 1,

[0095] <Formula 1>

[0096]

[0097] <Formula 2>

[0098]

[0099] <Formula 3>

[0100]

[0101] <Formula 4>

[0102] .

[0103] The present invention also provides an improved method for preparing a stereoisomer of a compound of formula 1 (i.e., (S)-quinuclidine-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 method for preparing a compound of formula 1a or a pharmaceutically acceptable salt thereof, the method comprising:

[0104] (a') reacting a compound of formula 4a with 3-chloro-4-isopropoxyphenylboronic acid and then with D-tartaric acid to prepare a compound of formula 3a;

[0105] (b') reacting the compound of formula 3a with a base to prepare a compound of formula 2a; and

[0106] (c') reacting the compound of formula 2a with (S)-4-nitrophenylquinuclidine-3-yl carbonate to prepare a compound of formula 1a,

[0107] <Formula 1a>

[0108]

[0109] <Formula 2a>

[0110]

[0111] <Formula 3a>

[0112]

[0113] <Formula 4a>

[0114] .

[0115] In the method of the present invention, the compound of formula 4 (ie, 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine) is a known compound and thus can be commercially purchased or synthesized according to literature.

[0116] According to the present invention, it was found that when the compound of Formula 4 is resolved by using a specific optical resolving agent (ie, N-acetyl-D-leucine), (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine can be prepared with high optical purity.

[0117] In one embodiment, the compound of formula 4a can be prepared by a method comprising the following steps:

[0118] (i) reacting the compound of formula 4 with N-acetyl-D-leucine in a water-miscible organic solvent or a mixed solvent of water and a water-miscible organic solvent to obtain a compound of formula 5; and

[0119] <Formula 4>

[0120]

[0121] <Formula 5>

[0122]

[0123] (ii) reacting the compound of formula 5 with a base to obtain the compound of formula 4a.

[0124] In step (i), a resolving agent, i.e., N-acetyl-D-leucine, can be used in a ratio of 0.3 to 10 equivalents based on 1 equivalent of the compound of formula 4, but is not limited thereto. The water-miscible organic solvent can be one or more selected from the group consisting of acetone, acetonitrile, C1-C5 alcohol, tetrahydrofuran, methyl ethyl ketone, isopropyl acetate, ethyl acetate, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran and dichloromethane, preferably acetone and acetonitrile. The volume ratio of the water-miscible organic solvent and water in the mixed solvent can be in the range of 3:1 to 20:1, for example, about 9:1. The reaction of step (i) can be carried out at a temperature of 0°C to 70°C (e.g., about 35°C) for 1 hour to 24 hours. The solid produced in step (i), i.e., (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine acetyl-D-leucine of formula 5, can be separated according to conventional methods such as filtration and drying (e.g., vacuum drying).

[0125] In step (ii), the base can 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 can be used. The base can be used in a ratio of 1 to 3 equivalents based on 1 equivalent of the compound of formula 5, but is not limited thereto. The reaction of step (ii) can 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 and dichloromethane, etc.). The volume ratio of the organic solvent to water in the mixed solvent can be in the range of 1:1 to 10:1, but is not limited thereto. The product, i.e., (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine, can be separated according to conventional methods such as washing, drying, and concentration.

[0126] In another embodiment, the compound of formula 4a can be prepared by a method comprising the following steps:

[0127] (p) reacting the compound of formula 9 with methyl iodide to prepare the compound of formula 8;

[0128] <Formula 8>

[0129]

[0130] <Formula 9>

[0131]

[0132] (q) reacting a compound of Formula 8 with (S)-(-)-methyl-2-propanesulfenamide to prepare a compound of Formula 7;

[0133] <Formula 7>

[0134]

[0135] (r) reducing the compound of Formula 7 to prepare a mixture of the compound of Formula 6a and the compound of Formula 6b;

[0136] <Formula 6a>

[0137]

[0138] <Formula 6b>

[0139]

[0140] (s) reacting a mixture of the compound of Formula 6a and the compound of Formula 6b with an acid to prepare 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

[0141] <Formula 4a>

[0142]

[0143] <Formula 4b>

[0144]

[0145] <Formula 5>

[0146]

[0147] (t) reacting the compound of formula 5 with a base to obtain a compound of formula 4a,

[0148] <Formula 4a>

[0149] .

[0150] In step (p), iodomethane can be used in a ratio of 2.0 to 3.0 equivalents based on 1 equivalent of formula 9 compound (5-bromo-2,3-dihydro-1H-inden-1-one), but is not limited thereto. The reaction of step (p) can 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 can be one or more selected from the group consisting of N-methyl-2-pyrrolidone, acetonitrile, tetrahydrofuran and dimethylformamide. The volume ratio of the water-soluble organic solvent and water in the mixed solvent can be in the range of 1:1 to 10:1, for example, about 6:1. Base can be selected from the group consisting of cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), potassium phosphate (K3PO4), triethylamine, diisopropylamine, potassium hydroxide, potassium acetate, potassium tert-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. Base can be used in a ratio of 2.0 to 3.0 equivalents based on 1 equivalent of formula 9 compound, but is not limited thereto. The reaction of step (p) can be carried out at a temperature of 0°C to 40°C for 1 to 20 hours. The product of step (p), 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one of formula 8, can be isolated by conventional methods such as extraction, filtration, concentration, and the like.

