Method for preparing optically active azabicyclo derivatives and preparation intermediates thereof

Abstract

The present invention relates to a process for the preparation of optically active azabicyclo derivatives useful as pharmaceutical compounds, intermediates for the preparation thereof, and a process for the preparation of the intermediates.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to a method for producing an optically active azabicyclic derivative useful as a pharmaceutical compound, an intermediate for the production thereof, and a method for producing the intermediate. BACKGROUND

[0002] Methods for producing optically active azabicyclic derivatives and methods for producing related substances thereof have been known, for example, as the method described in Patent Literature 1.

[0003] LIST OF REFERENCES PATENT LITERATURE [Patent Literature 1] WO 2020 / 045334 SUMMARY TECHNICAL PROBLEM An object of the present disclosure is to provide a method for producing an optically active azabicyclic derivative useful as a pharmaceutical compound.

[0004] SOLUTION TO PROBLEM The present disclosure provides an excellent industrial production method of an optically active azabicyclic derivative of formula (12) which is less in number of steps, simple, high in yield, and low in cost.

[0005] The present disclosure provides an excellent industrial method of manufacturing an optically active azabicyclic derivative of formula (8) which is less in number of steps, simple, high in yield, and low in cost.

[0006] In one embodiment, more specifically, intermediate (2) is prepared by reacting an inexpensive benzylamine derivative (1) with an inexpensive aldehyde (1a) (step A). ​​The obtained intermediate (2) is reacted with 1,3-cyclohexadiene to stereoselectively obtain intermediate (3) (step B). The obtained intermediate (3) is regioselectively and stereoselectively hydroxylated by a hydroboration-oxidation sequence to obtain intermediate (4) (step C), followed by deprotection of the amino group to prepare intermediate (5) (step D). The ester group in intermediate (5) is hydrolyzed to obtain intermediate (6) (step E), and the amino group in the obtained intermediate is protected to prepare intermediate (7) (step F). The hydroxyl group in the obtained intermediate (7) is oxidized to prepare intermediate (8) simply, in high yield and at low cost (step G). Intermediate (8) reacts with amine (8a) to obtain intermediate (9) (step H), the carbonyl group in intermediate (9) is converted to vinylidene to obtain intermediate (10) (step I), and then the amino group in intermediate (10) is deprotected to prepare intermediate (11) (step J). Finally, the obtained intermediate (11) is reacted with compound (11a) to prepare an optically active azabicyclic derivative (12). The method of (method 1) discovered allows for the preparation of derivative (12) in a small number of steps, simply, in high yield and at low cost.

[0007] In one embodiment, this disclosure provides a simple and high-yield method for preparing intermediate (8) by oxidizing the hydroxyl group in intermediate (7) to obtain intermediate (8) (step G), and also provides another method (method 1) for high-yield preparation of optically active azabicyclic derivative (12) from intermediate (8) in only 4 steps.

[0008] In one embodiment, more specifically, intermediate (2) is prepared by reacting an inexpensive benzylamine derivative (1) with an inexpensive aldehyde (1a) (step A). ​​The intermediate (2) is converted to intermediate (13) in high yield by reacting intermediate (2) with a 1,3-cyclohexadiene derivative (2a) (step M). The obtained intermediate (13) is deprotected to obtain intermediate (14) (step N), followed by further deprotection to obtain intermediate (15) and a new protection of the amino group to prepare intermediate (16) (steps O and P). Subsequently, the ester group in intermediate (16) is hydrolyzed to obtain intermediate (8) in simple, high yield, and low cost (step Q). Intermediate (8) is reacted with an amine (8a) to obtain intermediate (9) (step H). Furthermore, the carbonyl group in intermediate (9) is converted to vinylidene to obtain intermediate (10) (step I), followed by deprotection of the amino group in intermediate (10) to prepare intermediate (11) (step J). Finally, the obtained intermediate (11) is reacted with compound (11a) to prepare the optically active azabicyclic derivative (12). The method of (Method 2) discovered allows for the preparation of the derivative (12) in a small number of steps, with simple, high yield and low cost.

[0009] In one embodiment, this disclosure provides a simple and high-yield method for preparing intermediate (8) by reacting intermediate (2) with a 1,3-cyclohexadiene derivative (2a) to prepare intermediate (13) (step M), and also provides an additional method (method 2) for high-yield preparation of optically active azabicyclic derivative (12) from intermediate (8) in only 4 steps.

[0010] (Method 1) [Chemistry 1] (Method 2) [Chemistry 2] In other words, this disclosure typically provides the following.

[0011] (Project 1) A method for preparing a compound of formula (12) or a pharmaceutically acceptable salt thereof or a solvate thereof: [Chemistry 3] Where a, b, c, and d are independently 1 or 2. The method includes step G as shown below. Step G: Compounds of formula (7): [Chemistry 4] Where R 3 It is a protecting group for amino groups. Or a pharmaceutically acceptable salt thereof or a solvate thereof reacts with an oxidizing agent in the presence of a solvent to prepare a compound of formula (8): [Chemistry 5] Where R 3 The definition is as described above. Or its pharmaceutically acceptable salt, or its solvate.

[0012] (Project 2) The method of Project 1, wherein the solvent in step G includes ester solvents and / or halogen solvents.

[0013] (Project 3) The method of Project 1, wherein the solvent in step G includes ester solvents.

[0014] (Project 4) The method of Project 1, wherein the solvent in step G includes ethyl acetate.

[0015] (Project 5) The method of any one of Projects 1 to 4, wherein the reaction temperature in step G is -20°C to 50°C.

[0016] (Project 6) The method of any one of Projects 1 to 5, wherein the reaction temperature in step G is 0°C to 30°C.

[0017] (Project 7) The method of any one of Projects 1 to 6, wherein the oxidant used in step G is 1-methyl-2-azaadamantane-N-oxy, 2-hydroxy-2-azaadamantane, 9-azanoradamantane-N-oxy, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodo-3(1H)-one, potassium 2-iodo-5-methylbenzenesulfonate, "a combination of DMSO and oxaloyl chloride", acetic anhydride, sulfur trioxide-pyridine-complex, N,N'-dicyclohexylcarbodiimide, chromium trioxide, tetrapropylammonium perruthenate, sodium hypochlorite pentahydrate, or 2,2,6,6-tetramethylpiperidine-1-oxy.

[0018] (Project 8) The method of any one of items 1 to 6, wherein the oxidant used in step G is 2,2,6,6-tetramethylpiperidine-1-oxy.

[0019] (Project 9) The method of any one of items 1 to 8 further includes step H as shown below. Step H: Compounds of formula (8): [Chemistry 6] Where R 3 As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, in combination with a compound of formula (8a): [Chemistry 7] Where R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted in the presence of a solvent and a condensing agent to prepare a compound of formula (9): [Chemistry 8] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0020] (Project 10) The method of Project 9 also includes step I as shown below. Step I: Make the compound of formula (9) [Chemistry 9] Where R 3 R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted with a halomethyltriphenylphosphonium, a trialkylsilylmethyl anion, or a methyl sulfone derivative in the presence of a solvent and a base to prepare a compound of formula (10): [Chemistry 10] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0021] (Project 11) The method of Project 10 further includes step J as shown below. Step J: Compounds of formula (10): [Chemistry 11] Where R 3R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted with an acid to prepare a compound of formula (11): [Chemistry 12] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0022] (Project 12) The method of Project 11 further includes step K as shown below. Step K: Compounds of formula (11): [Chemistry 13] Where a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, in combination with a compound of formula (11a): [Chemistry 14] Where X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl, or methanesulfonyl. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted in the presence of a solvent and a base to prepare a compound of formula (12): [Chemistry 15] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0023] (Project 13) The method of Project 12 further includes step L as shown below. Step L: Compounds of formula (12): [Chemistry 16] Where a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacts with L(+)-tartaric acid in the presence of a solvent to prepare a compound of formula (12a): [Chemistry 17] Where a, b, c, and d are defined as above. Or its solvates.

[0024] (Project 14) The method of any one of items 1 to 13 further includes step A as shown below. Step A: Compounds of formula (1): [Chemistry 18] Where R 1 C is an optional replacement 1-6 Alkyl, and R 1A C is an optional replacement 6-10 Aryl, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, in combination with a compound of formula (1a): [Chemistry 19] Where R 2 C is an optional replacement 1-6 alkyl, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted in the presence of a solvent to prepare a compound of formula (2): [Chemistry 20] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0025] (Project 15) The method of Project 14 further includes step B as shown below. Step B: Compounds of formula (2): [Chemistry 21] Where R 1 R 1A and R 2 As defined above, The compound of formula (3) is prepared by reacting its pharmaceutically acceptable salt or solvate with 1,3-cyclohexadiene in the presence of a solvent and an acid: [Chemistry 22] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0026] (Project 16) The method of Project 15 further includes step C as shown below. Step C: Compounds of formula (3): [Chemistry 23] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacts with borane in the presence of a solvent, and then reacts with a peroxide and a base to prepare a compound of formula (4): [Chemistry 24] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0027] (Project 17) The method of Project 16 further includes step D as shown below. Step D: Compounds of formula (4): [Chemistry 25] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacts with hydrogen in the presence of a catalyst to deprotect the protecting group on the amino group to prepare the compound of formula (5): [Chemistry 26] Where R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0028] (Project 18) The method of Project 17 further includes step E as shown below. Step E: Compounds of formula (5): [Chemistry 27] Where R 2 As defined above, Or a pharmaceutically acceptable salt thereof, or an ester group of a solvate thereof, hydrolyzed to prepare a compound of formula (6): [Chemistry 28] Or its pharmaceutically acceptable salt, or its solvate.

[0029] (Project 19) The method of Project 18 further includes step F as shown below. Step F: Compounds of formula (6): [Chemistry 29] Or a pharmaceutically acceptable salt thereof, or the amino group of its solvate thereof is protected to prepare a compound of formula (7): [Chemistry 30] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0030] (Project 20) A method for preparing a compound of formula (12) or a pharmaceutically acceptable salt thereof or a solvate thereof: [Chemistry 31] Where a, b, c, and d are independently 1 or 2. The method includes the following step M, Step M: Compounds of formula (2): [Chemistry 32] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, in combination with a compound of formula (2a): [Chemistry 33] Where R 5a R 5b and R 5c Independently for C 1-6 Alkyl or C 6-10 Aryl, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted under acidic conditions in the presence of a solvent to prepare a compound of formula (13): [Chemistry 34] Where R 1 R 1A R 2 R 5a R 5b and R 5c As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0031] (Project 21) The method of Project 20, wherein the solvent in step M includes a halogen solvent.

[0032] (Project 22) The method of Project 20, wherein the solvent in step M includes dichloromethane and / or chloroform.

[0033] (Project 23) The method of Project 20, wherein the solvent in step M includes dichloromethane.

[0034] (Project 24) The method of any one of items 20 to 23, wherein the reaction temperature in step M is -100°C to -30°C.

[0035] (Project 25) The method of any one of items 20 to 23, wherein the reaction temperature in step M is -80°C to -10°C.

[0036] (Project 26) The method of any one of items 20 to 25, wherein the acid used in step M is methanesulfonic acid, trichloroacetic acid, dichloroacetic acid, difluoroacetic acid, trifluoroacetic acid, boron trifluoride-diethyl ether complex, or a mixture of trifluoroacetic acid and boron trifluoride-diethyl ether complex.

[0037] (Project 27) The method of any one of items 20 to 25, wherein the acid used in step M is a mixture of trifluoroacetic acid and boron trifluoride-ethyl ether complex.

[0038] (Project 28) The method of any one of items 20 to 27 further includes step A as shown below. Step A: Compounds of formula (1): [Chemistry 35] Where R 1 and R 1A As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, in combination with a compound of formula (1a): [Chemistry 36] Where R 2 As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted in the presence of a solvent to prepare a compound of formula (2): [Chemistry 37] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0039] (Project 29) The method of any one of items 20 to 28 further includes step N as shown below. Step N: Compounds of formula (13): [Chemistry 38] Where R 1 R 1A R 2 R 5a R 5b and R 5c As defined above, Or a pharmaceutically acceptable salt thereof, or the silanol ether group of its solvate, hydrolyzed to prepare a compound of formula (14): [Chemistry 39] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0040] (Project 30) The method of Project 29 also includes step O as shown below. Step O: Compounds of formula (14): [Chemistry 40] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacts with hydrogen in the presence of a catalyst to deprotect the protecting group on the amino group to prepare a compound of formula (15): [Chemistry 41] Where R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0041] (Project 31) The method of Project 30 further includes step P as shown below. Step P: Compounds of formula (15): [Chemistry 42] Where R 2 As defined above, Or a pharmaceutically acceptable salt thereof, or the amino group of its solvate thereof is protected to prepare a compound of formula (16): [Chemistry 43] Where R 2 and R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0042] (Project 32) The method of Project 31 further includes step Q as shown below. Step Q: Compounds of formula (16): [Chemistry 44] Where R 2 and R 3 As defined above, Or a pharmaceutically acceptable salt thereof, or an ester group of a solvate thereof, hydrolyzed to prepare a compound of formula (8): [Chemistry 45] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0043] (Project 33) The method of Project 32 further includes step H as shown below. Step H: Compounds of formula (8): [Chemistry 46] Where R3 As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, in combination with a compound of formula (8a): [Chemistry 47] Where R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted in the presence of a solvent and a condensing agent to prepare a compound of formula (9): [Chemistry 48] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0044] (Project 34) The method of Project 33 further includes step I as shown below. Step I: Make the compound of formula (9) [Chemistry 49] Where R 3 R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted with a halomethyltriphenylphosphonium and a base in the presence of a solvent to prepare a compound of formula (10): [Transformation 50] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0045] (Project 35) The method of Project 34 further includes step J as shown below. Step J: Compounds of formula (10): [Chemistry 51] Where R 3 R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted with an acid to prepare a compound of formula (11): [Chemistry 52] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0046] (Project 36) The method of Project 35 also includes step K as shown below. Step K: Compounds of formula (11): [Chemistry 53] Where a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, in combination with a compound of formula (11a): [Chemistry 54] Where X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl, or methanesulfonyl. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted in the presence of a solvent and a base to prepare a compound of formula (12): [Chemistry 55] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0047] (Project 37) The method of Project 36 also includes step L as shown below: Step L: Compounds of formula (11): [Chemistry 56] Where a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacts with L(+)-tartaric acid in the presence of a solvent to prepare a compound of formula (12a): [Chemistry 57] Where a, b, c, and d are defined as above. Or its solvates.

[0048] (Project 38) A method for preparing a compound of formula (8) or a pharmaceutically acceptable salt thereof or a solvate thereof: [Chem.58] Where R 3 It is a protecting group for amino groups. The method includes step G as shown below. Step G: Compounds of formula (7): [Chemistry 59] Where R 3 As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted with an oxidizing agent in the presence of a solvent to prepare a compound of formula (8): [Transformation 60] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0049] (Project 39) The method of Project 38 also includes step A as shown below: Step A: Compounds of formula (1): [Chemistry 61] Where R 1 C is an optional replacement 1-6 Alkyl, and R 1A C is an optional replacement 6-10 aryl groups, or pharmaceutically acceptable salts thereof, or solvates thereof, in combination with compounds of formula (1a): [Chemistry 62] Where R 2 C is an optional replacement 1-6 alkyl, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted in the presence of a solvent to prepare a compound of formula (2): [Chemistry 63] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0050] (Project 40) The method of Project 39 also includes step B as shown below: Step B: Compounds of formula (2): [Chemistry 64] Where R 1 R 1A and R 2 As defined above, The compound of formula (3) is prepared by reacting its pharmaceutically acceptable salt or solvate with 1,3-cyclohexadiene in the presence of a solvent and an acid: [Chemistry 65] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0051] (Project 41) The method of Project 40 also includes step C as shown below: Step C: Compounds of formula (3): [Chemistry 66] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacts with borane in the presence of a solvent, and then reacts with a peroxide and a base to prepare a compound of formula (4): [Chemistry 67] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0052] (Project 42) The method of Project 41 further includes step D as shown below: Step D: Compounds of formula (4): [Chemistry 68] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacts with hydrogen in the presence of a catalyst to deprotect the protecting group on the amino group to prepare the compound of formula (5): [Chemistry 69] Where R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0053] (Project 43) The method of Project 42 further includes step E as shown below. Step E: Compounds of formula (5): [Chemistry 70] Where R 2 As defined above, Or a pharmaceutically acceptable salt thereof, or an ester group of a solvate thereof, hydrolyzed to prepare a compound of formula (6): [Chemistry 71] Or its pharmaceutically acceptable salt, or its solvate.

[0054] (Project 44) The method of Project 43 further includes step F as shown below. Step F: Compounds of formula (6): [Chemistry 72] Or a pharmaceutically acceptable salt thereof, or the amino group of its solvate thereof is protected to prepare a compound of formula (7): [Chemistry 73] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0055] (Project 45) A method for preparing a compound of formula (8) or a pharmaceutically acceptable salt thereof or a solvate thereof: [Chemistry 74] Where R 3 It is a protecting group for amino groups. The method includes the following step M: Step M: Compounds of formula (2): [Chemistry 75] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, in combination with a compound of formula (2a): [Chemistry 76] Where R 5a R 5b and R 5c Independently for C 1-6 Alkyl or C 6-10 Aryl, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted under acidic conditions in the presence of a solvent to prepare a compound of formula (13): [Chemistry 77] Where R 1 R 1A R 2 R 5a R 5b and R 5c As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0056] (Project 46) The method of Project 45 also includes step A as shown below: Step A: Compounds of formula (1): [Chemistry 78] Where R 1 C is an optional replacement 1-6 Alkyl, and R 1A C is an optional replacement 6-10 Aryl, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, in combination with a compound of formula (1a): [Chemistry 79] Where R 2 C is an optional replacement 1-6 alkyl, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted in the presence of a solvent to prepare a compound of formula (2): [Chemistry 80] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0057] (Project 47) The method of item 45 or 46 further includes step N as shown below: Step N: Compound of formula (13) [Chemistry 81] Where R 1 R 1A R 2 R 5a R 5b and R 5c As defined above, Or a pharmaceutically acceptable salt thereof, or the silanol ether group of its solvate, hydrolyzed to prepare a compound of formula (14): [Chemistry 82] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0058] (Project 48) The method of Project 47 also includes the following step O: Step O: Compounds of formula (14): [Chemistry 83] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacts with hydrogen in the presence of a catalyst to deprotect the protecting group on the amino group to prepare a compound of formula (15): [Chemistry 84] Where R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0059] (Project 49) The method of Project 48 further includes step P as shown below. Step P: Compounds of formula (15): [Chemistry 85] Where R 2 As defined above, Or a pharmaceutically acceptable salt thereof, or the amino group of its solvate thereof is protected to prepare a compound of formula (16): [Chemistry 86] Where R 2 and R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0060] (Project 50) The method of Project 49 also includes step Q as shown below. Step Q: Compounds of formula (16): [Chemistry 87] Where R 2 and R 3 As defined above, Or a pharmaceutically acceptable salt thereof, or an ester group of a solvate thereof, hydrolyzed to prepare a compound of formula (8): [Chemistry 88] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0061] (Project 51) A method for preparing a compound of formula (12) or a pharmaceutically acceptable salt thereof or a solvate thereof: [Chemistry 89] Where a, b, c, and d are independently 1 or 2. The method includes step H as shown below. Step H: Compounds of formula (8): [Chemistry 90] Where R 3 As defined above, Or a pharmaceutically acceptable salt thereof, or a solvate thereof, in combination with a compound of formula (8a): [Chemistry 91] Where R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted in the presence of a solvent and a condensing agent to prepare a compound of formula (9): [Chemistry 92] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0062] (Project 52) The method of Project 51 further includes step I as shown below: Step I: Make the compound of formula (9) [Chemistry 93] Where R 3 R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted with a halomethyltriphenylphosphonium, a trialkylsilylmethyl anion, or a methyl sulfone derivative in the presence of a solvent and a base to prepare a compound of formula (10): [Chemistry 94] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0063] (Project 53) The method of Project 52 further includes the following step J: Step J: Compounds of formula (10): [Chemistry 95] Where R 3 R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted with an acid to prepare a compound of formula (11): [Chemistry 96] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0064] (Project 54) The method of Project 53 also includes step K as shown below: Step K: Compounds of formula (11): [Chemistry 97] Where a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, in combination with a compound of formula (11a): [Chem. 98] Where X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl, or methanesulfonyl. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacted in the presence of a solvent and a base to prepare a compound of formula (12): [Chemistry 99] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0065] (Project 55) The method of Project 54 also includes step L as shown below: Step L: Compounds of formula (12): [Chemistry 100] Where a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, reacts with L(+)-tartaric acid in the presence of a solvent to prepare a compound of formula (12a): [Chemistry 101] Where a, b, c, and d are defined as above. Or its solvates.

[0066] (Project 56) A mixture comprising 5-fluoro-2-[(4-{7-[(1 S ,3 S 4 R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy- N , N -Di(propyl-2-yl)benzamide or a pharmaceutically acceptable salt thereof or a solvation thereof, and compound A or a pharmaceutically acceptable salt thereof or a solvation thereof.

[0067] (Project 57) The mixture of Item 56, wherein compound A or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 0.15% or less of the mixture as determined by high performance liquid chromatography (HPLC).

[0068] (Project 58) The mixture of Item 56, wherein compound A or a pharmaceutically acceptable salt or solvation thereof is present in an amount of about 0.1% or less of the mixture as determined by high performance liquid chromatography (HPLC).

[0069] (Project 59) The mixture of Item 56, wherein compound A or a pharmaceutically acceptable salt or solvation thereof is present in an amount of about 0.05% or less of the mixture as determined by high performance liquid chromatography (HPLC).

[0070] (Project 60) The mixture according to any one of items 56 to 59 further comprises compound B or a pharmaceutically acceptable salt thereof or a solvation thereof.

[0071] (Project 61) According to Project 60, the mixture contains compound B or a pharmaceutically acceptable salt or solvate thereof, as determined by high performance liquid chromatography (HPLC), in an amount of about 0.15% or less of the mixture.

[0072] (Project 62) According to Project 60, the mixture contains compound B or a pharmaceutically acceptable salt or solvate thereof, as determined by high performance liquid chromatography (HPLC), in an amount of about 0.1% or less of the mixture.

[0073] (Project 63) According to Project 60, the mixture contains compound B or a pharmaceutically acceptable salt or solvate thereof, as determined by high performance liquid chromatography (HPLC), in an amount of about 0.05% or less of the mixture.

[0074] (Project 64) According to the mixture of Item 60, it also contains compound C or a pharmaceutically acceptable salt thereof or a solvation thereof.

[0075] (Project 65) According to item 64, the mixture contains compound C or a pharmaceutically acceptable salt or solvate thereof, as determined by high performance liquid chromatography (HPLC), in an amount of about 0.15% or less of the mixture.

[0076] (Project 66) According to item 64, the mixture contains compound C or a pharmaceutically acceptable salt or solvate thereof, as determined by high performance liquid chromatography (HPLC), in an amount of about 0.1% or less of the mixture.

[0077] (Project 67) According to item 64, the mixture contains compound C or a pharmaceutically acceptable salt or solvate thereof, as determined by high performance liquid chromatography (HPLC), in an amount of about 0.06% or less of the mixture.

[0078] (Project 68) A mixture comprising 5-fluoro-2-[(4-{7-[(1 S ,3 S 4 R )-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy- N , N -Di(propyl-2-yl)benzamide or a pharmaceutically acceptable salt thereof or a solvation thereof, and compound B or a pharmaceutically acceptable salt thereof or a solvation thereof.

[0079] (Project 69) The mixture of Item 68, wherein compound B or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 0.15% or less of the mixture as determined by high performance liquid chromatography (HPLC).

[0080] (Project 70) The mixture of Item 68, wherein compound B or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 0.1% or less of the mixture as determined by high performance liquid chromatography (HPLC).

[0081] (Project 71) The mixture of Item 68, wherein compound B or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 0.05% or less of the mixture as determined by high performance liquid chromatography (HPLC).

[0082] (Project 72) The mixture according to any one of items 68 to 71 further comprises compound C or a pharmaceutically acceptable salt thereof or a solvation thereof.

[0083] (Project 73) According to item 72, the mixture contains compound C or a pharmaceutically acceptable salt or solvate thereof, as determined by high performance liquid chromatography (HPLC), in an amount of about 0.15% or less of the mixture.

[0084] (Project 74) According to item 72, the mixture contains compound C or a pharmaceutically acceptable salt or solvate thereof, as determined by high performance liquid chromatography (HPLC), in an amount of about 0.1% or less of the mixture.

[0085] (Project 75) According to item 72, the mixture contains compound C or a pharmaceutically acceptable salt or solvate thereof, as determined by high performance liquid chromatography (HPLC), in an amount of about 0.06% or less of the mixture.

[0086] (Project 76) A mixture comprising 5-fluoro-2-[(4-{7-[(1 S ,3 S 4 R )-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidin-5-yl)oxy- N , N -Di(propyl-2-yl)benzamide or a pharmaceutically acceptable salt thereof or a solvation thereof, and compound C or a pharmaceutically acceptable salt thereof or a solvation thereof.

[0087] (Project 77) The mixture of Item 76, wherein compound C or a pharmaceutically acceptable salt or solvation thereof is present in an amount of about 0.15% or less of the mixture as determined by high performance liquid chromatography (HPLC).

[0088] (Project 78) The mixture of Item 76, wherein compound C or a pharmaceutically acceptable salt or solvation thereof is present in an amount of about 0.1% or less of the mixture as determined by high performance liquid chromatography (HPLC).

[0089] (Project 79) The mixture of Item 76, wherein compound C or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 0.06% or less of the mixture as determined by high performance liquid chromatography (HPLC).

[0090] (Project A1) Compounds of formula (12): [Chemistry 102] Where a, b, c, and d are independently 1 or 2. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method comprising step G shown below: Step G: Compounds of formula (7): [Chemistry 103] Where R 3 It is a protecting group for amino groups. Or a pharmaceutically acceptable salt thereof or a solvate thereof reacts with an oxidizing agent in the presence of a solvent to prepare a compound of formula (8): [Chemistry 104] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0091] (Project A2) The method further comprises step H as shown below: A compound of item A1, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Step H: Compounds of formula (8): [Chemistry 105] Where R 3 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (8a): [Chemistry 106] Where R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof or a solvate thereof, reacted in the presence of a solvent and a condensing agent to prepare a compound of formula (9): [Chemistry 107] Where R 3R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0092] (Project A3) The method further includes step I as shown below: A compound of item A2, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Step I: Compounds of formula (9): [Chemistry 108] Where R 3 R 4 a, b, c, and d are defined as above. The compound of formula (10) is prepared by reacting its pharmaceutically acceptable salt or solvation with a halomethyltriphenylphosphonium, trialkylsilylmethyl anion or methyl sulfone derivative in the presence of a solvent and a base. [Chemistry 109] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0093] (Project A4) The method further comprises the following steps: A compound of item A3, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the method includes step J as shown below: Step J: Compounds of formula (10): [Chemical 110] Where R 3 R 4 a, b, c, and d are defined as above. The compound of formula (11) is prepared by reacting its pharmaceutically acceptable salt or its solvate with an acid: [Chemistry 111] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0094] (Project A5) The method further comprises step K as shown below: (The compound of item A4, or a pharmaceutically acceptable salt thereof, or a solvate thereof) Step K: Compounds of formula (11): [Chemistry 112] Where a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof or a solvate thereof and a compound of formula (11a): [Chemistry 113] Where X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl, or methanesulfonyl. The compound of formula (12) is prepared by reacting its pharmaceutically acceptable salt or its solvate in the presence of a solvent and a base: [Chemistry 114] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0095] (Project A6) The method comprises the compound of item A5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the method further includes step L as shown below: Step L: Compounds of formula (12): [Chemistry 115] Where a, b, c, and d are defined as above. The compound of formula (12a) is prepared by reacting its pharmaceutically acceptable salt or solvation with L(+)-tartaric acid in the presence of a solvent: [Chemistry 116] Where a, b, c, and d are defined as above. Or its solvates.

[0096] (Project A7) The method comprises a compound of any one of items A1 to A6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the method further comprises step A as shown below. Step A: Compounds of formula (1): [Chemistry 117] Where R 1 C is an optional replacement 1-6 Alkyl, and R 1A C is an optional replacement 6-10Aryl, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (1a): [Chemistry 118] Where R 2 C is an optional replacement 1-6 alkyl, The compound of formula (2) is prepared by reacting its pharmaceutically acceptable salt or its solvate in the presence of a solvent: [Chemistry 119] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0097] (Project A8) The method further includes step B as shown below: The compound of item A7, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Step B: Compounds of formula (2): [Chemistry 120] Where R 1 R 1A and R 2 As defined above, The compound of formula (3) is prepared by reacting its pharmaceutically acceptable salt or solvation with 1,3-cyclohexadiene in the presence of a solvent and an acid: [Chemistry 121] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0098] (Project A9) The compound of item A8, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the method further comprises step C as shown below: Step C: Compounds of formula (3): [Chemistry 122] Where R 1 R 1A and R 2As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof is reacted with borane in the presence of a solvent, and then reacted with a peroxide and a base to prepare a compound of formula (4): [Chemistry 123] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0099] (Project A10) The compound of Project A9, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the method further comprises step D as shown below: Step D: Compounds of formula (4): [Chemistry 124] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof reacts with hydrogen in the presence of a catalyst to deprotect the protecting group on the amino group to prepare the compound of formula (5): [Chemistry 125] Where R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0100] (Project A11) The method further comprises step E as shown below: (The compound of item A10, or a pharmaceutically acceptable salt thereof, or a solvate thereof) Step E: Compounds of formula (5): [Chemistry 126] Where R 2 As defined above, The compound of formula (6) is prepared by hydrolyzing the ester group of its pharmaceutically acceptable salt or its solvate: [Chemistry 127] Or its pharmaceutically acceptable salt, or its solvate.

[0101] (Project A12) The method further comprises step F as shown below: (The compound of item A11, or a pharmaceutically acceptable salt thereof, or a solvate thereof) Step F: Compounds of formula (6): [Chemistry 128] The amino group of a pharmaceutically acceptable salt or its solvate is protected to prepare a compound of formula (7): [Chemistry 129] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0102] (Project A13) Compounds of formula (12): [Chemistry 130] Where a, b, c, and d are independently 1 or 2. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method comprising step M as shown below: Step M: Compounds of formula (2): [Chemistry 131] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (2a): [Chemistry 132] Where R 5a R 5b and R 5c Independently for C 1-6 Alkyl or C 6-10 Aryl, The compound of formula (13) is prepared by reacting its pharmaceutically acceptable salt or its solvate under acidic conditions in the presence of a solvent: [Chemistry 133] Where R 1 R 1A R 2 R 5a R 5band R 5c As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0103] (Project A14) The method comprises the compound of item A13, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the method further includes step A as shown below: Step A: Compounds of formula (1): [Chemistry 134] Where R 1 and R 1A As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (1a): [Chemistry 135] Where R 2 As defined above, The compound of formula (2) is prepared by reacting its pharmaceutically acceptable salt or its solvate in the presence of a solvent: [Chemistry 136] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0104] (Project A15) The method further comprises step N as shown below: A compound of item A13 or A14, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Step N: Compounds of formula (13): [Chemistry 137] Where R 1 R 1A R 2 R 5a R 5b and R 5c As defined above, The compound of formula (14) is prepared by hydrolysis of its pharmaceutically acceptable salt or its solvate's silenol ether group: [Chemistry 138] Where R1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0105] (Project A16) The method comprises the compound of item A15, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the method further includes step O as shown below: Step O: Compounds of formula (14): [Chemistry 139] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof reacts with hydrogen in the presence of a catalyst to deprotect the protecting group on the amino group to prepare a compound of formula (15): [Chemistry 140] Where R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0106] (Project A17) The method further comprises the following steps: A16: a compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the method includes step P as shown below: Step P: Compounds of formula (15): [Chemistry 141] Where R 2 As defined above, The amino group of a pharmaceutically acceptable salt or its solvate is protected to prepare a compound of formula (16): [Chemistry 142] Where R 2 and R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0107] (Project A18) The method further comprises step Q as shown below: (The compound of item A17, or a pharmaceutically acceptable salt thereof, or a solvate thereof) Step Q: Compounds of formula (16): [Chemistry 143] Where R 2 and R 3 As defined above, The compound of formula (8) is prepared by hydrolyzing the ester group of its pharmaceutically acceptable salt or its solvate: [Chemistry 144] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

[0108] (Project A19) The method further comprises step H as shown below: (The compound of item A18, or a pharmaceutically acceptable salt thereof, or a solvate thereof) Step H: Compounds of formula (8): [Chemistry 145] Where R 3 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (8a): [Chemistry 146] Where R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof or a solvate thereof, reacted in the presence of a solvent and a condensing agent to prepare a compound of formula (9): [Chemistry 147] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0109] (Project A20) The method further comprises step I as shown below: (The compound of item A19, or a pharmaceutically acceptable salt thereof, or a solvate thereof) Step I: Compounds of formula (9): [Chemistry 148] Where R3 R 4 a, b, c, and d are defined as above. The compound of formula (10) is prepared by reacting its pharmaceutically acceptable salt or solvation with a halomethyltriphenylphosphonium and a base in the presence of a solvent: [Chemistry 149] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0110] (Project A21) The method further comprises step J as shown below, of the compound of project A20, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Step J: Compounds of formula (10): [Chemistry 150] Where R 3 R 4 a, b, c, and d are defined as above. The compound of formula (11) is prepared by reacting its pharmaceutically acceptable salt or its solvate with an acid: [Chemistry 151] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0111] (Project A22) The method further comprises step K as shown below: (The compound of project A21, or a pharmaceutically acceptable salt thereof, or a solvate thereof) Step K: Compounds of formula (11): [Chemistry 152] Where a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof or a solvate thereof and a compound of formula (11a): [Chemistry 153] Where X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl, or methanesulfonyl. The compound of formula (12) is prepared by reacting its pharmaceutically acceptable salt or its solvate in the presence of a solvent and a base: [Chemistry 154] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0112] (Project A23) The method comprises the compound of project A22, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the method further includes step L as shown below: Step L: Compounds of formula (11): [Chemistry 155] Where a, b, c, and d are defined as above. The compound of formula (12a) is prepared by reacting its pharmaceutically acceptable salt or solvation with L(+)-tartaric acid in the presence of a solvent: [Chemistry 156] Where a, b, c, and d are defined as above. Or its solvates.