[0151] In step (q), (S)-(-)-methyl-2-propanesulfenamide can be used in a ratio of 1.0 to 2.0 equivalents based on 1 equivalent of the compound of formula 8, but it is not limited thereto. The reaction of step (q) can be preferably carried out in the presence of a titanium catalyst such as titanium ethoxide, titanium isopropoxide, etc. The titanium catalyst can be used in a ratio of 2.0 to 3.0 equivalents based on 1 equivalent of the compound of formula 8, but it is not limited thereto. The reaction of step (q) can be carried out in the presence of a solvent or in the absence of a solvent. When the reaction is carried out in the presence of a solvent, the solvent can be selected from toluene, C1~C 10One or more of the group consisting of alcohol, dichloromethane, tetrahydrofuran, acetonitrile, isopropyl acetate, dimethylformamide, dimethylacetamide, 2-methyltetrahydrofuran, ethyl acetate and 1,4-dioxane. The present invention has found that it is particularly preferred to carry out the reaction of step (q) at high temperature under a nitrogen atmosphere. Therefore, it is preferred to carry out the reaction of step (q) at a temperature of 70°C to 100°C under a nitrogen atmosphere (e.g., when purging nitrogen). 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-sulfenamide of formula 7, can be separated according to conventional methods such as concentration; or the product of step (q) can be used in subsequent reactions without separating the residue obtained by concentration.

[0152] In step (r), reduction can be performed with a reducing agent. The reducing agent can be one or more selected from the group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride. The reducing agent can be used in a ratio of 1.0 to 2.0 equivalents based on 1 equivalent of the compound of formula 7, but is not limited thereto. The reducing agent can be used at a temperature of 0°C to 50°C in, for example, tetrahydrofuran, toluene, C1-C 10 The reaction of step (r) can be carried out in an organic reagent such as alcohol, dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, 2-methyltetrahydrofuran and 1,4-dioxane. 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, can be used in subsequent reactions without separating the residue obtained by conventional methods such as extraction and concentration.

[0153] In step (s), the acid may be an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, etc. The acid may be used in a ratio of 2.0 to 10.0 equivalents based on 1 equivalent of the compound of formula 6. The reaction may be carried out at a temperature of 0°C to 50°C in an aqueous solution such as ethyl acetate, toluene, C1-C 10The reaction between the mixture of the compound of formula 6a and the compound of formula 6b and the acid is carried out in an organic solvent such as alcohol, dichloromethane, tetrahydrofuran, acetonitrile, isopropyl acetate, dimethylformamide, dimethylacetamide, 2-methyltetrahydrofuran, etc. From the reaction between the mixture of the compound of formula 6a and the compound of formula 6b and the acid, a mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine of formula 4a and (S)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine of formula 4b is preferably obtained in a weight ratio of 7:3 to 6:4. The obtained mixture can be separated according to conventional methods such as neutralization, extraction, and concentration; or the obtained mixture can be used in subsequent reactions without separating the residue obtained by concentration. The reaction between the mixture of the compound of formula 4a and the compound of formula 4b and N-acetyl-D-leucine can be carried out in the same manner as in step (i).

[0154] The reaction of step (t) can be carried out in the same manner as in step (ii).

[0155] For example, the method for preparing the stereoisomer of the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be as shown in Reaction Scheme 2 or Reaction Scheme 3 below.

[0156] <Reaction Scheme 2>

[0157]

[0158] <Reaction Scheme 3>

[0159]

[0160] The method of the present invention comprises reacting a compound of Formula 4 or a compound of Formula 4a with 3-chloro-4-isopropoxyphenylboronic acid and then reacting with D-tartaric acid to prepare a compound of Formula 3 or a compound of Formula 3a [step (a) or step (a')].

[0161] The reaction between the compound of formula 4 or the compound of formula 4a and 3-chloro-4-isopropoxyphenylboronic acid can be carried out by Suzuki reaction. That is, the reaction between the compound of formula 4 or the compound of formula 4a and 3-chloro-4-isopropoxyphenylboronic acid can be carried out in the presence of a metal catalyst and a base. In addition to the above-mentioned metal catalyst and base, the reaction between the compound of formula 4 or the compound of formula 4a and 3-chloro-4-isopropoxyphenylboronic acid can also be carried out in the presence of a ligand.

[0162] The metal catalyst can be one or more selected from the group consisting of palladium, copper, iron, cadmium, zinc and nickel; preferably, it can be 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]palladium(II) dichloride (Pd(dppf)Cl2) and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3).

[0163] The base can be selected from the group consisting of cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), potassium phosphate (K3PO4), triethylamine, diisopropylamine, potassium hydroxide, potassium acetate, potassium tert-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.

[0164] 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).

[0165] It can be one or more selected from water, C1~C 10 The reaction between the compound of Formula 4 or the compound of Formula 4a and 3-chloro-4-isopropoxyphenylboronic acid is carried out in the presence of a solvent 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 can be carried out in water and an organic solvent (e.g., C1 to C 10 The reaction can be carried out in a mixed solvent of organic solvent (e.g., ethanol, dichloromethane, tetrahydrofuran, acetone, acetonitrile, toluene, 2-methyltetrahydrofuran, etc.). The volume ratio of organic solvent to water in the mixed solvent can be in the range of 1:1 to 20:1, but is not limited thereto. The reaction can be carried out in the range of 50°C to the reflux temperature of the solvent used. Other reaction conditions (including the content of the palladium catalyst, ligand and base used) can be determined according to known methods for Suzuki reaction.

[0166] The product obtained according to the Suzuki reaction is crystallized in the form of a compound of formula 3 or a 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 can be used in a ratio of 0.4 to 2.0 equivalents based on 1 equivalent of the compound of formula 4 or the compound of formula 4a. The reaction can be carried out at 0°C to 70°C (e.g., about 50°C) in water and an organic reagent (e.g., acetone, C1~C 10 The reaction mixture is stirred for 0 to 3 hours (e.g., about 30 minutes) in a mixed solvent of (e.g., ethanol, dichloromethane, tetrahydrofuran, acetonitrile, isopropyl acetate, toluene, 2-methyltetrahydrofuran, ethyl acetate, etc.) or an organic solvent (e.g., acetone, etc.). The volume ratio of the organic solvent to water in the mixed solvent can be in the range of 5:1 to 30:1, but is not limited thereto. The product, i.e., the compound of Formula 3 or the compound of Formula 3a, can be separated according to conventional methods such as filtration and drying (e.g., vacuum drying).