[0113] (Project A24) Compounds of formula (12): [Chemistry 157] Where a, b, c, and d are independently 1 or 2. Or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method comprising step H as shown below: Step H: Compounds of formula (8): [Chemistry 158] Where R 3 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (8a): [Chemistry 159] Where R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof or a solvate thereof, reacted in the presence of a solvent and a condensing agent to prepare a compound of formula (9): [Chemistry 160] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0114] (Project A25) The method further comprises step I as shown below: (The compound of item A24, or a pharmaceutically acceptable salt thereof, or a solvate thereof) Step I: Make the compound of formula (9) [Chemistry 161] Where R 3 R 4 a, b, c, and d are defined as above. The compound of formula (10) is prepared by reacting its pharmaceutically acceptable salt or solvation with a halomethyltriphenylphosphonium, trialkylsilylmethyl anion or methyl sulfone derivative in the presence of a solvent and a base. [Chemistry 162] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0115] (Project A26) The method comprises the compound of item A25, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the method further includes step J as shown below: Step J: Compounds of formula (10): [Chemistry 163] Where R 3 R 4 a, b, c, and d are defined as above. The compound of formula (11) is prepared by reacting its pharmaceutically acceptable salt or its solvate with an acid: [Chemistry 164] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0116] (Project A27) The method further comprises step K as shown below: (The compound of item A26, or a pharmaceutically acceptable salt thereof, or a solvate thereof) Step K: Compounds of formula (11): [Chemistry 165] Where a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof or a solvate thereof and a compound of formula (11a): [Chemistry 166] Where X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl, or methanesulfonyl. The compound of formula (12) is prepared by reacting its pharmaceutically acceptable salt or its solvate in the presence of a solvent and a base: [Chemistry 167] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

[0117] (Project A28) The method comprises the compound of item A27, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the method further includes step L as shown below: Step L: Compounds of formula (12): [Chemistry 168] Where a, b, c, and d are defined as above. The compound of formula (12a) is prepared by reacting its pharmaceutically acceptable salt or solvation with L(+)-tartaric acid in the presence of a solvent: [Chemistry 169] Where a, b, c, and d are defined as above. Or its solvates.

[0118] This disclosure considers that one or more of the foregoing features may be provided in explicit combinations as well as further combinations beyond the explicit combinations. Further embodiments and advantages of this disclosure will be understood by those skilled in the art upon reading and understanding the following detailed description, if necessary.

[0119] Invention Effects In one embodiment, according to method 1 of this disclosure, intermediate (8) can be prepared in high yield and with high purity, with fewer protection and deprotection steps than known methods. Furthermore, an optically active azabicyclic derivative (12) suitable for use as a pharmaceutical can be prepared from intermediate (8) in high yield and with high purity in only 4 steps.

[0120] In one embodiment, according to method 2 of this disclosure, intermediate (8) can be prepared using intermediate (2a) in fewer steps than in method 1, and an optically active azabicyclic derivative (12) suitable for use as a drug can be prepared from intermediate (8) in high yield and high purity in only 4 steps.

[0121] Description of the implementation plan The present disclosure is described below, showing the best mode of implementation. It should be understood that, unless otherwise stated, the singular expressions throughout this specification also include plural concepts. Therefore, unless otherwise stated, singular articles (e.g., "a," "an," "the," etc. in the English language) should also be understood to include their plural forms. Furthermore, it should be understood that, unless otherwise stated, the terms used in this specification have meanings commonly used in the relevant art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In case of conflict, this specification (including definitions) shall prevail.

[0122] The compounds disclosed herein may also exist as solvates (e.g., hydrates), and therefore the compounds of formulas (1), (1a), (2), (2a), (3), (4), (5), (6), (7), (8), (8a), (9), (10), (11), (11a), (12), (12a), (13), (14), (15) and (16), or their tautomers or optionally pharmaceutically acceptable salts of solvates (e.g., hydrates) are also included in the compounds disclosed herein.

[0123] Compounds of formulas (1), (1a), (2), (2a), (3), (4), (5), (6), (7), (8), (8a), (9), (10), (11), (11a), (12), (12a), (13), (14), (15), and (16) may have one or more asymmetric carbon atoms, or may exhibit geometric isomerism or axial chirality, i.e., they may exist as a variety of stereoisomers. In this disclosure, these stereoisomers, mixtures thereof, and racemates thereof are also included in the compounds of this disclosure.

[0124] Furthermore, compounds of formulas (1), (1a), (2), (2a), (3), (4), (5), (6), (7), (8), (8a), (9), (10), (11), (11a), (12), (12a), (13), (14), (15) and (16), one or more of which 1 H (hydrogen) is 2 H (D: deuterated hydrogen) substitution is also included in compounds of formulas (1), (1a), (2), (2a), (3), (4), (5), (6), (7), (8), (8a), (9), (10), (11), (11a), (12), (12a), (13), (14), (15) and (16).

[0125] The crystals of compounds of formulas (1), (1a), (2), (2a), (3), (4), (5), (6), (7), (8), (8a), (9), (10), (11), (11a), (12), (12a), (13), (14), (15) and (16), or their tautomers or optionally their pharmaceutically acceptable salts, may have crystalline polymorphs, which are also included in the compounds disclosed herein.

[0126] In this disclosure, the number of carbon atoms in the definition of "substituent" can be expressed as, for example, "C". 1-6 Specifically, the expression "C" 1-6 "Alkyl" has the same meaning as alkyl having 1 to 6 carbon atoms. Furthermore, substituents not explicitly accompanied by the terms "may be substituted," "optionally substituted," or "substituted" in this disclosure refer to "unsubstituted" substituents. For example, "C..." 1-6 "alkyl" indicates "unsubstituted" C 1-6 alkyl.

[0127] In this disclosure, the term "group" refers to a monovalent group. For example, "alkyl group" refers to a monovalent saturated hydrocarbon group. Furthermore, the term "group" may be omitted in the description of substituents in this disclosure.

[0128] The terms used in this article are explained below.

[0129] In this disclosure, there is no particular limitation on the number of substituents in a group defined by "may be substituted," "optionally substituted," or "substituted," as long as it can be substituted, including 0, 1, or more. Furthermore, unless otherwise stated, the definitions of each group also apply to cases where the group is used as part of another group or as a substituent.

[0130] In this disclosure, the substituent in "optionally substituted..." can be appropriately selected according to the group to be substituted. For example, "optionally substituted C..." 1-6 "alkyl" indicates a C-aryl group that is optionally substituted at any substituted position with a fluorine atom, a chlorine atom, a phenyl group, a methoxy group, and / or a hydroxyl group. 1-6 Alkyl groups, including methyl, ethyl, n-propyl and isopropyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-methoxyethyl and benzyl. Preferably, it is methyl, ethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-methoxyethyl or benzyl.

[0131] The "C" 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and "C6 alkyl" refers to an alkyl group having 6 carbon atoms. The same applies to other numbers of carbon atoms. The "C"... 1-6 "alkyl" preferably includes "C" 1-4 "alkyl", more preferably including "C" 1-3 Alkyl group. The "C" 1-3 "alkyl" includes, for example, methyl, ethyl, propyl, and 1-methylethyl. Except for the "C"... 1-3 In addition to the examples listed in "alkyl", "C" 1-4 "alkyl" also includes, for example, butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. In addition to the aforementioned "C 1-4 In addition to the examples listed in "alkyl", "C" 1-6 "Alkyl" also includes, for example, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, etc.

[0132] The "C" 6-10 "Aryl" indicates an aromatic hydrocarbon cyclic group having 6 to 10 carbon atoms. The "C"... 6-10 "Aryl" includes, for example, phenyl, 1-naphthyl and 2-naphthyl.

[0133] In the reaction disclosed herein, a phase transfer catalyst, such as a tetrabutylammonium salt, may be added if necessary, provided that it does not adversely affect the reaction.

[0134] The term "alkali" includes both organic and inorganic alkalis.

[0135] The “organic base” includes, for example, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, triethylamine, N,N,N',N'-tetramethylethane-1,2-diamine, N,N-dimethylaniline, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylpiperidine, piperidine, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]-5-nonene, 1,8-diazabicyclo[5.4.0]-7-undecene, N-methylmorpholine, diazabicycloundecene, methylamine, ethylamine, diisopropylamine, 4-dimethylaminopyridine, 2,6-dimethylpyridine, pyrimidine and pyridine, or mixtures thereof, but is not limited thereto. More preferably, it comprises sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N,N,N',N'-tetramethylethane-1,2-diamine, 1,4-diazabicyclo[2.2.2]octane, N-methylpiperidine, pyrimidine, and pyridine. Even more preferably, it comprises sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N,N,N',N'-tetramethylethane-1,2-diamine, 1,4-diazabicyclo[2.2.2]octane, N-methylpiperidine, pyrimidine, and pyridine. Most preferably, it comprises sodium tert-butoxide, potassium tert-butoxide, triethylamine, and N,N-diisopropylethylamine.

[0136] The "inorganic base" includes, for example, ammonia, lithium hydroxide, sodium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and cesium carbonate, or mixtures thereof, but is not limited thereto. Preferably, it includes lithium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and cesium carbonate. More preferably, it includes sodium carbonate, potassium carbonate, sodium bicarbonate, and cesium carbonate. Most preferably, it includes potassium carbonate.

[0137] The term "acid" includes both organic and inorganic acids.

[0138] The term "organic acid" includes organic acids and Lewis acids, such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, trichloroacetic acid, dichloroacetic acid, difluoroacetic acid, citric acid, oxalic acid, tartaric acid, 1,1'-bi(2-naphthol), 1,1'-binaphthyl-2,2'-hydrogen phosphate diester, 3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-hydrogen phosphate diester, 3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-hydrogen phosphate diester, boron trifluoride-diethyl ether complex, trimethylchlorosilane, diethylaluminum chloride, zinc bromide, titanium tetrachloride, and magnesium bromide in diethyl ether, or mixtures thereof, but is not limited thereto. More preferably, it includes trifluoroacetic acid and boron trifluoride-diethyl ether complex, or mixtures thereof.

[0139] The “inorganic acid” includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, and sulfuric acid, or mixtures thereof, but is not limited thereto. Preferably, it includes hydrochloric acid.

[0140] The term "alcohol solvent" refers to a solvent that is a compound containing one or more hydroxyl groups in its molecule, is liquid at the reaction temperature, and has the property of dissolving or dispersing the reaction substrate.

[0141] The "alcohol solvent" includes, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, and tert-butanol. Preferably, it includes methanol, ethanol, and 2-propanol. More preferably, it includes ethanol.

[0142] The term "amide solvent" refers to a solvent that is a compound containing one or more amide bonds in its molecule, is liquid at the reaction temperature, and has the property of dissolving or dispersing the reaction substrate. The "amide solvent" includes, for example, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-diethylformamide, N-methyl-2-pyrrolidone, tetramethylurea, and hexamethylphosphoric triamine. The "amide solvent" preferably includes N,N-dimethylformamide and N-methyl-2-pyrrolidone. More preferably, it includes N,N-dimethylformamide.

[0143] The term "halogen solvent" refers to a solvent that is a compound containing one or more halogen atoms in its molecule, is liquid at the reaction temperature, and has the property of dissolving or dispersing the reaction substrate. The "halogen solvent" includes, for example, dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene. The "halogen solvent" preferably includes dichloromethane.

[0144] The term "ether solvent" refers to a solvent that is a compound containing one or more ether bonds in its molecule, is liquid at the reaction temperature, and has the property of dissolving or dispersing the reaction substrate. Ether solvents include, for example, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, and 1,4-dioxane. Preferably, the ether solvent includes tetrahydrofuran, methyl tert-butyl ether, and 1,4-dioxane.

[0145] The term "ester solvent" refers to a solvent that is a compound containing one or more ester bonds in its molecule, is liquid at the reaction temperature, and has the property of dissolving or dispersing the reaction substrate. Ester solvents include, for example, ethyl acetate and isopropyl acetate. Ethyl acetate is preferred as an ester solvent.

[0146] The "protecting group of amino group" includes, for example Protective Groups in Organic Synthesis The protecting group described in (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999). The "protecting group of the amino group" includes, for example, tert-butyloxycarbonyl and benzyloxycarbonyl. Preferably, it includes tert-butyloxycarbonyl.

[0147] The term "amino protecting agent" refers to a reagent used to protect amino groups. The "amino protecting agent" includes, for example, di-tert-butyl dicarbonate and benzyl chloroformate. Preferably, it includes di-tert-butyl dicarbonate.

[0148] The term "condensing agent" refers to a reagent that condenses a carboxyl group and an amino group to form an amide group through a dehydration reaction. The "condensing agent" includes, for example, 1-hydroxybenzotriazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and mixtures thereof, but is not limited thereto. The "condensing agent" preferably comprises a mixture of 1-hydroxybenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0149] The "halomethyltriphenylphosphonium" includes, for example, methyltriphenylphosphonium bromide and methyltriphenylphosphonium iodide. The "halomethyltriphenylphosphonium" preferably includes methyltriphenylphosphonium bromide.

[0150] The "trialkylsilylmethyl anion" includes, for example, (trimethylsilyl)methyllithium and (trimethylsilyl)methylmagnesium. The "(trialkylsilyl)methyllithium" preferably includes (trimethylsilyl)methyllithium.

[0151] The “methyl sulfone derivative” includes, for example, 1-methyl-2-(methylsulfonyl)benzimidazole and 2-(methylsulfonyl)benzothiazole. The “methyl sulfone derivative” preferably includes 1-methyl-2-(methylsulfonyl)benzimidazole.

[0152] The "peroxide" includes, for example, hydrogen peroxide, cumene hydroperoxide, benzoyl peroxide, peracetic acid, and sodium perborate, including their hydrates. The "peroxide" preferably includes hydrogen peroxide and sodium perborate, including their hydrates. The "peroxide" more preferably includes sodium perborate, including its hydrate.

[0153] The term "borane" includes, for example, borane and 9-boranebicyclo[3.3.1]nonane, as well as those dimers and those complexes with solvents. The term "borane" preferably includes borane and borane-tetrahydrofuran complexes.

[0154] The "oxidizing agent" includes, for example, 1-methyl-2-azaadamantane-N-oxy, 2-hydroxy-2-azaadamantane, 9-azanoradamantane-N-oxy, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoyl-3-(1H)-one, potassium 2-iodo-5-methylbenzenesulfonate, a combination of DMSO and oxalyl chloride, acetic anhydride, sulfur trioxide-pyridine complex, N,N'-dicyclohexylcarbodiimide, chromium trioxide, tetrapropylammonium perruthenate, sodium hypochlorite pentahydrate, or 2,2,6,6-tetramethylpiperidine-1-oxy and sodium periodate. The "oxidizing agent" preferably includes 2,2,6,6-tetramethylpiperidine-1-oxy and sodium periodate, more preferably 2,2,6,6-tetramethylpiperidine-1-oxy.

[0155] The "re-oxidizing agent" includes, for example, oxygen, potassium persulfate complex salt, morpholine N-oxide, trichloroisocyanuric acid, sodium hypochlorite, and iodophenyldiacetic acid. The "re-oxidizing agent" preferably includes trichloroisocyanuric acid.

[0156] In this disclosure, the term "at least one selected independently from..." in the description of solvents, etc., means that when two or more of these options are selected, the two or more options include mixtures thereof.

[0157] As used herein, unless otherwise stated, the term "pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically acceptable acid, including both inorganic and organic acids. Furthermore, "optionally, its pharmaceutically acceptable salt" means that it may be a pharmaceutically acceptable salt at an optional time, such as in the preparation of an intermediate, indicating that a pharmaceutically unacceptable salt may be used up to a certain step. Pharmaceutically acceptable salts include, for example, acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, vinylsulfonic acid, formic acid, fumaric acid, furanoic acid, gluconic acid, glutamic acid, glucuronic acid, galacturonic acid, glycidic acid, hydrobromic acid, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, pyruvic acid, pantothenic acid, phenylacetic acid, propionic acid, phosphoric acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid, but are not limited thereto.

[0158] "Purification" refers to any operation that increases the purity of a desired substance and reduces the concentration of substances other than the desired substance to a level lower than that prior to purification. Purification can be accomplished using various methods, such as precipitation, recrystallization, sublimation, distillation, solvent extraction, the use of molecular sieves, and the application of various chromatographic methods. Purification does not include filtration using filter paper, diatomaceous earth, etc.

[0159] Among the compounds of formulas (1), (1a), (2), (2a), (3), (4), (5), (7), (8), (8a), (9), (10), (11), (11a), (12), (12a), (13), (14), (15) and (16) disclosed herein, preferred R 1 R 1A R 2 R 3 R 4 R 5a R 5b R 5c The implementation schemes for a, b, c, and d are as follows, but are not limited to these.

[0160] Preferred R 1 The implementation plan includes C 1-3 alkyl.

[0161] More preferred R 1 The implementation plan includes methyl.

[0162] Preferred R 1A The implementation plan includes C 6-10 Aryl.

[0163] More preferred R 1A The implementation plan includes phenyl.

[0164] Preferred R 2 The implementation plan includes C 1-3 alkyl.

[0165] More preferred R 2 The implementation scheme includes ethyl.

[0166] Preferred R 3 The implementation scheme includes tert-butyloxycarbonyl and benzyloxycarbonyl.

[0167] More preferred R 3 The implementation scheme includes tert-butyloxycarbonyl.

[0168] Preferred R 4 The implementation scheme includes tert-butyloxycarbonyl and benzyloxycarbonyl.

[0169] More preferred R 4 The implementation scheme includes tert-butyloxycarbonyl.

[0170] Preferred R 5a R 5b and R 5c The implementation plan independently includes C 1-4 Alkyl and phenyl.

[0171] More preferred R 5a R5b and R 5c The implementation scheme independently includes methyl and phenyl.

[0172] Even better R 5a R 5b and R 5c The implementation plan includes methyl.

[0173] The preferred implementations of a, b, c, and d independently include 1 and 2.

[0174] The preferred embodiments of a and c independently include 1 and 2.

[0175] More preferred embodiments of a and c include 1.

[0176] The preferred implementations of b and d independently include 1 and 2.

[0177] More preferred embodiments of b and d include 2.

[0178] Preferred embodiments of X include fluorine, chlorine, bromine, iodine, p-toluenesulfonyl, and methanesulfonyl.

[0179] A more preferred embodiment of X includes chlorine, bromine, and p-toluenesulfonyl.

[0180] A further preferred embodiment of X includes chlorine.

[0181] The compounds of formula (1) include the following (1-A).

[0182] (1-A) The compound of formula (1), wherein R 1 C 1-3 Alkyl, and R 1A C 6-10 Aryl, Or its pharmaceutically acceptable salt, or its solvate.

[0183] Preferred embodiments of the compound of formula (1) include the following (1-B).

[0184] (1-B) The compound of formula (1), wherein R 1 It is methyl, and R 1A It is a phenyl group. Or its pharmaceutically acceptable salt, or its solvate.

[0185] The compounds of formula (1a) include the following (1a-A).

[0186] (1a-A) The compound of formula (1a), wherein R 2 C 1-3 alkyl, Or its pharmaceutically acceptable salt, or its solvate.

[0187] Preferred embodiments of the compound of formula (1a) include the following (1a-B).

[0188] (1a-B) The compound of formula (1a), wherein R 2 It is ethyl. Or its pharmaceutically acceptable salt, or its solvate.

[0189] The compounds of formula (2) include the following (2-A).

[0190] (2-A) The compound of formula (2), wherein R 1 and R 2 Independently for C 1-3 Alkyl, and R 1A C 6-10 Aryl, Or its pharmaceutically acceptable salt, or its solvate.

[0191] The preferred embodiments of the compound of formula (2) include the following (2-B).

[0192] (2-B) The compound of formula (2), wherein R 1 It is methyl. R 2 It is ethyl, and R 1A It is a phenyl group. Or its pharmaceutically acceptable salt, or its solvate.

[0193] The compounds of formula (2a) include the following (2a-A).

[0194] (2a-A) The compound of formula (2a), wherein R 5a R 5b and R 5c Independently for C 1-4 Alkyl or phenyl, Or its pharmaceutically acceptable salt, or its solvate.

[0195] Preferred embodiments of the compound of formula (2a) include the following (2a-B).

[0196] (2a-B) The compound of formula (2a), wherein R 5a R 5b and R 5c It is methyl. Or its pharmaceutically acceptable salt, or its solvate.

[0197] The compounds of formula (3) include the following (3-A).

[0198] (3-A) The compound of formula (3), wherein R 1 and R 2 Independently for C 1-3 Alkyl, and R 1A C 6-10 Aryl, Or its pharmaceutically acceptable salt, or its solvate.

[0199] The preferred embodiments of the compound of formula (3) include the following (3-B).

[0200] (3-B) The compound of formula (3), wherein R 1 It is methyl. R 2 It is ethyl, and R 1A It is a phenyl group. Or its pharmaceutically acceptable salt, or its solvate.

[0201] The compounds of formula (4) include the following (4-A).

[0202] (4-A) The compound of formula (4), wherein R 1 and R 2 Independently for C 1-3 Alkyl, and R 1A C 6-10 Aryl, Or its pharmaceutically acceptable salt, or its solvate.

[0203] The preferred embodiments of the compound of formula (4) include the following (4-B).

[0204] (4-B) The compound of formula (4), wherein R 1 It is methyl. R 2 It is ethyl, and R 1A It is a phenyl group. Or its pharmaceutically acceptable salt, or its solvate.

[0205] The compounds of formula (5) include the following (5-A).

[0206] (5-A) The compound of formula (5), wherein R 2 C 1-3 alkyl, Or its pharmaceutically acceptable salt, or its solvate.

[0207] The preferred embodiments of the compound of formula (5) include the following (5-B).

[0208] (5-B) The compound of formula (5), wherein R 2 It is ethyl. Or its pharmaceutically acceptable salt, or its solvate.

[0209] The compounds of formula (7) include the following (7-A).

[0210] (7-A) The compound of formula (7), wherein R 3 It is tert-butyloxycarbonyl. Or its pharmaceutically acceptable salt, or its solvate.

[0211] The compounds of formula (8) include the following (8-A).

[0212] (8-A) The compound of formula (8), wherein R 3 It is tert-butyloxycarbonyl. Or its pharmaceutically acceptable salt, or its solvate.

[0213] The compounds of formula (8a) include the following (8a-A).

[0214] (8a-A) The compound of formula (8a), wherein a, b, c, and d are independently 1 or 2, and R 4 It is tert-butyloxycarbonyl. Or its pharmaceutically acceptable salt, or its solvate.

[0215] Preferred embodiments of the compound of formula (8a) include the following (8a-B).

[0216] (8a-B) The compound of formula (8a), wherein a and c are both 1. b and d are 2, and R 4 It is tert-butyloxycarbonyl. Or its pharmaceutically acceptable salt, or its solvate.

[0217] The compounds of formula (9) include the following (9-A).

[0218] (9-A) The compound of formula (9), wherein a, b, c, and d are independently 1 or 2, and R 3 and R 4 It is tert-butyloxycarbonyl. Or its pharmaceutically acceptable salt, or its solvate.

[0219] The preferred embodiments of the compound of formula (9) include the following (9-B).

[0220] (9-B) The compound of formula (9), wherein a and c are both 1. b and d are 2, and R 3 and R 4 It is tert-butyloxycarbonyl. Or its pharmaceutically acceptable salt, or its solvate.

[0221] The compounds of formula (10) include the following (10-A).

[0222] (10-A) The compound of formula (10), wherein a, b, c, and d are independently 1 or 2, and R 3 and R 4 It is tert-butyloxycarbonyl. Or its pharmaceutically acceptable salt, or its solvate.

[0223] Preferred embodiments of the compound of formula (10) include the following (10-B).

[0224] (10-B) The compound of formula (10), wherein a and c are both 1. b and d are 2, and R 3 and R 4 It is tert-butyloxycarbonyl. Or its pharmaceutically acceptable salt, or its solvate.

[0225] The compounds of formula (11) include the following (11-A).

[0226] (11-A) The compound of formula (11), wherein a, b, c, and d are independently 1 or 2. Or its pharmaceutically acceptable salt, or its solvate.

[0227] Preferred embodiments of the compound of formula (11) include the following (11-B).

[0228] (11-B) The compound of formula (11), wherein a and c are both 1, and b and d are both 2. Or its pharmaceutically acceptable salt, or its solvate.

[0229] The compounds of formula (11a) include the following (11a-A).

[0230] (11a-A) The compound of formula (11a), wherein X is chlorine, bromine, or p-toluenesulfonyl. Or its pharmaceutically acceptable salt, or its solvate.

[0231] Preferred embodiments of the compound of formula (11a) include the following (11a-B).

[0232] (11a-B) The compound of formula (11a), wherein X is chlorine. Or its pharmaceutically acceptable salt, or its solvate.

[0233] The compounds of formula (12) include the following (12-A).

[0234] (12-A) The compound of formula (12), wherein a, b, c, and d are independently 1 or 2. Or its pharmaceutically acceptable salt, or its solvate.

[0235] Preferred embodiments of the compound of formula (12) include the following (12-B).

[0236] (12-B) The compound of formula (12), wherein a and c are both 1, and b and d are both 2. Or its pharmaceutically acceptable salt, or its solvate.

[0237] The compounds of formula (12a) include the following (12a-A).

[0238] (12a-A) The compound of formula (12a), wherein a, b, c, and d are independently 1 or 2. Or its pharmaceutically acceptable salt, or its solvate.

[0239] Preferred embodiments of the compound of formula (12a) include the following (12a-B).

[0240] (12a-B) The compound of formula (12a), wherein a and c are both 1, and b and d are both 2. Or its pharmaceutically acceptable salt, or its solvate.

[0241] The compounds of formula (13) include the following (13-A).

[0242] (13-A) The compound of formula (13), wherein R 1 C 1-3 alkyl, R 1A C 6-10 Aryl, and R 5a R 5b and R 5c Independently for C 1-4 alkyl, Or its pharmaceutically acceptable salt, or its solvate.

[0243] Preferred embodiments of the compound of formula (13) include the following (13-B).

[0244] (13-B) The compound of formula (13), wherein R 1 It is methyl. R 1A It is phenyl, and R 5a R 5b and R 5cIt is methyl. Or its pharmaceutically acceptable salt, or its solvate.

[0245] The compounds of formula (14) include the following (14-A).

[0246] (14-A) The compound of formula (14), wherein R 1 and R 2 Independently for C 1-3 Alkyl, and R 1A C 6-10 Aryl, Or its pharmaceutically acceptable salt, or its solvate.

[0247] Preferred embodiments of the compound of formula (14) include the following (14-B).

[0248] (14-B) The compound of formula (14), wherein R 1 It is methyl. R 2 It is ethyl, and R 1A It is a phenyl group. Or its pharmaceutically acceptable salt, or its solvate.

[0249] The compounds of formula (15) include the following (15-A).

[0250] (15-A) The compound of formula (15), wherein R 2 C 1-3 alkyl, Or its pharmaceutically acceptable salt, or its solvate.

[0251] Preferred embodiments of the compound of formula (15) include the following (15-B).

[0252] (15-B) The compound of formula (15), wherein R 2 It is ethyl. Or its pharmaceutically acceptable salt, or its solvate.

[0253] The compounds of formula (16) include the following (16-A).

[0254] (16-A) The compound of formula (16), wherein R 2 C1-3 Alkyl, and R 3 It is tert-butyloxycarbonyl. Or its pharmaceutically acceptable salt, or its solvate.

[0255] Preferred embodiments of the compound of formula (16) include the following (16-B).

[0256] (16-B) The compound of formula (16), wherein R 2 It is ethyl, and R 3 It is tert-butyloxycarbonyl. Or its pharmaceutically acceptable salt, or its solvate.

[0257] The invention will now be described in further detail with reference to preferred embodiments, but the scope of the invention is not limited to these preferred embodiments. Modifications may be made to the following without departing from the scope of this disclosure. The compound names given in the following preferred embodiments do not necessarily follow IUPAC nomenclature.

[0258] The following describes methods for preparing the disclosed compounds (1), (1a), (2), (2a), (3), (4), (5), (6), (7), (8), (8a), (9), (10), (11), (11a), (12), (12a), (13), (14), (15), and (16), or their tautomers, stereoisomers, mixtures thereof, racemic mixtures thereof, or optionally pharmaceutically acceptable salts or solvates thereof, which are used as intermediates in the preparation of optically active azabicyclic derivatives (formula (12)). Optically active azabicyclic derivatives of formula (12) and their intermediates can be prepared from known compounds by the methods described below or similar methods, or by synthetic methods known to those skilled in the art. They can be prepared by appropriate combinations of methods.

[0259] Furthermore, the compounds obtained in each step can be used as reaction solutions or as reaction compositions for the next reaction, but they can also be separated from the reaction mixture using conventional methods and can be easily purified by separation methods such as recrystallization, distillation, and chromatography.

[0260] Unless otherwise stated, each symbol of the compounds in the following reactions has the same meaning as described above.

[0261] The manufacturing method of the present invention is described below. Starting materials not described below are commercially available or can be prepared by methods known to or based on those skilled in the art.

[0262] (Method 1) [Chemistry 170] (Method 2) [Chemistry 171] Where R 1 R 1A R 2 R 3 R 4 R 5a R 5b R 5c a, b, c, and d are as defined in Project 1 and / or other projects.

[0263] Steps A, B, C, D, E, F, G, H, K, I, L, M, N, O, P and Q are described below with reference to preferred embodiments, but this disclosure is limited thereto.

[0264] Step A [Chemistry 172] Among them, R 1 R 1A and R 2 As defined in Project 1 and / or other projects.

[0265] This step is to obtain the compound of formula (2) by reacting the compound of formula (1) with the compound of formula (1a) in a solvent.

[0266] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include halogen solvents, preferably dichloromethane, chloroform, 1,2-dichloroethane and chlorobenzene, and more preferably dichloromethane.

[0267] The amount of solvent used in this article is typically 2 to 20 parts by weight of the compound of formula (1), preferably 5 to 20 parts by weight, and more preferably 8 to 15 parts by weight.

[0268] The amount of compound of formula (1a) used is typically 1.0 eq - 10.0 eq, preferably 1.0 eq - 5.0 eq, more preferably 1.0 eq - 2.0 eq, and most preferably 1.0 eq - 1.2 eq, relative to 1 eq of the compound of formula (1).

[0269] The reaction time is typically from about 0.5 hours to 12 hours, preferably from 0.5 hours to 8 hours.

[0270] The reaction temperature is typically from -30°C to 120°C, preferably from -30°C to 130°C, more preferably from -30°C to 50°C, and even more preferably from -20°C to 30°C.

[0271] As an additive to accelerate the reaction, a desiccant may be added, and its amount is preferably from 1.0 to 5.0 parts by weight based on the weight of the compound of formula (1a). The desiccant includes sodium sulfate, magnesium sulfate, and molecular sieves, more preferably sodium sulfate.

[0272] R 1 and R 2 The preferred option is as defined above.

[0273] Compounds of formula (1a) can be used instead of compounds of formula (1a) obtained by the following methods: compounds of formula (1a-B) and formula (1a-C).

[0274] [Chemistry 173] Where R 2 As defined in Project 1 and / or other projects.

[0275] This step involves oxidizing the compound of formula (1a-A) in a solvent to obtain compounds of formula (1a-B) and (1a-C).

[0276] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include halogen solvents and mixtures of halogen solvents and water, preferably dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, and any mixture of halogen solvents and water, more preferably dichloromethane and mixtures of dichloromethane and water.

[0277] The oxidants used in this article include 2,2,6,6-tetramethylpiperidine-1-oxy, 1-methyl-2-azaadamantane-N-oxy, 2-hydroxy-2-azaadamantane, 9-azanoradamantane-N-oxy, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzyl-3(1H)-one, potassium 2-iodo-5-methylbenzenesulfonate, a mixture of DMSO and oxalyl chloride, acetic anhydride, sulfur trioxide-pyridine complex, N,N'-dicyclohexylcarbodiimide, chromium trioxide, tetrapropylammonium perruthenate, sodium hypochlorite pentahydrate, and sodium periodate, preferably sodium periodate.

[0278] The amount of solvent used in this document is typically 2 to 20 parts by weight of the compound of formula (1a-A), preferably 5 to 20 parts by weight, and more preferably 8 to 15 parts by weight.

[0279] The amount of oxidant used herein is typically 1.0 eq - 5.0 eq, preferably 1.0 eq - 2.0 eq, and more preferably 1.0 eq - 1.5 eq, relative to 1 eq of the compound of formula (1a-A).

[0280] The reaction time is typically from about 1 hour to 48 hours, preferably from 5 hours to 36 hours, and more preferably from 12 hours to 24 hours.

[0281] The reaction temperature is typically from 0°C to 50°C, preferably from 5°C to 40°C, and more preferably from 10°C to 30°C.

[0282] R 2 The preferred option is as defined above.

[0283] Step B [Chemistry 174] Among them, R 1 R 1A and R 2 As defined in Project 1 and / or other projects.

[0284] This step is to obtain the compound of formula (3) by reacting the compound of formula (2) with 1,3-cyclohexadiene in the presence of a solvent and an acid.

[0285] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include halogen solvents, preferably dichloromethane, chloroform, 1,2-dichloroethane and chlorobenzene, and more preferably dichloromethane.

[0286] The acids used in this article include organic acids, preferably trifluoroacetic acid, boron trifluoride-diethyl ether complex and mixtures thereof, more preferably a mixture of trifluoroacetic acid and boron trifluoride-diethyl ether complex.