[0167] The method of the present invention comprises reacting a compound of Formula 3 or a compound of Formula 3a with a base to prepare a compound of Formula 2 or a compound of Formula 2a [step (b) or step (b')].

[0168] The alkali used in step (b) or step (b') can 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 alkali can be used in a ratio of 1 to 5 equivalents based on 1 equivalent of the compound of formula 3 or the compound of formula 3a, but is not limited thereto. The reaction between the compound of formula 3 or the compound of formula 3a and the alkali can be carried out in a mixed solvent of water and an organic solvent (such as isopropyl acetate, ethyl acetate, dichloromethane, toluene, 2-methyltetrahydrofuran, etc.). The volume ratio of the organic solvent to water in the mixed solvent can 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, can be separated according to conventional methods such as washing, concentration (such as reduced pressure concentration).

[0169] The method of the present invention comprises reacting a compound of Formula 2 or a compound of Formula 2a with (S)-4-nitrophenylquinuclidin-3-yl carbonate to prepare a compound of Formula 1 or a compound of Formula 1a [step (c) or step (c')].

[0170] (S) -4- nitrophenyl quinuclidine -3- base carbonate can be prepared according to known methods (such as WO2021 / 096238). For example, (S) -4- nitrophenyl quinuclidine -3- base carbonate can be obtained by reacting (S) -(+) -3- quinuclidine alcohol with bis (4- nitrophenyl) carbonate in the presence of a base or in the absence of a base. When reacting in the presence of a base, the base can be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, sodium phosphate, 1,8- diazabicyclo [5.4.0] 11 carbon -7- ene, 1,4- diazabicyclo [2.2.2] octane, 1,5- diazabicyclo [4.3.0] non-5-ene, pyridine, triethylamine, diisopropylamine and diisopropylethylamine. One or more bases in the group consisting of. The base may be used in a ratio of 1 to 3 equivalents based on 1 equivalent of (S)-(+)-3-quinuclidinol, but is not limited thereto.

[0171] Through the present invention, it is found that the reaction between (S)-(+)-3-quinuclidine alcohol and bis(4-nitrophenyl) carbonate can be carried out in a one-pot reaction; and the reaction between the compound of formula 2 or the compound of formula 2a and (S)-4-nitrophenylquinuclidine-3-yl carbonate. Therefore, the reaction between (S)-(+)-3-quinuclidine alcohol and bis(4-nitrophenyl) carbonate; and the reaction between the compound of formula 2 or the compound of formula 2a and (S)-4-nitrophenylquinuclidine-3-yl carbonate can be carried out in a one-pot reaction.

[0172] The reaction between the compound of formula 2 or the compound of formula 2a and (S)-4-nitrophenylquinuclidine-3-yl carbonate can be carried out in the presence of a base or in the absence of a base. When reacting in the presence of a base, the base can be selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, sodium phosphate, 1,8-diazabicyclo [5.4.0] undecyl-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 can be used in a ratio of 1 to 3 equivalents based on 1 equivalent of the compound of formula 2 or the compound of formula 2a, but is not limited thereto. The reaction between the compound of formula 2 or the compound of formula 2a and (S)-4-nitrophenylquinuclidine-3-yl carbonate can 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 obtained compound of formula 1 or formula 1a can be isolated in the form of a pharmaceutically acceptable salt (e.g., in the form of camphorsulfonate).

[0173] The present invention includes within its scope a process for preparing a compound of formula 4a which is used as a starting material in preparing a compound of formula 1a or a pharmaceutically acceptable salt thereof.

[0174] In one embodiment, the present invention includes a process for preparing a compound of formula 4a comprising:

[0175] (i) reacting the compound of formula 4 with N-acetyl-D-leucine in a water-miscible organic solvent or a mixed solvent of water and a water-miscible organic solvent to obtain a compound of formula 5; and

[0176] <Formula 4>

[0177]

[0178] <Formula 5>

[0179]

[0180] (ii) reacting the compound of formula 5 with a base to obtain a compound of formula 4a,

[0181] <Formula 4a>

[0182] .

[0183] The reactions of step (i) and step (ii) can be carried out as described above.

[0184] In another embodiment, the present invention includes a process for preparing a compound of formula 4a:

[0185] (p) reacting the compound of formula 9 with methyl iodide to prepare the compound of formula 8;

[0186] <Formula 8>

[0187]

[0188] <Formula 9>

[0189]

[0190] (q) reacting a compound of Formula 8 with (S)-(-)-methyl-2-propanesulfenamide to prepare a compound of Formula 7;

[0191] <Formula 7>

[0192]

[0193] (r) reducing the compound of Formula 7 to prepare a mixture of the compound of Formula 6a and the compound of Formula 6b;

[0194] <Formula 6a>

[0195]

[0196] <Formula 6b>

[0197]

[0198] (s) reacting a mixture of the compound of Formula 6a and the compound of Formula 6b with an acid to prepare 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

[0199] <Formula 4a>

[0200]

[0201] <Formula 4b>

[0202]

[0203] <Formula 5>

[0204]

[0205] (t) reacting the compound of formula 5 with a base to obtain a compound of formula 4a,

[0206] <Formula 4a>

[0207] .

[0208] The reactions of step (p) to step (t) can be carried out as described above.

[0209] Also included within the scope of the present invention are novel intermediates useful for preparing compounds of Formula 1 or Formula 1a, or pharmaceutically acceptable salts thereof.

[0210] In one embodiment, the present invention includes compounds of Formula 2 useful for preparing compounds of Formula 1 or pharmaceutically acceptable salts thereof:

[0211] <Formula 2>

[0212] .

[0213] In another embodiment, the present invention includes compounds of Formula 2a useful for preparing compounds of Formula 1a or pharmaceutically acceptable salts thereof:

[0214] <Formula 2a>

[0215] .

[0216] In another embodiment, the present invention includes compounds of Formula 3 useful for preparing compounds of Formula 1 or pharmaceutically acceptable salts thereof:

[0217] <Formula 3>

[0218] .

[0219] In another embodiment, the present invention includes compounds of Formula 3a useful for preparing compounds of Formula 1a or pharmaceutically acceptable salts thereof:

[0220] <Formula 3a>

[0221] .

[0222] In another embodiment, the present invention includes compounds of Formula 5 useful for preparing compounds of Formula 1a:

[0223] <Formula 5>

[0224] .

[0225] 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.

[0226] Example 1: (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene-1-aminoacetyl-D-leucine (Compound 5)

[0227] After 5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (44 g, 183.2 mmol) was dissolved in a mixed solvent of acetone (792 mL) and pure water (88 mL) at room temperature, N-acetyl-D-leucine (14.3 g, 82.4 mmol) was added thereto. The reaction mixture was stirred at 35 ° C for about 19 hours. The obtained solid was filtered and then dried in a vacuum to obtain 24.0 g of the title compound. (Yield: 31.7%, optical purity: 99.5%)

[0228] Example 2: (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene-1-aminoacetyl-D-leucine (Compound 5)

[0229] After 5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (3 g, 12.5 mmol) was dissolved in a mixed solvent of acetonitrile (54 mL) and pure water (6 mL) at room temperature, N-acetyl-D-leucine (1.0 g, 5.6 mmol) was added thereto. The reaction mixture was stirred at 25 ° C for about 20 hours. The obtained solid was filtered and then dried in a vacuum to obtain 1.9 g of the title compound. (Yield: 36.8%, optical purity: 93.0%)

[0230] Example 3: (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (Compound 4a)

[0231] At room temperature, a mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine acetyl-D-leucine (44g, 0.106mol), isopropyl acetate (220mL) and pure water (220mL) was stirred, and 50% sodium hydroxide (14.5g, 0.181mmol) was added thereto. The reaction mixture was stirred for 20 minutes and then layer separated. The aqueous layer was extracted with isopropyl acetate (132mL). The mixed organic layer was washed with pure water (88mL), dried over magnesium sulfate (22g), and then concentrated under reduced pressure to obtain 25.5g of the title compound. (yield: 100%, optical purity: 99.5%)

[0232] Example 4: 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (Compound 8)

[0233] A solution of 85% potassium hydroxide (3.9 g, 59.2 mmol) dissolved in pure water (5 mL) was cooled to 0 to 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 methyl iodide (7.1 g, 49.8 mmol) was added to the potassium hydroxide solution while keeping the temperature below 30 ° C. The reaction mixture was stirred at room temperature for about 4 hours. Isopropyl acetate (20 mL) and toluene (10 mL) were added to the reaction mixture, which was then stirred. After separating the organic layer, the resulting aqueous layer was extracted with isopropyl acetate (30 mL). The mixed organic layer was washed with pure water (30 mL) and then concentrated to obtain 4.8 g of the title compound. (Yield: 84.7%)

[0234] 1H-NMR (400 MHz, CDCl3) δ 7.64 (d, 2H), 7.28 (d, 1H), 2.99 (s, 2H), 1.25 (s, 6H)

[0235] Example 5: 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (Compound 8)

[0236] A solution of 85% potassium hydroxide (23.5 g, 355.4 mmol) dissolved in pure water (30 mL) was cooled to 0 to 5 ° C. A mixture of 5-bromo-2,3-dihydro-1H-indene-1-one (30 g, 142.1 mmol), N-methyl-2-pyrrolidone (180 mL) and methyl iodide (44.4 g, 312.8 mmol) was added to the potassium hydroxide solution while keeping the temperature below 30 ° C. The reaction mixture was stirred at room temperature for about 4 hours. After pure water (450 mL) was slowly added to the reaction mixture, toluene (300 mL) was added thereto. The reaction mixture was stirred and then filtered with a celite pad. After separating the organic layer from the filtrate, the resulting aqueous layer was extracted with toluene (300 mL). The mixed organic layer was washed with 10% sodium chloride solution and then concentrated to obtain 30.8 g of the title compound. (Yield: 90.6%)

[0237] 1 H-NMR (400 MHz, CDCl3) δ 7.64 (d, 2H), 7.28 (d, 1H), 2.99 (s, 2H), 1.25 (s, 6H)

[0238] Example 6: (S,Z)-N-(5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfenamide (Compound 7)

[0239] 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-methylpropanesulfenamide (10.1 g, 83.6 mmol) was added to the mixture, which was stirred at 85° C. for about 19 hours under a nitrogen stream. The reaction mixture was concentrated and the residue was used in the subsequent reaction without further purification.

[0240] 1H-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)

[0241] Example 7: (S,Z)-N-(5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfenamide (Compound 7)

[0242] 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-methylpropanesulfenamide (27.4 g, 225.8 mmol) was added to the mixture, which was stirred at 85° C. for 6 hours under a nitrogen stream. The reaction mixture was concentrated and the residue was used in the subsequent reaction without further purification.

[0243] 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)

[0244] Example 8: Mixture of (S)-N-((R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfenamide (Compound 6a) and (S)-N-((S)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfenamide (Compound 6b)

[0245] 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, which was then stirred while the temperature was slowly raised to room temperature. After the reaction was completed, the reaction mixture was cooled to 0 ° C, and a citric acid solution (2.9 L) was slowly added thereto. The reaction mixture was extracted with ethyl acetate (965 mL). The obtained organic layer was washed with 10% sodium chloride solution (965 mL) and then concentrated. The resulting residue was used in subsequent reactions without further purification.

[0246] The residue was identified as a mixture of the compound of Formula 6a and the compound of Formula 6b. NMR data measured after separation using silica gel column chromatography (eluent: hexane / ethyl acetate) are as follows.