[0287] The amount of solvent used in this article is typically 2 to 20 parts by weight of the compound of formula (2), preferably 3 to 10 parts by weight, and more preferably 4 to 8 parts by weight.

[0288] The amount of 1,3-cyclohexadiene used herein is typically 1.0 eq to 10.0 eq, preferably 1.0 eq to 5.0 eq, more preferably 1.0 eq to 2.0 eq, and most preferably 1.0 eq to 1.6 eq, relative to the compound of formula (2) of 1 eq.

[0289] The amount of acid used herein is typically 0.3 eq - 3.0 eq, preferably 0.5 eq - 2.0 eq, more preferably 0.5 eq - 1.5 eq, and most preferably 0.8 eq - 1.2 eq, relative to the compound of formula (2) of 1 eq.

[0290] The reaction time is typically from about 0.5 hours to 24 hours, preferably from 5 hours to 20 hours.

[0291] The reaction temperature is typically -80°C to 60°C, preferably -70°C to 50°C, and more preferably -70°C to 30°C.

[0292] R 1 and R 2 The preferred option is as defined above.

[0293] Step C [Chemistry 175] Where R 1 R 1A and R 2 As defined in Project 1 and / or other projects.

[0294] This step involves reacting the compound of formula (3) with borane in the presence of a solvent, followed by reaction with a peroxide and a base to obtain the compound of formula (4).

[0295] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include ether solvents, preferably diethyl ether, tetrahydrofuran and methyl tert-butyl ether, and more preferably methyl tert-butyl ether.

[0296] The boranes used in this document include boranes and 9-boronadicyclo[3.3.1]nonane, which include dimers and their complexes with solvents, preferably borane-tetrahydrofuran complexes.

[0297] The bases used in this article include inorganic bases, preferably lithium hydroxide, sodium hydroxide, and potassium hydroxide, and more preferably sodium hydroxide.

[0298] The peroxides used herein include hydrogen peroxide, cumene hydroperoxide, benzoyl peroxide, peracetic acid, and sodium perborate, which include their hydrates, preferably hydrogen peroxide and sodium perborate, which include their hydrates, more preferably sodium perborate, which includes its hydrates.

[0299] The amount of solvent used in this article is typically from 1 to 20 parts by weight of the compound of formula (3), preferably from 1 to 10 parts by weight, and more preferably from 1 to 2 parts by weight.

[0300] The amount of borane used herein is typically 1.0 eq - 10.0 eq, preferably 1.0 eq - 5.0 eq, more preferably 1.0 eq - 2.0 eq, and most preferably 1.0 eq - 1.6 eq, relative to 1 eq of the compound of formula (3).

[0301] The amount of peroxide used herein is typically 1.0 eq - 20.0 eq, preferably 1.0 eq - 10.0 eq, and more preferably 1.0 eq - 6.0 eq, relative to 1 eq of the compound of formula (3).

[0302] The reaction time is typically from about 0.5 hours to 24 hours, preferably from 3 hours to 20 hours.

[0303] The reaction temperature is typically -50°C to 50°C, preferably -40°C to 40°C, and more preferably -30°C to 30°C.

[0304] R 1 and R 2 The preferred option is as defined above.

[0305] Step D [Chemistry 176] Among them, R 1 R 1A and R 2 As defined in Project 1 and / or other projects.

[0306] This step is to obtain the compound of formula (5) by reacting the compound of formula (4) with hydrogen in the presence of a solvent and a catalyst.

[0307] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include alcohol solvents, preferably ethanol and methanol, and more preferably methanol.

[0308] The catalysts used in this paper preferably include Pd / C.

[0309] The amount of solvent used in this article is typically 2 to 20 parts by weight of the compound of formula (4), preferably 2 to 10 parts by weight, and more preferably 2 to 5 parts by weight.

[0310] The amount of catalyst used herein is typically from 1.0 to 30.0 parts by weight of the compound of formula (4), preferably from 5.0 to 20.0 parts by weight, and more preferably from 7.0 to 15.0 parts by weight.

[0311] The reaction time is typically from about 0.5 hours to 48 hours, preferably from 12 hours to 30 hours.

[0312] The reaction temperature is typically between 0°C and 60°C, preferably between 10°C and 50°C, and more preferably between 15°C and 40°C.

[0313] R 1 and R 2 The preferred option is as defined above.

[0314] Step E [Chemistry 177] Where R 2 As defined in Project 1 and / or other projects.

[0315] This step is to obtain the compound of formula (6) by reacting the compound of formula (5) with a base in the presence of a solvent.

[0316] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include ether solvents, preferably tetrahydrofuran and 1,4-dioxane, more preferably dioxane.

[0317] The bases used in this article are preferably sodium hydroxide and potassium hydroxide, more preferably sodium hydroxide. The bases can be used in the form of their aqueous solutions.

[0318] The amount of solvent used in this article is typically 2 to 20 parts by weight of the compound of formula (5), preferably 5 to 15 parts by weight, and more preferably 8 to 15 parts by weight.

[0319] The amount of base used herein is typically 1.0 eq - 3.0 eq, preferably 1.0 eq - 2.0 eq, and more preferably 1.0 eq - 1.5 eq, relative to 1 eq of the compound of formula (5).

[0320] The reaction time is typically from about 0.5 hours to 24 hours, preferably from 1 hour to 10 hours, and more preferably from 2 hours to 5 hours.

[0321] The reaction temperature is typically from 0°C to 60°C, preferably from 0°C to 40°C, and more preferably from 5°C to 30°C.

[0322] R 2 The preferred option is as defined above.

[0323] Step F [Chemistry 178] Where R 3 As defined in Project 1 and / or other projects.

[0324] This step is to obtain the compound of formula (7) by reacting the compound of (6) with an amino protecting agent in the presence of a solvent.

[0325] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include ether solvents, preferably tetrahydrofuran and 1,4-dioxane, more preferably dioxane.

[0326] The amino protecting reagents used in this paper are preferably di-tert-butyl dicarbonate or benzyloxycarbonyl chloride, and more preferably di-tert-butyl dicarbonate.

[0327] The amount of solvent used in this article is typically 2 to 20 parts by weight of the compound of formula (6), preferably 5 to 15 parts by weight, and more preferably 8 to 15 parts by weight.

[0328] The amount of amino protecting agent used herein is typically 1.0 eq to 3.0 eq, preferably 1.0 eq to 2.0 eq, and more preferably 1.0 eq to 1.5 eq, relative to 1 eq of the compound of formula (6).

[0329] The reaction time is typically from about 0.5 hours to 48 hours, preferably from 5 hours to 36 hours, and more preferably from 12 hours to 24 hours.

[0330] The reaction temperature is typically -20°C to 50°C, preferably -10°C to 40°C, and more preferably 0°C to 30°C.

[0331] R 3 The preferred option is as defined above.

[0332] Step G [Chemistry 179] Where R 3 As defined in Project 1 and / or other projects.

[0333] This step is to obtain the compound of formula (8) by reacting the compound of formula (7) with an oxidizing agent and a re-oxidizing agent in the presence of a solvent.

[0334] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include ester solvents and halogen solvents, preferably ester solvents, and more preferably ethyl acetate.

[0335] The oxidants used in this article include 2,2,6,6-tetramethylpiperidine-1-oxy, 1-methyl-2-azaadamantane-N-oxy, 2-hydroxy-2-azaadamantane, 9-azanoradamantane-N-oxy, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzyl-3(1H)-one, potassium 2-iodo-5-methylbenzenesulfonate, "a combination of DMSO and oxaloyl chloride", acetic anhydride, sulfur trioxide-pyridine complex, N,N'-dicyclohexylcarbodiimide, chromium trioxide, tetrapropylammonium perruthenate and sodium hypochlorite pentahydrate, preferably 2,2,6,6-tetramethylpiperidine-1-oxy.

[0336] The reoxidants used in this article preferably include trichloroisocyanuric acid, sodium hypochlorite, iodophenylacetic acid, air, oxygen, potassium persulfate complex salt and morpholine N-oxide, and more preferably trichloroisocyanuric acid.

[0337] The amount of solvent used in this article is typically 2 to 80 parts by weight of the compound of formula (7), preferably 10 to 70 parts by weight, and more preferably 20 to 60 parts by weight.

[0338] The amount of oxidant used herein is typically 0.01 eq - 0.2 eq, preferably 0.01 eq - 0.1 eq, and more preferably 0.01 eq - 0.08 eq, relative to 1 eq of the compound of formula (7).

[0339] The amount of reoxidant used herein is typically 0.3 eq - 2.0 eq, preferably 0.3 eq - 1.5 eq, and more preferably 0.3 eq - 1.0 eq, relative to 1 eq of the compound of formula (7).

[0340] The reaction time is typically from about 0.5 hours to 15 hours, preferably from 1 hour to 12 hours, and more preferably from 1 hour to 8 hours.

[0341] The reaction temperature is typically -20°C to 50°C, preferably -10°C to 30°C, and more preferably -10°C to 10°C.

[0342] R 3 The preferred option is as defined above.

[0343] Step H [Chemistry 180] Where a, b, c, d, R 3 and R 4 As defined in Project 1 and / or other projects.

[0344] This step is to obtain the compound of formula (9) by reacting the compound of formula (8) with the compound of formula (8a) in the presence of a solvent, a base and a condensing agent.

[0345] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include amide solvents, preferably N,N-dimethylformamide and N-methyl-2-pyrrolidone, more preferably N,N-dimethylformamide.

[0346] The bases used in this article include organic bases, preferably triethylamine, diisopropylethylamine and pyridine, more preferably triethylamine and N,N-diisopropylethylamine, and most preferably triethylamine.

[0347] The condensing agents used herein include thionyl chloride, diphenyl azidophosphate, propylphosphonic anhydride, 1,1-carbonyldiimidazole, 1H-benzotriazol-1-yloxytripyrrolidone phosphonium hexafluorophosphate, {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethyl}dimethylammonium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethylureon hexafluorophosphate, 1-hydroxyazabenzotriazole, 1-hydroxybenzotriazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, and mixtures thereof, preferably a mixture of 1-hydroxybenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0348] The amount of solvent used in this document is typically 2 to 20 parts by weight of the compound of formula (8), preferably 5 to 15 parts by weight, and more preferably 7 to 12 parts by weight.

[0349] The amount of compound of formula (8a) used is typically 1.0 eq - 10.0 eq, preferably 1.0 eq - 5.0 eq, more preferably 1.0 eq - 2.0 eq, and most preferably 1.0 eq - 1.5 eq, relative to 1 eq of the compound of formula (8).

[0350] The amount of base used herein is typically 1.0 eq - 10.0 eq, preferably 1.0 eq - 5.0 eq, more preferably 1.0 eq - 2.0 eq, and most preferably 1.0 eq - 1.6 eq, relative to 1 eq of the compound of formula (8).

[0351] The amount of condensing agent used herein is typically 1.0 eq - 10.0 eq, preferably 1.0 eq - 5.0 eq, more preferably 1.0 eq - 2.0 eq, and most preferably 1.0 eq - 1.6 eq, relative to 1 eq of the compound of formula (8).

[0352] The reaction time is typically from about 0.5 hours to 24 hours, preferably from 0.5 hours to 5 hours, and more preferably from 0.5 hours to 2 hours.

[0353] The reaction temperature is typically between 0°C and 60°C, preferably between 0°C and 40°C, and more preferably between 10°C and 30°C.

[0354] R 3 and R 4 The preferred option is as defined above.

[0355] Step I [Chemistry 181] Where a, b, c, d, R 3 and R 4 As defined in Project 1 and / or other projects.

[0356] This step is to obtain the compound of formula (10) by reacting the compound of formula (9) with halomethyltriphenylphosphonium in the presence of a solvent and a base.

[0357] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include ether solvents, preferably diethyl ether, tetrahydrofuran and methyl tert-butyl ether, and more preferably tetrahydrofuran.

[0358] The bases used in this article include inorganic bases, preferably sodium tert-butoxide, potassium tert-butoxide, and sodium methoxide, and more preferably sodium tert-butoxide and potassium tert-butoxide.

[0359] The halogenated methyltriphenylphosphonium used in this article includes methyltriphenylphosphonium bromide and methyltriphenylphosphonium iodide, with methyltriphenylphosphonium bromide being preferred.

[0360] The amount of solvent used in this article is typically 2 to 30 parts by weight of the compound of formula (9), preferably 5 to 20 parts by weight, and more preferably 8 to 15 parts by weight.

[0361] The amount of halomethyltriphenylphosphonium used herein is typically 1.0 eq - 10.0 eq, preferably 1.0 eq - 5.0 eq, more preferably 1.0 eq - 3.0 eq, and most preferably 1.5 eq - 2.5 eq, relative to 1 eq of the compound of formula (9).

[0362] The amount of base used herein is typically 1.0 eq - 10.0 eq, preferably 1.0 eq - 5.0 eq, more preferably 1.0 eq - 3.0 eq, and most preferably 1.5 eq - 2.0 eq, relative to 1 eq of the compound of formula (9).

[0363] The reaction time is typically from about 0.5 hours to 24 hours, preferably from 0.5 hours to 6 hours, and more preferably from 1 hour to 3 hours.

[0364] The reaction temperature is typically from 0°C to 100°C, preferably from 10°C to 60°C, and more preferably from 10°C to 40°C.

[0365] R 3 and R 4 The preferred option is as defined above.

[0366] Step J [Chemistry 182] Where a, b, c, d, R 3 and R 4 As defined in Project 1 and / or other projects.

[0367] This step is to obtain the compound of formula (11) by reacting the compound of formula (10) with an acid in the presence of a solvent.

[0368] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include ether solvents, preferably diethyl ether, tetrahydrofuran and methyl tert-butyl ether, and more preferably tetrahydrofuran.

[0369] The acids used in this article preferably include hydrochloric acid, hydrobromic acid, and trifluoroacetic acid, with hydrochloric acid being more preferred.

[0370] The amount of acid used herein is typically 1.0 eq - 20.0 eq, preferably 5.0 eq - 15.0 eq, and more preferably 7.0 eq - 12.0 eq, relative to 1 eq of the compound of formula (10).

[0371] The reaction time is typically from about 0.5 hours to 24 hours, preferably from 0.5 hours to 6 hours, and more preferably from 1 hour to 5 hours.

[0372] The reaction temperature is typically from 0°C to 100°C, preferably from 10°C to 80°C, and more preferably from 20°C to 50°C.

[0373] Step K [Chemistry 183] Where a, b, c, d and X are as defined in Project 1 and / or other projects.

[0374] This step is to obtain the compound of formula (12) by reacting the compound of formula (11) with the compound of formula (11a) in the presence of a solvent and a base.

[0375] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include ether solvents and acetonitrile, with acetonitrile being preferred.

[0376] The bases used in this article include organic bases, preferably triethylamine, diisopropylethylamine and pyridine, more preferably triethylamine and N,N-diisopropylethylamine, and most preferably triethylamine.

[0377] The amount of solvent used herein is typically 2 to 20 parts by weight of the compound of formula (11), preferably 2 to 10 parts by weight, and more preferably 2 to 6 parts by weight.

[0378] The amount of base used herein is typically 1.0 eq - 30.0 eq, preferably 5.0 eq - 25.0 eq, and more preferably 10.0 eq - 20.0 eq, relative to 1 eq of the compound of formula (11).

[0379] The amount of compound of formula (11a) used is typically 0.5 eq - 3.0 eq, preferably 0.6 eq - 1.5 eq, and more preferably 0.6 eq - 1.2 eq, relative to 1 eq of the compound of formula (11).

[0380] The reaction time is typically from about 0.5 hours to 48 hours, preferably from 5 hours to 48 hours, and more preferably from 10 hours to 48 hours.

[0381] The reaction temperature is typically -20°C to 60°C, preferably -10°C to 30°C, and more preferably -5°C to 20°C.

[0382] Step L [Chemistry 184] Where a, b, c, and d are as defined in Project 1 and / or other projects.

[0383] This step is to obtain the compound of formula (12a) by reacting the compound of formula (12) with L(+)-tartaric acid in the presence of a solvent.

[0384] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include alcohol solvents and mixtures of alcohol solvents and water, preferably methanol, ethanol, 2-propanol and any mixture of alcohol and water, and more preferably ethanol and mixtures of ethanol and water.

[0385] The amount of alcohol solvent used in this article is generally 2 to 30 parts by weight based on the weight of the compound of formula (12), preferably 5 to 20 parts by weight, and more preferably 8 to 15 parts by weight.

[0386] The amount of water used in this article is typically 0.01 to 2 parts by weight of the compound of formula (12), preferably 0.05 to 1.5 parts by weight, and more preferably 0.05 to 1 part by weight.

[0387] The amount of L(+)-tartaric acid used herein is typically 0.5 eq to 2.0 eq, preferably 0.7 eq to 1.5 eq, and more preferably 1.0 eq to 1.5 eq, relative to the compound of formula (12) of 1 eq.

[0388] The reaction time is typically from about 0.5 hours to 5 hours, preferably from 0.5 hours to 3 hours, and more preferably from 0.5 hours to 2 hours.