[0247] <Compound of Formula 6a>

[0248] 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)

[0249] <Compound of Formula 6b>

[0250] 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)

[0251] Example 9: (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene-1-aminoacetyl-D-leucine (Compound 5)

[0252] A mixture of the residue obtained in Example 8 (i.e., a mixture of a compound of Formula 6a and a compound of Formula 6b) (181.4 g, 526.8 mmol) and ethyl acetate (1.8 L) was cooled to 0 ° C and then stirred. Concentrated hydrochloric acid (35%) (183 mL) was added to the reaction mixture, heated to room temperature, and then stirred for 4 hours. Pure water (907 mL) was added to the reaction mixture, cooled to 0 ° C, and then the pH was adjusted to pH 9 to 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 obtained residue and then re-concentrated. Acetone (2.27 L) and pure water (253 mL) were added to the obtained concentrated residue and then stirred at room temperature. N-acetyl-D-leucine (68.4 g, 395.1 mmol) was added to the reaction mixture and then stirred at 35 ° C for about 16 hours. The obtained solid was filtered and then vacuum dried to obtain 84.3 g of the title compound. (Yield: 38.7% (3-step yield from the compound of Formula 8), optical purity: 99.2%)

[0253] 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)

[0254] Example 10: (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (Compound 4a)

[0255] A mixture of (R)-5-bromo-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine acetyl-D-leucine (7.5 g, 18.1 mmol), isopropyl acetate (37 mL) and pure water (37 mL) was stirred at room temperature. 50% sodium hydroxide (2.5 g, 53.0 mmol) was added thereto under stirring. After layer separation, the aqueous layer was extracted with isopropyl acetate (23 mL). The mixed organic layer was washed with pure water (20 mL), dried over magnesium sulfate (3.8 g), and then concentrated under reduced pressure to obtain 4.5 g of the title compound. (Yield: 100%, optical purity: 97.5%)

[0256] 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)

[0257] Example 11: 5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S,3S)-2,3-dihydroxysuccinic acid (Compound 3)

[0258] 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 pure water (10 mL) was refluxed for 7 hours under stirring. The reaction mixture was concentrated under reduced pressure, and then extracted with pure water (15 mL), ethyl acetate (35 mL) and dichloromethane (25 mL). The separated organic layer was washed with pure water (25 mL) and then concentrated under reduced pressure. Acetone (45 mL) was added to the concentrated residue, and then a solution of D-tartaric acid (1.56 g, 0.0104 mol) dissolved in pure water (5 mL) was added thereto. The reaction mixture was heated to 50 ° C, stirred for 30 minutes, and then cooled to room temperature. The obtained solid was filtered and then vacuum dried to obtain 7.9 g of the title compound. (Yield: 93.7%, purity: 94.8%)

[0259] 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)

[0260] Example 12: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S,3S)-2,3-dihydroxysuccinic acid (Compound 3a)

[0261] 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 pure water (6 mL) was stirred at 60°C for 4 hours. Pure water (15 mL) was added to the reaction mixture which had been concentrated under reduced pressure, and then extracted with ethyl acetate (15 mL). The obtained extract was washed with pure water (15 mL) and then concentrated under reduced pressure. Acetone (27 mL) was added to the concentrated residue, and then D-tartaric acid (0.94 g, 0.006 mol) and pure water (3 mL) were added thereto. The reaction mixture was heated to 50 ° C, stirred for 30 minutes, and then cooled to room temperature. The solid obtained was filtered and then vacuum dried to obtain 4.4 g of the title compound. (Yield: 87.0%)

[0262] 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)

[0263] Example 13: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S,3S)-2,3-dihydroxysuccinic acid (Compound 3a)

[0264] 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 pure water (5 mL) was stirred at 60°C for 4 hours. Pure water (25 mL) was added to the reaction mixture which had been concentrated under reduced pressure, and then extracted with ethyl acetate (15 mL). The obtained extract was washed with pure water (25 mL) and then concentrated under reduced pressure. Acetone (45 mL) was added to the concentrated residue, and then D-tartaric acid (1.56 g, 10.41 mmol) and pure water (5 mL) were added thereto. The reaction mixture was heated to 50 ° C, stirred for 30 minutes, and then cooled to room temperature. The obtained solid was filtered and then vacuum dried to obtain 6.7 g of the title compound. (Yield: 79.5%)

[0265] 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)

[0266] Example 14: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S,3S)-2,3-dihydroxysuccinic acid (Compound 3a)

[0267] 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 pure water (150 mL) was refluxed for 2 hours under stirring. The reaction mixture was concentrated under reduced pressure, and then methyl tert-butyl ether (500 mL) and 3N hydrochloric acid solution (500 mL) were slowly added thereto. Pure water (250 mL) was added to the separated organic layer. The reaction mixture was neutralized with a 50% sodium hydroxide solution. The separated organic layer was washed with pure water and then concentrated under reduced pressure. Acetone (250 mL) was added to the obtained concentrated residue, and then concentrated under reduced pressure. Acetone (450 mL) was added to the concentrated residue, and then a solution of D-tartaric acid (15.6 g, 0.104 mol) in acetone (250 mL) was added thereto. The reaction mixture was refluxed for 30 minutes under stirring and then cooled to room temperature. The solid obtained was filtered and then vacuum dried to obtain 71.3 g of the title compound. (yield: 84.6%)

[0268] 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)

[0269] Example 15: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S,3S)-2,3-dihydroxysuccinic acid (Compound 3a)

[0270] 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 pure water (20 mL) was refluxed for 3 hours under stirring. Pure water (50 mL) was added to the reaction mixture, which was concentrated under reduced pressure and then extracted with ethyl acetate (50 mL). The obtained extract was washed with pure water (50 mL) and then concentrated under reduced pressure. Acetone (90 mL) was added to the concentrated residue, and then D-tartaric acid (3.13 g, 0.021 mol) and pure water (10 mL) were added thereto. The reaction mixture was heated to 50 ° C, stirred for 30 minutes, and then cooled to room temperature. The obtained solid was filtered and then vacuum dried to obtain 13.95 g of the title compound. (Yield: 82.7%)

[0271] 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)

[0272] Example 16: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S,3S)-2,3-dihydroxysuccinic acid (Compound 3a)

[0273] 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 pure water (4.8 mL) was refluxed for 4 hours under stirring. Pure water (15 mL) was added to the reaction mixture that had been concentrated under reduced pressure, and then extracted with ethyl acetate (15 mL). The obtained extract was washed with pure water (15 mL) and then concentrated under reduced pressure. Acetone (27 mL) was added to the concentrated residue, and then D-tartaric acid (0.94 g, 0.006 mol) and pure water (3 mL) were added thereto. The reaction mixture was heated to 50 ° C, stirred for 30 minutes, and then cooled to room temperature. The obtained solid was filtered and then vacuum dried to obtain 4.3 g of the title compound. (Yield: 85.0%)

[0274] 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)

[0275] Example 17: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S,3S)-2,3-dihydroxysuccinic acid (Compound 3a)

[0276] 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 pure water (3.9 mL) was refluxed for 4 hours under stirring. Pure water (15 mL) was added to the reaction mixture that had been concentrated under reduced pressure, and then extracted with ethyl acetate (15 mL). The obtained extract was washed with pure water (15 mL) and then concentrated under reduced pressure. Acetone (27 mL) was added to the concentrated residue, and then D-tartaric acid (0.94 g, 0.006 mol) and pure water (3 mL) were added thereto. The reaction mixture was heated to 50 ° C, stirred for 30 minutes, and then cooled to room temperature. The obtained solid was filtered and then vacuum dried to obtain 4.3 g of the title compound. (Yield: 85.0%)

[0277] 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)

[0278] Example 18: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S,3S)-2,3-dihydroxysuccinic acid (Compound 3a)

[0279] 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 pure water (3.0 mL) was refluxed for 2 hours under stirring. Pure water (15 mL) was added to the reaction mixture that had been concentrated under reduced pressure, and then extracted with ethyl acetate (15 mL). The obtained extract was washed with pure water (15 mL) and then concentrated under reduced pressure. Acetone (27 mL) was added to the concentrated residue, and then D-tartaric acid (0.94 g, 0.006 mol) and pure water (3 mL) were added thereto. The reaction mixture was heated to 50 ° C, stirred for 30 minutes, and then cooled to room temperature. The solid obtained was filtered and then vacuum dried to obtain 4.2 g of the title compound. (Yield: 83.0%)

[0280] 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)

[0281] Example 19: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S,3S)-2,3-dihydroxysuccinic acid (Compound 3a)

[0282] 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 pure water (2.1 mL) was refluxed for 2 hours under stirring. Pure water (15 mL) was added to the reaction mixture that had been concentrated under reduced pressure, and then extracted with ethyl acetate (15 mL). The obtained extract was washed with pure water (15 mL) and then concentrated under reduced pressure. Acetone (27 mL) was added to the concentrated residue, and then D-tartaric acid (0.94 g, 0.006 mol) and pure water (3 mL) were added thereto. The reaction mixture was heated to 50 ° C, stirred for 30 minutes, and then cooled to room temperature. The solid obtained was filtered and then vacuum dried to obtain 4.4 g of the title compound. (Yield: 87.0%)

[0283] 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)

[0284] Example 20: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S,3S)-2,3-dihydroxysuccinic acid (Compound 3a)

[0285] 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 pure water (20 mL) was stirred at 55° C. for 4 hours. Pure water (50 mL) was added to the reaction mixture which had been concentrated under reduced pressure, and then extracted with ethyl acetate (50 mL). The obtained extract was washed with pure water (50 mL) and then concentrated under reduced pressure. Acetone (90 mL) was added to the concentrated residue, and then D-tartaric acid (3.13 g, 0.021 mol) and pure water (10 mL) were added thereto. The reaction mixture was heated to 50 ° C, stirred for 30 minutes, and then cooled to room temperature. The obtained solid was filtered and then vacuum dried to obtain 13.95 g of the title compound. (Yield: 82.7%)

[0286] 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)

[0287] Example 21: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S,3S)-2,3-dihydroxysuccinic acid (Compound 3a)

[0288] 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 pure water (3 mL) was refluxed for 7 hours under stirring. Pure water (15 mL) was added to the reaction mixture that had been concentrated under reduced pressure, and then extracted with ethyl acetate (15 mL). The obtained extract was washed with pure water (15 mL) and then concentrated under reduced pressure. Acetone (27 mL) was added to the concentrated residue, and then D-tartaric acid (0.94 g, 0.006 mol) and pure water (3 mL) were added thereto. The reaction mixture was heated to 50 ° C, stirred for 30 minutes, and then cooled to room temperature. The obtained solid was filtered and then vacuum dried to obtain 4.1 g of the title compound. (Yield: 81.1%)

[0289] 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)

[0290] Example 22: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S,3S)-2,3-dihydroxysuccinic acid (Compound 3a)

[0291] 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 pure water (6 mL) was refluxed for 24 hours under stirring. Pure water (25 mL) was added to the reaction mixture that had been concentrated under reduced pressure, and then extracted with ethyl acetate (25 mL). The obtained extract was washed with pure water (25 mL) and then concentrated under reduced pressure. Acetone (45 mL) was added to the concentrated residue, and then D-tartaric acid (1.56 g, 0.0104 mol) and pure water (3 mL) were added thereto. The reaction mixture was heated to 50 ° C, stirred for 30 minutes, and then cooled to room temperature. The solid obtained was filtered and then vacuum dried to obtain 7.0 g of the title compound. (yield: 83%)

[0292] 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)

[0293] Example 23: 5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (Compound 2)