[0389] The reaction temperature is typically between 0°C and 80°C, preferably between 20°C and 70°C, and more preferably between 40°C and 70°C.

[0390] Step M [Chemistry 185] Where R 1 R 2 R 5a R 5b and R 5c As defined in Project 1 and / or other projects.

[0391] This step is to obtain the compound of formula (13) by reacting the compound of formula (2) with the compound of formula (2a) in the presence of a solvent and an acid.

[0392] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include halogen solvents, preferably dichloromethane, chloroform, 1,2-dichloroethane and chlorobenzene, and more preferably dichloromethane.

[0393] The acids used in this article include organic acids, preferably trifluoroacetic acid, boron trifluoride-diethyl ether complex and mixtures thereof, more preferably a mixture of trifluoroacetic acid and boron trifluoride-diethyl ether complex.

[0394] The amount of solvent used in this article is typically 2 to 20 parts by weight of the compound of formula (2), preferably 3 to 10 parts by weight, and more preferably 3 to 8 parts by weight.

[0395] The amount of compound of formula (2a) used is typically 1.0 eq - 10.0 eq, preferably 1.0 eq - 5.0 eq, more preferably 1.0 eq - 2.0 eq, and most preferably 1.0 eq - 1.5 eq, relative to 1 eq of the compound of formula (2).

[0396] The amount of acid used herein is typically 1.0 eq - 10.0 eq, preferably 1.0 eq - 5.0 eq, more preferably 1.0 eq - 2.0 eq, and most preferably 1.0 eq - 1.5 eq, relative to 1 eq of the compound of formula (2).

[0397] The reaction time is typically from about 0.5 hours to 24 hours, preferably from 0.5 hours to 10 hours, and more preferably from 0.5 hours to 5 hours.

[0398] The reaction temperature is typically -100°C to 30°C, preferably -90°C to 20°C, and more preferably -80°C to 10°C.

[0399] R 1 R 2 R 5a R 5b and R 5c The preferred option is as defined above.

[0400] Step N [Chemistry 186] Where R 1 R 2 R 5a R 5b and R 5c As defined in Project 1 and / or other projects.

[0401] This step involves obtaining the compound of formula (14) by hydrolyzing the compound of formula (13) with water.

[0402] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include halogen solvents, preferably dichloromethane, chloroform, 1,2-dichloroethane and chlorobenzene, and more preferably dichloromethane.

[0403] The amount of solvent used in this document is typically 2 to 20 parts by weight of the compound of formula (13), preferably 3 to 10 parts by weight, and more preferably 3 to 8 parts by weight.

[0404] The amount of water used herein is typically 1.0 eq - 100.0 eq, preferably 5.0 eq - 50.0 eq, and more preferably 5.0 eq - 30.0 eq, relative to 1 eq of the compound of formula (13).

[0405] The reaction time is typically from about 0.5 hours to 5 hours, preferably from 0.5 hours to 3 hours, and more preferably from 0.5 hours to 2 hours.

[0406] The reaction temperature is typically -50°C to 50°C, preferably -20°C to 20°C, and more preferably -10°C to 10°C.

[0407] R 1 R 2 R 5a R 5b and R 5c The preferred option is as defined above.

[0408] Steps O and P [Chemistry 187] Where R 1 R 2 and R 3 As defined in Project 1 and / or other projects.

[0409] This step involves reacting the compound of formula (14) with hydrogen in the presence of a solvent, a catalyst, and an amino protecting agent to obtain the compound of formula (16) via the compound of formula (15).

[0410] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include alcohol solvents, preferably ethanol and methanol, and more preferably ethanol.

[0411] The catalysts used in this paper preferably include Pd / C.

[0412] The amino protecting agent used in this article preferably includes di-tert-butyl dicarbonate.

[0413] The amount of solvent used herein is typically from 0.01 to 2.0 parts by weight of the compound of formula (14), preferably from 0.01 to 1.0 parts by weight, and more preferably from 0.01 to 0.5 parts by weight.

[0414] The amount of catalyst used herein is typically from 1.0 to 30.0 parts by weight of the compound of formula (14), preferably from 5.0 to 20.0 parts by weight, and more preferably from 7.0 to 15.0 parts by weight.

[0415] The amount of amino protecting agent used herein is typically 1.0 eq to 3.0 eq, preferably 1.0 eq to 2.0 eq, and more preferably 1.0 eq to 1.5 eq, relative to 1 eq of the compound of formula (14).

[0416] The reaction time is typically from about 0.5 hours to 12 hours, preferably from 1 hour to 8 hours, and more preferably from 2 hours to 6 hours.

[0417] The reaction temperature is typically between 0°C and 60°C, preferably between 10°C and 50°C, and more preferably between 15°C and 40°C.

[0418] R 1 R 2 and R 3 The preferred option is as defined above.

[0419] Step Q [Chemistry 188] Where R 2 and R 3 As defined in Project 1 and / or other projects.

[0420] This step is to obtain the compound of formula (8) by reacting the compound of formula (16) with a base in the presence of a solvent.

[0421] The solvents used in this article are not particularly limited, as long as their boiling point is higher than the reaction temperature of this reaction. They include alcohol solvents, preferably ethanol and methanol, and more preferably methanol.

[0422] The bases used in this document preferably include sodium hydroxide and potassium hydroxide, more preferably sodium hydroxide. The bases may be used in the form of their aqueous solutions.

[0423] The amount of solvent used herein is typically 2 to 50 parts by weight of the compound of formula (16), preferably 5 to 40 parts by weight, and more preferably 8 to 35 parts by weight.

[0424] The amount of base used herein is typically 1.0 eq - 10.0 eq, preferably 2.0 eq - 8.0 eq, and more preferably 3.0 eq - 6.0 eq, relative to 1 eq of the compound of formula (16).

[0425] The reaction time is typically from about 0.5 hours to 24 hours, preferably from 1 hour to 10 hours, and more preferably from 3 hours to 8 hours.

[0426] The reaction temperature is typically between 0°C and 80°C, preferably between 20°C and 70°C, and more preferably between 30°C and 60°C.

[0427] R 2 and R 3 The preferred option is as defined above.

[0428] The order in which reagents are added is not limited to those listed above.

[0429] The invention is described in more detail with reference to the following reference examples and embodiments, but should not be limited thereto. Compounds are identified by elemental analysis, mass spectrometry, high-performance liquid chromatography-mass spectrometry (LCMS), infrared absorption (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, high-performance liquid chromatography (HPLC), etc.

[0430] The respective RTs are shown in the table below, which were obtained by analyzing each compound under the respective HPLC measurement conditions shown in the table.

[0431] The following abbreviations may be used in this article.

[0432] Me: Methyl Et: Ethyl tBu: tert-butyl Ph: Phenyl DMF: N,N-Dimethylformamide TFA: Trifluoroacetic acid THF: Tetrahydrofuran DMSO: Dimethyl sulfoxide DCM: Dichloromethane MTBE: Methyl tert-butyl ether TCCA: Trichloroisocyanuric acid TEMPO: 2,2,6,6-Tetramethylpiperidine-1-oxy WSC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide HOBt: 1-Hydroxybenzotriazole wt%: weight % v / w: Volume / Weight, which represents the volume-to-weight ratio of the base material. RT: Retention Time RRT: Relative Retention Time The symbols used in NMR are: s for singlet, d for doublet, t for triplet, q for quartet, and m for multiplet.

[0433] Room temperature refers to 10℃ to 30℃. Example

[0434] The invention will now be described in more detail with reference to the following examples and reference embodiments, but should not be limited thereto. Modifications may be made to the following without departing from the scope of this disclosure. The compound names given in the following examples and reference embodiments do not necessarily follow IUPAC nomenclature.

[0435] Example 1: Preparation of (R,E)-2-((1-phenylethyl)imino)ethyl acetate [Chemistry 189] Under a nitrogen atmosphere, (R)-1-phenylethyl-1-amine (compound 1, 3000 g) was dissolved in DCM (11925 g). Na₂SO₄ (3000 g) was added to the solution. The suspension was cooled to -20 to -10 °C. Ethyl 2-oxoacetate (5160 g, 50% toluene solution) was added dropwise to the suspension at -20 to -10 °C. The mixture was heated to 15 to 25 °C and stirred for 2 to 4 h until complete conversion. The reaction mixture was filtered and the resulting filter cake was washed with DCM (6000 g). The filtrate (compound 2, DCM solution considered 100% yield, calculated amount of compound 2: 5080 g) was used directly for the next step.

[0436] Example 1A: Preparation of (R,E)-2-((1-phenylethyl)imino)ethyl acetate [Chemistry 190] A solution of compound 1a (13.37 g, 64.8 mmol) in CH₂Cl₂ (105 mL) was prepared in a 125 mL Erlenmeyer flask and then transferred to a 1000 mL three-necked flask equipped with a top stirrer. Water (7.5 mL) was added, and NaIO₄ (18.25 g, 85.3 mmol, 1.32 equivalents) was added in small portions with vigorous stirring. The resulting suspension was stirred vigorously at room temperature for 18 hours. The precipitate was then removed by vacuum filtration. The reaction flask was rinsed with CH₂Cl₂ (20 mL) and the washings were filtered off.

[0437] The combined filtrate (entry 1) was cooled to 0°C and compound 1 (9 mL, 69.8 mmol) was added dropwise to the filtrate. The resulting turbid mixture was stirred at 0°C for 1 hour. The reaction mixture was treated with water (50 mL). The resulting mixture was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (25 mL). The organic layers were combined and concentrated under vacuum until the total volume of the solution was reduced to 75 mL. The resulting solution was dried over Na2SO4 and filtered into a 1000 mL three-necked flask equipped with a top stirrer and an internal temperature probe. The filter cake was washed with CH2Cl2 (25 mL) and the filtrates were combined (entry 2).

[0438] Example 2: Preparation of ethyl (1S,3S,4R)-2-((R)-1-phenylethyl)-2-azabicyclo[2.2.2]oct-5-en-3-carboxylate [Chemistry 191] The filtrate from the previous step (containing 5.08 kg of (R,E)-2-((1-phenylethyl)imino)ethyl acetate, compound 2) was stirred at atmospheric pressure and cooled to -60 to -50 °C. TFA (2.84 kg), BF3·OEt2 (3.50 kg effective content, 7.46 kg of 47% solution), and 1,3-cyclohexadiene (2.6 kg) were added dropwise to the reaction mixture at -60 to -50 °C. The reaction mixture was stirred at -60 to -50 °C for 4 h. The reaction mixture was then heated to 10 to 20 °C and stirred for 10 to 15 h until complete conversion. The reaction mixture was diluted with DCM (7.92 kg) and quenched with NaHCO3 (37.24 kg, 10% aqueous solution). Additional DCM (15.24 kg) was then added and the mixture was stirred. The lower organic phase was collected and concentrated under vacuum to 4 to 6 v / v at 45 °C or lower. Then, toluene (26.52 kg) was added and the mixture was concentrated under vacuum to 4 to 6 v / w at 60 °C. Toluene (26.52 kg) was added and the mixture was concentrated to 8–10 v / w and stirred at 55 to 60 °C for 1 h. The resulting mixture was cooled to 35 to 45 °C and stirred for 16 h to obtain a suspension. The mixture was filtered and the wet filter cake was washed with MTBE (7.52 kg) to obtain a crude product containing 15% of its isomers as a white solid (salt mixture). The solid was dissolved in DCM (30.48 kg). NaHCO3 (20.32 kg, 10% aqueous solution) was added in portions and the solution was adjusted to pH 8 to 9 at 15 to 25 °C and stirred for 1 h. The organic phase was collected and the aqueous phase was extracted with DCM (15.24 kg). The organic phases were combined and concentrated under vacuum to obtain a crude compound 3 as a mixture of isomers of free bases.

[0439] Purification Silicone pad purification: Crude compound 3 (308 g of free base) was dissolved in n-heptane (616 g) to obtain a clear solution. Silica gel (616 g) was added to a Buchner funnel to obtain a silica gel mat. The crude compound 3 / n-heptane solution was filtered through the silica gel mat. The silica gel mat was then washed with n-heptane (8 kg) for elution. The filtrate was concentrated to obtain compound 3 (243 g) with a recovery rate of 78.9% (yield) and a purity of 99%.

[0440] Example 3: Preparation of (1S,3S,4S)-5-hydroxy-2-((R)-1-phenylethyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid ethyl ester [Chemistry 192] (1S,3S,4R)-2-((R)-1-phenylethyl)-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate (compound 3, 202 g) was dissolved in MTBE (299 g) under a nitrogen atmosphere. The reaction mixture was cooled to -20 to -10 °C. BH3THF (1 mol / L, 891 g) was added dropwise to the mixture at -20 to -10 °C. The mixture was stirred for 4 to 6 h and then monitored by HPLC. Pure water (848 g) was added dropwise at no more than 10 °C. NaBO3·4H2O (327 g) as solid was added in portions with stirring at 0 to 10 °C. The mixture was stirred at 0 to 10 °C for 14 to 18 h and then monitored by HPLC. The mixture was quenched by adding sodium sulfite (20% aqueous solution, 892 g) at no more than 30 °C and diluted with ethyl acetate (455 g). The reaction mixture was filtered and the filter cake was washed with EtOAc (202 g). The filtrate was allowed to stand to separate into layers. The upper organic phase was collected and dried with Na2SO4 (404 g) to remove residual Na2SO4. The drying agent was removed by filtration and the solid was washed with ethyl acetate (404 g). The filtrate was concentrated under vacuum at 45 °C to 4 to 5 v / w to give crude (1S,3S,4S)-5-hydroxy-2-((R)-1-phenylethyl)-2-azabicyclo[2.2.2]octane-3-carboxylate (compound 4) as a pale yellow solution. This crude product solution was considered to be in 100% yield and was used directly for the next step.

[0441] Example 4: Preparation of (1S,3S,4S)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid ethyl ester [Chemistry 193] Under inert conditions, 10% Pd / C (0.19 kg, 65% water content) was added to a solution of ethyl (1S,3S,4S)-5-hydroxy-2-((R)-1-phenylethyl)-2-azabicyclo[2.2.2]octane-3-carboxylate (compound 4, 6.08 kg solution, containing 1.49 kg). The reaction was carried out at 20 to 30 °C for 16 to 24 h under hydrogen at 0.5 to 0.8 MPa. The reaction mixture was filtered through a diatomaceous earth mat (0.6 kg). The filter cake was washed with ethyl acetate (1.49 kg) and the filtrate was concentrated to give crude product 4. This crude product was considered to be in 100% yield and was used directly in the next reaction.

[0442] Example 5: Preparation of (1S,3S,4S)-2-(tert-Butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid [Chemistry 194] The (1S,3S,4S)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate (compound 5) from the previous step was mixed with MTBE (464.7 g) and n-heptane (427.2 g). The resulting solution was extracted with pure water (1.05 kg), and the upper organic layer was removed as liquid waste. The lower aqueous phase containing compound 5 was mixed with 1,4-dioxane (1.05 kg) and cooled to 10 to 15 °C. Then, a 30% NaOH aqueous solution (154.13 g) was added dropwise to the reaction mixture at 0 to 20 °C. The reaction mixture was stirred at 10 to 20 °C for 3 to 4 h to obtain compound 6. (Boc)₂O (275.4 g) was diluted with 1,4-dioxane (105 g) and added to the above reaction mixture at 5 to 20 °C. The reaction mixture was stirred at 10–20 °C for 16–20 h and cooled to 0–10 °C. A premixed solvent (EtOAc 810 g, MeOH 90 g) was added. The pH was adjusted to 1–3 at 0–10 °C using a 4.0 M HCl aqueous solution (351.25 g). Solid NaCl (314.9 g) was added. The organic layer was collected and the aqueous phase was extracted three times with the mixed solvent (EtOAc 810 g, MeOH 90 g). The organic phases were combined and dried over Na₂SO₄ (418.8 g). The mixture was filtered and the filter cake was washed with ethyl acetate (209.4 g). The filtrate was concentrated to 2–3 v / w. The concentrated mixture was stirred at 20–30 °C for 16–17 h and then cooled to 5–10 °C to obtain a suspension. The suspension was filtered and the filter cake was washed with n-heptane (284.78 g). The wet filter cake was dried to obtain 116.9 g of compound 7, with a yield of 41.03%.

[0443] Example 6: Preparation of (1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carboxylic acid [Chemistry 195] (1S,3S,4S)-2-(tert-Butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid (compound 7, 50 g) was suspended in a reaction vessel containing EtOAc (500 g). The mixture was cooled to -5 to 5 °C. TEMPO (1.45 g) was added in a single batch at -5 to 5 °C, followed by the addition of solid TCCA (32.1 g) in portions. The reaction mixture was stirred at -5 to 5 °C for 4 to 6 h to achieve complete conversion. The reaction mixture was diluted with EtOAc (1500 g) and the suspension was filtered through a diatomaceous earth pad (30 g). The filter cake was washed with EtOAc (100 g). The mixture was then rinsed with FeSO4 solution (102.5 g FeSO4 in 187 g pure water) at 0 to 10 °C. 4- The filtrate was quenched with 7H2O. The aqueous phase was removed and the organic phase was dried with Na2SO4 (100 g) at 20 to 30 °C for 14 to 18 h. The reaction mixture was filtered and the filter cake was washed with EtOAc (100 g). The filtrate was concentrated under vacuum at 45 °C to 2 to 3 v / w to obtain a suspension. n-Heptane (204 g, 6 v / w) was added to promote further precipitation. The mixture was filtered and the product filter cake was washed with n-Heptane. The wet filter cake was dried under vacuum at 35 to 45 °C to obtain compound 8 (45.37 g) with a yield of 91.4% and an HPLC purity of 97.5.

[0444] Example 7A: (1 S ,3 S 4 S Preparation of tert-butyl octane-2-carboxylate (2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate [Chemistry 196] Compound 8 (20 g, 74.27 mmol) and HOBt H2O (11.60 g, 1.02 eq.) were placed in a 1 L five-necked separatory flask. DMF (60 mL, 3 v / w) was added to the mixture at 25 ± 5 °C. The mixture was cooled to 0 ± 5 °C. DMF (60 mL, 3 v / w) and WSC HCl (15.66 g, 1.1 eq.) in water (10 mL, 0.5 v / w) were added to the mixture at 0 ± 5 °C. The mixture was stirred at 0 ± 5 °C for 1 hour. 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (17.65 g, 1.1 eq.) in DMF (40 mL, 4 v / w) was added to the mixture at 0 ± 5 °C. The reaction mixture was stirred at 0 ± 5 °C for 2 hours. Et3N (8.27 g, 1.1 eq.) was added to the mixture at 0 ± 5 °C. The reaction mixture was stirred for more than 12 hours. Water (90 mL, 4.5 v / w) was added to the mixture at 0 ± 5 °C. The mixture was stirred at 0 ± 5 °C for 2 hours. The precipitate was collected by filtration and then washed three times with water (60 mL, 3 v / w). The filter cake was dried under reduced pressure at 60 ± 5 °C to give compound 9 (33.61 g) as a nearly white crystalline powder. The yield was 94.8% (97.9 HPLC area %, analyzed by method 1).

[0445] 1H-NMR (CDCl3) δ: 4.79 and 4.73 (all 1H, m), 4.70 and 4.55 (all 1H, m), 3.73-3.25 (all 8H, m), 2.67-2.29 (all 4H, m), 2.01-1.50 (all 7H, m), 1.50-1.41 (all 12H, m), 1.39 (6H, s).

[0446] Example 7B: (1 S ,3 S 4 S Preparation of tert-butyl octane-2-carboxylate (2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate [Chemistry 197] Compound 8 (1000 g, 3.71 mmol) and HOBt H2O (580 g, 1.02 eq.) were placed in a 20 L separatory flask. DMF (3 L, 3 v / w) was added to the mixture at 25 ± 5 °C. The mixture was cooled to 0 ± 5 °C. WSC HCl (783 g, 1.1 eq.) in DMF (3 L, 3 v / w) and water (500 mL, 0.5 v / w) was added to the mixture at 0 ± 5 °C. The mixture was stirred at 0 ± 5 °C for 1 hour. Tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (882 g, 1.05 eq.) in DMF (4 L, 4 v / w) was added to the mixture at 0 ± 5 °C. The reaction mixture was stirred at 0 ± 5 °C for 2 hours. Et3N (413 g, 1.1 eq.) was added to the mixture at 0 ± 5 °C. The reaction mixture was stirred for 2 h. The reaction mixture was heated to 25 ± 5 °C and then stirred for more than 12 h. Water (4.5 L, 4.5 v / w) was added to the mixture at 25 ± 5 °C. The mixture was stirred at 25 ± 5 °C for 2 h. The precipitate was collected by filtration and then washed three times with water (3 L, 3 v / w). The filter cake was dried under reduced pressure at 60 ± 5 °C to give compound 9 (1695 g) as a nearly white crystalline powder. The yield was 95.6% (98.7 HPLC area %, analyzed by method 1).

[0447] 1H-NMR (CDCl3) δ: 4.79 and 4.73 (all 1H, each m), 4.70 and 4.55 (all 1H, each m), 3.73-3.25 (all 8H, m), 2.67-2.29 (all 4H, m), 2.01-1.50 (all 7H, m), 1.50-1.41 (all 12H, m), 1.39 (6H, s).

[0448] Example 8A: Preparation of ((1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]oct-3-yl)(2,7-diazaspiro[3.5]non-7-yl)methyl ketone dihydrochloride [Chemistry 198] Place PPh3MeBr (46.37 g, 1.55 eq.) in a 1 L five-necked separatory flask. Add THF (240 mL, 6 v / w) to the flask at 20 ± 5 °C. t14.10 g (1.50 eq.) of BuOK was added to the mixture at 20 ± 5 °C. The mixture was stirred at 20 ± 5 °C for 1 hour. Compound 9 (40 g, 83.752 mmol) in THF (240 mL, 6 v / w) was added to the mixture at 20 ± 5 °C. The reaction mixture was stirred at 20 ± 5 °C for 17.5 hours. Concentrated HCl (48.8 mL, 7 eq.) was added to the mixture at 20 ± 5 °C. The reaction mixture was heated to 40 ± 5 °C. The reaction mixture was stirred at 40 ± 5 °C for 6 hours. The reaction mixture was cooled to 20 ± 5 °C. The reaction mixture was stirred at 20 ± 5 °C for 16 hours. The precipitate was collected by filtration and washed three times with THF (120 mL, 3 v / w). The filter cake was dried under reduced pressure at 50 ± 5 °C to give compound 11 (36.66 g) as a nearly white crystalline powder. The yield was 87.5%, determined by qNMR. HPLC area percentage was 94.6%, analyzed by method 2.

[0449] 1 H-NMR (D2O) δ: 5.18 (1H, s), 5.04 (1H, s), 4.61 (1H, s), 4.02-3.93(4H, m), 3.83 (1H, br-s), 3.70-3.62 (1H, m), 3.60-3.51 (1H, m), 3.50-3.44(2H, m), 2.85-2.73 (2H, m), 2.68-2.58 (1H, m), 2.08-1.88 (5H, m), 1.81-1.69(2H, m), 1.68-1.55 (1H, m).

[0450] Example 8B: Preparation of ((1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]oct-3-yl)(2,7-diazaspiro[3.5]non-7-yl)methyl ketone dihydrochloride [Chemistry 199] Place PPh3MeBr (637 g, 1.55 eq.) in a 10 L five-necked separatory flask. Add THF (3.3 L, 6 v / w) to the flask at 20 ± 5 °C. t194 g (1.50 eq.) of BuOK was added to the mixture at 20 ± 5 °C. The mixture was stirred at 20 ± 5 °C for 1 hour. Compound 9 (550 g, 1.15 mmol) in THF (3.3 L, 6 v / w) was added to the mixture at 20 ± 5 °C. The reaction mixture was stirred at 20 ± 5 °C for 18 hours. Concentrated HCl (816 g, 7 eq.) was added to the mixture at 20 ± 5 °C. The reaction mixture was heated to 40 ± 5 °C. The reaction mixture was stirred at 40 ± 5 °C for 6 hours. The reaction mixture was cooled to 20 ± 5 °C. The reaction mixture was stirred at 20 ± 5 °C for 15 hours. The precipitate was collected by filtration and washed three times with THF (2750 mL, 5 v / w). The filter cake was dried under reduced pressure at 50 ± 5 °C to give compound 11 (277 g) as a nearly white crystalline powder. The yield was 87.3%, determined by qNMR. 86.4% HPLC area, analyzed by method 2.

[0451] 1 H-NMR (D2O) δ: 5.18 (1H, s), 5.04 (1H, s), 4.61 (1H, s), 4.02-3.93(4H, m), 3.83 (1H, br-s), 3.70-3.62 (1H, m), 3.60-3.51 (1H, m), 3.50-3.44(2H, m), 2.85-2.73 (2H, m), 2.68-2.58 (1H, m), 2.08-1.88 (5H, m), 1.81-1.69(2H, m), 1.68-1.55 (1H, m).

[0452] Example 9A: 5-Fluoro-2-[(4-{7-[(1 S ,3 S 4 R )-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]non-2-ylpyrimidin-5-yl)oxy]- N , N Preparation of 2-di(propyl-2-yl)benzamide [Chemistry 200] Compound 11 (6.27 g, 0.018 mol) was placed in a 300 mL five-necked separatory flask. MeCN (40 mL, 8 v / w, based on salt-free compound 11) was added to the flask. The mixture was cooled to 5 ± 5 °C. Et3N (15.0 mL, 6 eq.) was added to the mixture at 5 ± 5 °C. The reaction mixture was stirred at 5 ± 5 °C for 0.5 h. 2-((4-chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-diisopropylbenzamide (6.01 g, 0.95 eq.) in MeCN (30 mL, 6 v / w) was added to the suspension at 5 ± 5 °C. The reaction mixture was stirred at 5 ± 5 °C for 23 h. The precipitate was collected by filtration and washed with cooled MeCN (20 mL, 4 v / w). The filter cake was dried by filtration at room temperature for more than 1 h. The filter cake was washed three times with water (40 mL, 8 v / w). The filter cake was dried under reduced pressure at 60 ± 5 °C to give compound 12 (8.74 g) as a nearly white crystalline powder. The yield was 82.2% (99.2 HPLC area %, analyzed by method 3).

[0453] Compound 12 (8.0 g, 13.542 mol) was placed in a 200 mL five-necked separatory flask. MeCN (30 mL, 3.75 v / w) and water (10 mL, 1.25 v / w) were added to the flask. The mixture was heated to 60 ± 5 °C. The mixture was stirred at 60 ± 5 °C for 1 hour. Water (40 mL, 5 v / w) was added to the mixture at 60 ± 5 °C. The mixture was stirred at 60 ± 5 °C for 1 hour. Water (40 mL, 5 v / w) was added to the mixture at 60 ± 5 °C. The mixture was stirred at 60 ± 5 °C for 1 hour. The mixture was cooled to 20 ± 5 °C and held for 4 hours. The mixture was stirred at 20 ± 5 °C for 12 hours. The precipitate was collected by filtration and then washed twice with water (16 mL, 2 v / w). The filter cake was dried under reduced pressure at 50 ± 5 °C to give compound 12 (7.63 g) as a nearly white crystalline powder. The yield was 95.4% (99.8% HPLC area, analyzed by method 3).

[0454] 1H-NMR (CDCl3) δ: 8.28(1H, s),7.75 (1H, s),7.23-7.19 (2H, m), 7.03-6.99 (1H,m) 4.36-4.24 (5H, m), 4.04-4.01 (2H, m), 3.67-3.50 (3H, m), 3.31(4H, brs), 2.62 (1H, brs), 1.44-1.23 (4H, m), 1.43 (3H, d, J=6.7 Hz), 1.33(3H, d, J=6.7 Hz), 1.03 (3H, d, J=6.0 Hz), 0.99 (3H, d, J=6.7 Hz), 0.67-0.61(1H,m), 0.38-0.36(2H,m), 0.01-0.00(2H,m).

[0455] Example 9B: 5-Fluoro-2-[(4-{7-[(1 S ,3 S 4 R )-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]non-2-ylpyrimidin-5-yl)oxy]- N , N Preparation of 2-di(propyl-2-yl)benzamide [Chemical Engineering 201] Compound 11 (233.5 g, 0.848 mol) was placed in a 10 L separatory flask. MeCN (1868 mL, 8 v / w, based on salt-free compound 11) was added to the flask. Et3N (515 g, 6 eq.) was added to the mixture at 5 ± 5 °C. The reaction mixture was stirred at 5 ± 5 °C for 0.5 h. The mixture was then cooled to 5 ± 5 °C. 2-((4-chloropyrimidin-5-yl)oxy]-5-fluoro-N,N-diisopropylbenzamide (283.4 g, 0.95 eq.) in MeCN (1400 mL, 6 v / w) was added to the suspension at 5 ± 5 °C. The reaction mixture was stirred at 5 ± 5 °C for 24 h. The precipitate was collected by filtration and washed with cooled MeCN (934 mL, 4 v / w). The filter cake was dried by filtration at room temperature for more than 1 h. The filter cake was resuspended in water (3735 mL, 16 v / w) and stirred for 3 h. The precipitate was collected by filtration and washed twice with water (1868 mL, 8 v / w). The filter cake was dried under reduced pressure at 60 ± 5 °C to give compound 12 (446 g) as a nearly white crystalline powder. The yield was 89.1% (98.8 HPLC area %, analyzed by method 3).

[0456] Compound 12 (400 g, 0.677 mol) was placed in a 10 L separatory flask. MeCN (1500 mL, 3.75 v / w) and water (500 mL, 1.25 v / w) were added to the flask. The mixture was heated to 60 ± 5 °C. The mixture was stirred at 60 ± 5 °C for 3 hours. Water (1600 mL, 4 v / w) was added to the mixture at 60 ± 5 °C. The mixture was stirred at 60 ± 5 °C for 2 hours. The mixture was cooled to 40 ± 5 °C and held for 2 hours. The mixture was stirred at 40 ± 5 °C for 2 hours. Water (2400 mL, 6 v / w) was added to the mixture at 40 ± 5 °C. The mixture was stirred at 40 ± 5 °C for 1 hour. The mixture was cooled to 20 ± 5 °C and held for 2 hours. The mixture was stirred at 20 ± 5 °C for 11 hours. The precipitate was collected by filtration and then washed twice with water (800 mL, 2 v / w). The filter cake was dried under reduced pressure at 60 ± 5 °C to give compound 12 (347 g) as a nearly white crystalline powder. The yield was 86.9% (99.6 HPLC area %, analyzed by method 3).

[0457] 1H-NMR (CDCl3) δ: 8.28(1H, s),7.75 (1H, s),7.23-7.19 (2H, m), 7.03-6.99 (1H,m), 4.36-4.24 (5H, m), 4.04-4.01 (2H, m), 3.67-3.50 (3H, m), 3.31(4H, brs), 2.62 (1H, brs), 1.44-1.23 (4H, m), 1.43 (3H, d, J=6.7 Hz), 1.33(3H, d, J=6.7 Hz), 1.03 (3H, d, J=6.0 Hz), 0.99 (3H, d, J=6.7 Hz), 0.67-0.61(1H,m), 0.38-0.36(2H,m), 0.01-0.00(2H,m).

[0458] Example 10A: 5-Fluoro-2-[4-{7-[(1 S ,3 S 4 R )-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]non-2-ylpyrimidin-5-yl)oxy- N , N Preparation of 2-di(propyl-2-yl)benzamide mono-L-tartrate [Chemical Engineering 202] Compound 12 (3.0 g, 5.078 mmol) was placed in a 100 mL four-necked round-bottom flask. EtOH (19.5 mL, 6.5 v / w) was added to the flask. The mixture was heated to 40 ± 5 °C. The solution was cooled to 25 ± 5 °C. L-(+)-tartaric acid (762 mg, 1.0 eq.) dissolved in EtOH (9.6 mL, 3.2 v / w) and water (0.9 mL, 0.3 v / w) was added to the mixture at 25 ± 5 °C. The mixture was heated to 60 ± 5 °C. Seed crystals were added to the mixture at 60 ± 5 °C. The mixture was stirred at 60 ± 5 °C for 2 hours. EtOH (15 mL, 5 v / w) was added to the mixture at 60 ± 5 °C. The mixture was stirred at 60 ± 5 °C for 2 hours. The suspension was cooled to 0 ± 5 °C. The mixture was stirred at 0 ± 5 °C for 14 hours. The precipitate was collected by filtration and then washed twice with cooled EtOH (4.5 mL, 1.5 v / w). The filter cake was dried under reduced pressure at 50 ± 5 °C to give compound 13 (3.47 g) as a white crystalline powder. The yield was 92.3% (99.9% HPLC area, analyzed by method 3).

[0459] 1H-NMR (DMSO-d6) δ: 8.28(1H, s),7.73 (1H, d, J = 5.5 Hz) ,7.26-7.17(2H, m), 7.02 (1H, m) 5.08 (1H, s), 4.85 (1H, s), 4.32 (1H, s), 4.06-3.83 (total 6H, m), 3.68 (1H, m), 3.63-3.39 (total 4H, m), 3.32 (2H, br s), 2.66 (1H, m), 2.54 (1H, br s), 2.39 (1H, m), 1.91-1.64 (total, 5H, m), 1.60-1.47 (3H, m), 1.42(3H, d, J = 6.9 Hz), 1.33 (3H, d, J = 6.4 Hz), 1.08 (3H, d, J = 6.9 Hz), 0.98(3H, d, J = 6.4 Hz).