[0294] Under stirring, 50% sodium hydroxide (1.7 g, 0.022 mol) was added to a mixture of 5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S, 3S)-2,3-dihydroxysuccinic acid (7.3 g, 0.018 mol), dichloromethane (73 mL) and pure water (51 mL). The reaction mixture was stirred at room temperature for about 30 minutes and then layer separated. The organic layer was washed with pure water (37 mL) and then concentrated under reduced pressure to obtain 6.0 g of the title compound. (yield: 100.0%)

[0295] 1H 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)

[0296] Example 24: (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-amine (Compound 2a)

[0297] Under stirring, to a mixture of (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (2S, 3S)-2,3-dihydroxysuccinic acid (20.0 g, 0.049 mol), dichloromethane (200 mL) and pure water (140 mL), 50% sodium hydroxide (4.8 g, 0.059 mol) was added. The reaction mixture was stirred at room temperature for about 30 minutes, and then the layers were separated. The organic layer was washed with pure water (75 mL), and then concentrated under reduced pressure to obtain 16.3 g of the title compound. (Yield: 100.0%)

[0298] 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)

[0299] Example 25: (S)-quinuclidine-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound 1a)

[0300] 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°C to 45°C for 21 hours. (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 to the reaction mixture. The reaction mixture was refluxed for about 15 hours under stirring and then cooled to room temperature. Pure 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 that had been concentrated under reduced pressure. Pure water (1320 mL) and isopropyl acetate (1650 mL) were added to the resulting residue. The separated organic layer was washed with 2N sodium hydroxide solution (1100 mL) and pure water (550 mL), and then concentrated under reduced pressure to obtain 148.5 g of the title compound. (Yield: 92.2%)

[0301] 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)

[0302] Example 26: (S)-quinuclidine-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound 1a)

[0303] A mixture of (S)-3-quinuclidine alcohol (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. (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (3.0 g, 9.09 mmol) and acetonitrile (9 mL) were added to the reaction mixture. The reaction mixture was stirred at 70 ° C for about 15 hours and then cooled to room temperature. Pure water (24 mL) and 50% sodium hydroxide were added to the reaction mixture, which was then stirred at room temperature for about 1 hour. Pure 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% sodium bicarbonate solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 3.8 g of the title compound. (yield: 86.5%)

[0304] 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)

[0305] Example 27: (S)-quinuclidine-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound 1a)

[0306] 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. (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (10.0 g, 0.03 mol) and acetonitrile (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, 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 about 1 hour and then concentrated under reduced pressure. Pure water (120 mL) and isopropyl acetate (150 mL) were added to the obtained residue. The separated organic layer was washed with 2N sodium hydroxide solution (100 mL) and pure water (50 mL), and then concentrated under reduced pressure to obtain 13.0 g of the title compound. (Yield: 88.8%)

[0307] 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)

[0308] 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]heptane-1-yl) methanesulfonate ((1S)-(+)-10-camphorsulfonate of Compound 1)

[0309] 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 to 45 ° C for 2 hours. 5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-amine (6.0 g, 0.018 mol) and tetrahydrofuran (18 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 (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. Pure water (72 mL) and isopropyl acetate (105 mL) were added to the resulting residue. The separated organic layer was washed with 2N sodium hydroxide solution (60mL) and pure water (30mL) in sequence, and then concentrated under reduced pressure. The obtained residue was dissolved in methyl ethyl ketone (78mL). The obtained solution was heated to 50°C, and then (1S)-(+)-10-camphorsulfonic acid (4.2g, 0.018mol) was added thereto. The reaction mixture was 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 methyl ethyl ketone (18mL). The obtained solid was vacuum dried to obtain 4.0g of the title compound. (Yield: 30.7%, purity: 93.6%)

[0310] 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)

[0311] 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]heptane-1-yl) methanesulfonate ((1S)-(+)-10-camphorsulfonate of compound 1a)

[0312] After (S)-quinuclidine-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 pure water (33 mL) was added thereto. The reaction mixture was 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 methyl ethyl ketone (330 mL). The obtained solid was vacuum dried to obtain 178.0 g of the title compound. (Yield: 80.9%, optical purity: 99.5%)

[0313] 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)

[0314] Comparative Example: (S)-quinuclidine-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound 1a)

[0315] 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 pure water (20 mL) was stirred at 60° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and then pure water (100 mL) and ethyl acetate (200 mL) were added thereto. Pure water (100 mL) was added to the separated organic layer, and then the pH thereof 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%)

[0316] 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)

[0317] Test example: Measurement of palladium residue

[0318] The residual amount of palladium in the product prepared in comparative example, embodiment 25 and embodiment 29 was measured. Specifically, we used ORS (Octopole reaction system), which reduces interference to the collision of ionized atoms by injecting helium. The 7800 ICP-MS model of Agilent (Agilent) was used as instrument. Calibration curve was made using multi-element stock solution (Agilent (Agilent)), and various palladium residual amounts were measured by quantitative analysis of the sample pretreated with diluted hydrochloric acid solution. The result is as shown in Table 1.

[0319] [Table 1]

[0320]

[0321] It can be seen from the results in Table 1 that when compound 1 is prepared according to the present invention, the residual amount of 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, the method comprising: (a) reacting a compound of formula 4 with 3-chloro-4-isopropoxyphenylboronic acid and then with D-tartaric acid to prepare a compound of formula 3; (b) reacting the compound of formula 3 with a base to prepare a compound of formula 2; as well as (c) reacting the compound of formula 2 with (S)-4-nitrophenylquinuclidine-3-yl carbonate to prepare a compound of formula 1, <Formula 1> <Formula 2> <Formula 3> <Formula 4> 。 2. A method for preparing a compound of formula 1a or a pharmaceutically acceptable salt thereof, the method comprising: (a') reacting a compound of formula 4a with 3-chloro-4-isopropoxyphenylboronic acid and then with D-tartaric acid to prepare a compound of formula 3a; (b') reacting a compound of formula 3a with a base to prepare a compound of formula 2a; as well as (c') reacting the compound of formula 2a with (S)-4-nitrophenylquinuclidine-3-yl carbonate to prepare a compound of formula 1a, <Formula 1a> <Formula 2a> <Formula 3a> <Formula 4a> 。 3. The method according to claim 2, wherein the compound of formula 4a is obtained by a method comprising the following steps: (i) reacting the compound of formula 4 with N-acetyl-D-leucine in a water-miscible organic solvent or a mixed solvent of water and a water-miscible organic solvent to obtain a compound of formula 5; and <Formula 4> <Formula 5> (ii) reacting the compound of formula 5 with a base to obtain the compound of formula 4a.

4. The method according to claim 3, wherein the water-miscible organic solvent is one or more selected from the group consisting of acetone, acetonitrile, C1-C5 alcohol, tetrahydrofuran, methyl ethyl ketone, isopropyl acetate, ethyl acetate, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran and dichloromethane.

5. The method according to claim 3, wherein the alkali 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.

6. The method according to claim 2, wherein the compound of formula 4a is obtained by a method comprising the following steps: (p) reacting the compound of formula 9 with methyl iodide to prepare the compound of formula 8; <Formula 8> <Formula 9> (q) reacting a compound of Formula 8 with (S)-(-)-methyl-2-propanesulfenamide to prepare a compound of Formula 7; <Formula 7> (r) reducing the compound of Formula 7 to prepare a mixture of the compound of Formula 6a and the compound of Formula 6b; <Formula 6a> <Formula 6b> (s) reacting a mixture of the compound of Formula 6a and the compound of Formula 6b with an acid to prepare 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 a compound of formula 4a, <Formula 4a> 。 7. The method according to claim 6, wherein the reaction of step (p) is carried out in the presence of a base selected from the group consisting of cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), potassium phosphate (K3PO4), triethylamine, diisopropylamine, potassium hydroxide, potassium acetate, potassium tert-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.

8. The method according to 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. The method according to claim 6, wherein step (r) is performed by using one or more reducing agents selected from the group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride.

10. The method 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 method according to claim 6, wherein the water-miscible organic solvent in step (s) is one or more selected from the group consisting of acetone, acetonitrile, C1-C5 alcohol, tetrahydrofuran, methyl ethyl ketone, isopropyl acetate, ethyl acetate, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran and dichloromethane.

12. The method according to claim 6, wherein the alkali 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.

13. The method according to claim 1 or claim 2, wherein the compound of formula 4 or the compound of formula 4a is reacted with 3-chloro-4-isopropoxyphenylboronic acid in the presence of a metal catalyst and a base.

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

15. The method of claim 13, wherein the base is selected from the group consisting of cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), potassium phosphate (K3PO4), triethylamine, diisopropylamine, potassium hydroxide, potassium acetate, potassium tert-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 method 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 method according to claim 13, wherein the at least one selected from water, C1-C 10 The reaction is carried out in the presence of a solvent 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. The method according to claim 1 or claim 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 claim 2, wherein (S)-4-nitrophenylquinuclidin-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-quinuclidine with bis(4-nitrophenyl) carbonate and the reaction of the compound of formula 2 or the compound of formula 2a with (S)-4-nitrophenylquinuclidine-3-yl carbonate are carried out in a one-pot reaction.

21. The method of claim 1 or claim 2, wherein the compound of formula 2 or the compound of formula 2a is reacted with (S)-4-nitrophenylquinuclidin-3-yl carbonate in the absence of a base.

22. The method of claim 1 or claim 2, wherein the compound of formula 2 or the compound of formula 2a is reacted with (S)-4-nitrophenylquinuclidin-3-yl carbonate 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 of claim 1 or claim 2, wherein the compound of Formula 2 or the compound of Formula 2a is reacted with (S)-4-nitrophenylquinuclidine-3-yl carbonate in the presence of 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: reacting the compound of Formula 4 with N-acetyl-D-leucine in a water-miscible organic solvent or a mixed solvent of water and a water-miscible organic solvent to obtain a compound of Formula 5; and <Formula 4> <Formula 5> (ii) reacting the compound of formula 5 with a base to obtain a compound of formula 4a, <Formula 4a> 。 25. The method according to claim 24, wherein the water-miscible organic solvent is one or more selected from the group consisting of acetone, acetonitrile, C1-C5 alcohol, tetrahydrofuran, methyl ethyl ketone, isopropyl acetate, ethyl acetate, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran and dichloromethane.

26. 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: (p) reacting the compound of formula 9 with methyl iodide to prepare a compound of formula 8; <Formula 8> <Formula 9> (q) reacting a compound of Formula 8 with (S)-(-)-methyl-2-propanesulfenamide to prepare a compound of Formula 7; <Formula 7> (r) reducing the compound of Formula 7 to prepare a mixture of the compound of Formula 6a and the compound of Formula 6b; <Formula 6a> <Formula 6b> (s) reacting a mixture of the compound of Formula 6a and the compound of Formula 6b with an acid to prepare 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 a compound of formula 4a, <Formula 4a> 。 28. The method of claim 27, wherein the reaction of step (p) is carried out in the presence of a base selected from the group consisting of cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), potassium phosphate (K3PO4), triethylamine, diisopropylamine, potassium hydroxide, potassium acetate, potassium tert-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.

29. The method according to 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. The method of claim 27, wherein step (r) is performed by using one or more reducing agents selected from the group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride.

31. The method 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 method according to claim 27, wherein the water-miscible organic solvent in step (s) is one or more selected from the group consisting of acetone, acetonitrile, C1-C5 alcohol, tetrahydrofuran, methyl ethyl ketone, isopropyl acetate, ethyl acetate, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran and dichloromethane.

33. 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. Compound of formula 2 <Formula 2> 。 35. Compound of formula 2a <Formula 2a> 。 36. Compound of formula 3 <Formula 3> 。 37. Compound of formula 3a <Formula 3a> 。 38. Compound of formula 5 <Formula 5> 。

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