[0460] Example 10B: 5-Fluoro-2-[4-{7-[(1 S ,3 S 4 R )-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]non-2-ylpyrimidin-5-yl)oxy- N, N Preparation of 2-di(propyl-2-yl)benzamide mono-L-tartrate [Chemical Engineering 203] Compound 12 (10 g, 16.93 mmol) was placed in a 300 mL separatory flask. EtOH (65 mL, 6.5 v / w) was added to the flask. The mixture was heated to 60 ± 5 °C. L-(+)-tartaric acid (2.59 g, 1.02 eq.) dissolved in EtOH (32 mL, 3.2 v / w) and water (3 mL, 0.3 v / w) was added to the mixture at 60 ± 5 °C. Seed crystals were added to the mixture at 60 ± 5 °C. The mixture was stirred at 60 ± 5 °C for 2 hours. EtOH (50 mL, 5 v / w) was added to the mixture at 60 ± 5 °C. The mixture was stirred at 60 ± 5 °C for 2 hours. The suspension was cooled to 0 ± 5 °C. The mixture was stirred at 0 ± 5 °C for 14 hours. The precipitate was collected by filtration and then washed twice with cooled EtOH (15 mL, 1.5 v / w). The filter cake was dried under reduced pressure at 50 ± 5 °C to give compound 13 (11.79 g) as a white crystalline powder. The yield was 94.0%.

[0461] The impurity distribution is shown in Table 1: In analytical method 3, the target compound has a purity of 99.9%, containing 0.05% of compound A and 0.05% of compound B as impurities. On the other hand, in analytical method 4, the target compound has a purity of 99.8%, containing 0.06% of compound C and <0.05% of enantiomers. Relative retention time (RRT) refers to the ratio of the measured retention time to the retention time of the target compound (compound 12).

[0462] [Table 1] Impurities Analytical Method Content (%) RT (min) RRT LC-MS [M+H] + ]]> Compound A Method 3 0.05 16.6 0.83 609.36 Compound B Method 3 0.05 36.2 1.82 906.48 Compound C Method 4 0.06 11.1 0.92 591.34

[0463] Compound 13 (12.6 g, 17.01 mmol) was placed in a 300 mL five-necked separatory flask. EtOH (50 mL, 4 v / w) and water (8.1 mL, 0.65 v / w) were added to the flask. The mixture was heated to 60 ± 5 °C. EtOH (92 mL, 7.4 v / w) was added to the mixture at 60 ± 5 °C. Seed crystals were added to the mixture at 60 ± 5 °C. The mixture was stirred at 60 ± 5 °C for 2 hours. The suspension was cooled to 0 ± 5 °C. The mixture was stirred at 0 ± 5 °C for 14 hours. The precipitate was collected by filtration and washed twice with cooled EtOH (15 mL, 1.2 v / w). The filter cake was dried under reduced pressure at 50 ± 5 °C to give compound 13 (11.1 g) as a white crystalline powder. The yield was 88.2% (99.9% HPLC area, analyzed by method 3, 100% ee, analyzed by method 4).

[0464] 1H-NMR (DMSO-d6) δ: 8.28(1H, s),7.73 (1H, d, J = 5.5 Hz) ,7.26-7.17(2H, m), 7.02 (1H, m) 5.08 (1H, s), 4.85 (1H, s), 4.32 (1H, s), 4.06-3.83 (total 6H, m), 3.68 (1H, m), 3.63-3.39 (total 4H, m), 3.32 (2H, br s), 2.66 (1H, m), 2.54 (1H, br s), 2.39 (1H, m), 1.91-1.64 (total 5H, m), 1.60-1.47 (3H, m), 1.42(3H, d, J = 6.9 Hz), 1.33 (3H, d, J = 6.4 Hz), 1.08 (3H, d, J = 6.9 Hz), 0.98(3H, d, J = 6.4 Hz).

[0465] Example 11: Preparation of (1S,3S,4S)-5-oxo-2-((R)-2-phenylethyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid ethyl ester [Chemical 204] TFA (0.38 ml, 4.97 mmol) and BF3-OET2 (0.62 ml, 4.97 mmol) were added to a solution of compound 2 (1.17 g, assumed 4.87 mmol) in dichloroethane (5 ml) at -78 °C, and the mixture was stirred for 15 min. 2-(trimethylsilyloxy)-1,3-cyclohexadiene (940 mg, 5.34 mmol) was added (washed twice with 0.25 ml dichloromethane; added slowly to maintain the temperature below -50 °C); the mixture was stirred for 2 h, then allowed to warm naturally (over approximately 30 min); water (1 ml) was added at 0 °C, and stirring continued for 15 min. The reaction mixture was neutralized with an aqueous solution of NaHCO3 (25 ml), and extracted with ethyl acetate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation (and stored under refrigeration); the concentrate was purified the next day by silica gel column chromatography (30 g neutral silica; eluent was ethyl acetate / hexane in a ratio of 1 / 19 to 1 / 3) to give compound 15 (634 mg, 43.2%, pale yellow liquid containing impurities).

[0466] LC-MS; [M+H] + 302.0.

[0467] Example 12: Preparation of 3-ethyl 2-(tert-butyl) octane-2,3-dicarboxylic acid ester (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylic acid ester [Chemical Engineering 205] To a solution of compound 15 (634 mg, 2.10 mmol) in ethanol (10 ml), (Boc)₂O (500 mg, 2.29 mmol) and 10% Pd-C (160 mg, 50% wet weight) were added, the mixture was placed under a hydrogen atmosphere and stirred at room temperature for 4 hours. The mixture was then filtered through diatomaceous earth and washed with ethanol (3 ml x 3). The solvent was removed by vacuum distillation, and the concentrate was purified by silica gel column chromatography (15 g neutral silica, eluting solvent ethyl acetate / hexane in a 1 / 15–1 / 4 ratio) to give compound 16 (306 mg, 49%, colorless, viscous liquid).

[0468] LC-MS; [M+H] + 298.0.

[0469] [Chemical Engineering 206] .

[0470] Example 13: Preparation of (1S,3S,4S)-2-(tert-Butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carboxylic acid [Chemical 207] To a solution of compound 16 (306 mg, 1.02 mmol) in methanol (11 mL), 1.0 mL of 5 N NaOH aqueous solution was added, and the mixture was stirred at 50 °C for 5 hours. The mixture was cooled to room temperature and neutralized by adding 2 N HCl aqueous solution. Part of the solvent was removed by concentration, followed by extraction with chloroform. The organic phase was dried over anhydrous magnesium sulfate. The solvent was evaporated by vacuum distillation, and the concentrate was purified by silica gel column chromatography (15 g neutral silica, eluting solvent chloroform / methanol in a 1 / 0–12.5 / 1 ratio). Chloroform (1 mL) was added to the concentrate (203 mg). Hexane (4 mL) was slowly added, and the mixture was stirred for 30 minutes. The solid was filtered, washed with chloroform / hexane (1 / 4, 1 mL x 2) and hexane (1 mL x 2), and dried to obtain compound 8 (124 mg, 45%, white solid product).

[0471] LC-MS; [MH] - 298.0.

[0472] [Chemical Engineering 208] Comparative Example 1: As a comparative example 1, the method disclosed in WO 2020 / 045334 for preparing the target compound of the present invention can be summarized as follows.

[0473] [Chemical Engineering 209] 1. Comparison of the manufacturing method of "Invention Method 1" and "Comparative Example 1" The difference between "Method 1" as defined in this disclosure and the method of Comparative Example 1 above is that Method 1 of this disclosure prepares compound (12) from compound (7) in 5 steps, while the method of Comparative Example 1 prepares compound 13A (which corresponds to compound (7) in Method 1 of this disclosure) in 6 steps. Specifically, the method of Comparative Example 2 includes the steps of protecting and deprotecting the carboxylic acid in steps 7 and 10, which are unnecessary in Method 1 of this disclosure. Furthermore, this disclosure can prepare compound (12) from compound (7) in a total yield of 61%, while the total yield of compound (13A) prepared from compound (7A) in Comparative Example 1 is only 31%.

[0474] Therefore, Method 1 of this disclosure does not require additional protection and deprotection, which are necessary steps in Comparative Example 1. Thus, due to the minimal liquid separation or purification operations using silica gel columns, the experimental procedures in Method 1 of this disclosure are simple, and the overall yield is more than twice that of Comparative Example 1. Therefore, Method 1 of this disclosure can prepare the target compound in a higher yield of the desired intermediate 12.

[0475] 2. Comparison of the manufacturing method of "Invention Method 2" and "Comparative Example 1" The difference between "Method 2" as defined in this disclosure and the method of Comparative Example 1 above is that Method 2 in this disclosure prepares compound (12) from compound (1) in 10 steps, while the method of Comparative Example 1 prepares compound 13A (which corresponds to compound (12) in Method 2 of this disclosure) from compound 1A (which corresponds to compound (12) in Method 2 of this disclosure) in 12 steps. Specifically, in Method 2 of this disclosure, a compound (13) having a trimethylsilyloxy group is prepared in step M, and the trimethylsilyloxy group can be hydrolyzed to form a carbonyl group, which can efficiently prepare compound (14) without oxidation. Using the method of this disclosure, compound (12) can be prepared from compound (1) in a total yield of 7%, while the total yield of compound (13A) prepared from compound (1A) in Comparative Example 1 is only 3%.

[0476] Therefore, Method 2 of this disclosure does not require an oxidation reaction, which is a necessary step in Comparative Example 1. Thus, due to the near absence of liquid separation operations or purification operations using silica gel columns, the experimental procedures in Method 2 of this disclosure are simple, and the overall yield is more than twice that of Comparative Example 1. Therefore, Method 2 of this disclosure can prepare the target compound with significant efficiency.

[0477] Comparative Example 2: As a comparative example 2 other than comparative example 1, the method disclosed in WO 2020 / 045334 for preparing the target compound of the present invention can be summarized as follows.

[0478] [Chemical 210] 3. Comparison of the manufacturing method of "Invention Method 1" and "Comparative Example 2" Method 1 of this disclosure and the methods of Comparative Example 2 have the same number of reaction steps starting from the starting materials. However, the method of Comparative Example 2 requires the use of Swern oxidation for alcohol oxidation, which is unsuitable as an industrial production method because it requires very low temperature conditions and produces dimethyl sulfide, which emits an unpleasant odor, and highly toxic carbon monoxide. On the other hand, Method 1 of this disclosure uses TEMPO oxidation in step G, which is ideal as an industrial production method because the oxidation can be carried out at approximately room temperature and does not produce dimethyl sulfide or carbon monoxide, which is precisely the problem with the method of Comparative Example 2.

[0479] Regarding the introduction of the diazaspirocyclic moiety into the target compound, step 14 of the method in Comparative Example 2 is performed before the hydroxyl group on the azabicycle is oxidized to a ketone, while step H of Method 1 of the present invention is performed after the hydroxyl group on the azabicycle is oxidized to a ketone. The hydroxyl group here may result in a mixture of stereoisomers. Therefore, by introducing the structurally complex diazaspirocyclic moiety after oxidizing such a structurally troublesome hydroxyl group to a ketone, Method 1 of the present invention can reduce the complexity of its purification and analysis.

[0480] Therefore, Method 1 of this disclosure does not require the industrially unsuitable oxidation reaction that caused problems in the method of Comparative Example 2, and alcohol oxidation can be carried out under mild conditions. Furthermore, the experimental procedures in Method 1 of this disclosure are simple due to the minimal liquid separation operations or purification operations using silica gel columns. Moreover, by changing the timing of the introduction of the diazaspirocyclic moiety, the complexity of purification and analysis can be reduced compared to the method of Comparative Example 2. Therefore, Method 1 of this disclosure can prepare the target compound with significant efficiency.

[0481] 4. Comparison of the manufacturing method of "Invention Method 2" and "Comparative Example 2" The difference between "Method 2" as defined in this disclosure and the method of Comparative Example 2 above is that Method 2 in this disclosure prepares compound (12) from compound (1) in 10 steps, while the method of Comparative Example 2 prepares compound 13A (which corresponds to compound (12) in Method 2 of this disclosure) from compound 1A (which corresponds to compound (12) in Method 2 of this disclosure) in 11 steps. Specifically, in Method 2 of this disclosure, compound (13) having a trimethylsilyloxy group is prepared in step M, and the trimethylsilyloxy group can be hydrolyzed to form a carbonyl group, thereby efficiently preparing compound (14) without an oxidation reaction. Using the method of this disclosure, compound (12) can be prepared from compound (1) in a total yield of 7%, while the total yield of compound (14A) prepared from compound (1A) in Comparative Example 2 is only 5%.

[0482] Furthermore, in Method 2 of this disclosure, Formula (13) has an enol ether, that is, this portion does not have stereoisomers caused by the hydroxyl moiety, such as compound (7A) of Comparative Example 2. Therefore, Method 1 of the present invention can reduce the complexity of its purification and analysis.

[0483] Therefore, Method 2 of this disclosure does not require an oxidation reaction, which is a necessary step in Comparative Example 2. Thus, since there is almost no liquid separation operation or purification operation using a silica gel column, the complexity of purification and analysis can be reduced. The experimental operation in Method 2 of this disclosure is simple, and the overall yield is more than twice that of Comparative Example 2. Therefore, Method 2 of this disclosure can prepare the target compound with significant effect.

Claims

1. A method for preparing a compound of formula (12) or a pharmaceutically acceptable salt thereof or a solvate thereof: [Chemistry 1] Where a, b, c, and d are independently 1 or 2. The method includes step G as shown below. Step G: Compounds of formula (7): [Chemistry 2] Where R 3 It is a protecting group for amino groups. Or a pharmaceutically acceptable salt thereof or a solvate thereof reacts with an oxidizing agent in the presence of a solvent to prepare a compound of formula (8): [Chemistry 3] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

2. The method according to claim 1, wherein the solvent in step G comprises ester solvents and / or halogen solvents.

3. The method according to claim 1, wherein the solvent in step G comprises an ester solvent.

4. The method of claim 1, wherein the solvent in step G comprises ethyl acetate.

5. The method according to any one of claims 1 to 4, wherein the reaction temperature in step G is from -20°C to 50°C.

6. The method according to any one of claims 1 to 5, wherein the reaction temperature in step G is from 0°C to 30°C.

7. The method according to any one of claims 1 to 6, wherein the oxidant used in step G is 1-methyl-2-azaadamantane-N-oxy, 2-hydroxy-2-azaadamantane, 9-azanoradamantane-N-oxy, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzyl-3(1H)-one, potassium 2-iodo-5-methylbenzenesulfonate, "a combination of DMSO and oxalyl chloride", acetic anhydride, sulfur trioxide-pyridine complex, N,N'-dicyclohexylcarbodiimide, chromium trioxide, tetrapropylammonium perruthenate, sodium hypochlorite pentahydrate, or 2,2,6,6-tetramethylpiperidine-1-oxy.

8. The method according to any one of claims 1 to 6, wherein the oxidant used in step G is 2,2,6,6-tetramethylpiperidine-1-oxy.

9. The method according to any one of claims 1 to 8, further comprising step H as shown below: Step H: Compounds of formula (8): [Chemistry 4] Where R 3 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (8a): [Chemistry 5] Where R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof or a solvate thereof, reacted in the presence of a solvent and a condensing agent to prepare a compound of formula (9): [Chemistry 6] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

10. The method of claim 9, further comprising step I as shown below: Step I: Make the compound of formula (9) [Chemistry 7] Where R 3 R 4 a, b, c, and d are defined as above. The compound of formula (10) is prepared by reacting its pharmaceutically acceptable salt or solvation with a halomethyltriphenylphosphonium, trialkylsilylmethyl anion or methyl sulfone derivative in the presence of a solvent and a base. [Chemistry 8] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

11. The method of claim 10, further comprising step J as shown below: Step J: Compounds of formula (10): [Chemistry 9] Where R 3 R 4 a, b, c, and d are defined as above. The compound of formula (11) is prepared by reacting its pharmaceutically acceptable salt or its solvate with an acid: [Chemistry 10] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

12. The method of claim 11, further comprising step K as shown below: Step K: Compounds of formula (11): [Chemistry 11] Where a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof or a solvate thereof and a compound of formula (11a): [Chemistry 12] Where X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl, or methanesulfonyl. The compound of formula (12) is prepared by reacting its pharmaceutically acceptable salt or its solvate in the presence of a solvent and a base: [Chemistry 13] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

13. The method of claim 12, further comprising step L as shown below: Step L: Compounds of formula (12): [Chemistry 14] Where a, b, c, and d are defined as above. The compound of formula (12a) is prepared by reacting its pharmaceutically acceptable salt or solvation with L(+)-tartaric acid in the presence of a solvent: [Chemistry 15] Where a, b, c, and d are defined as above. Or its solvates.

14. The method according to any one of claims 1 to 13, further comprising step A as shown below: Step A: Compounds of formula (1): [Chemistry 16] Where R 1 C is an optional replacement 1-6 Alkyl, and R 1A C is an optional replacement 6-10 Aryl, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (1a): [Chemistry 17] Where R 2 C is an optional replacement 1-6 alkyl, The compound of formula (2) is prepared by reacting its pharmaceutically acceptable salt or its solvate in the presence of a solvent: [Chemistry 18] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

15. The method of claim 14, further comprising step B as shown below: Step B: Compounds of formula (2): [Chemistry 19] Where R 1 R 1A and R 2 As defined above, The compound of formula (3) is prepared by reacting its pharmaceutically acceptable salt or solvation with 1,3-cyclohexadiene in the presence of a solvent and an acid: [Chemistry 20] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

16. The method of claim 15, further comprising step C as shown below: Step C: Compounds of formula (3): [Chemistry 21] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof is reacted with borane in the presence of a solvent, and then reacted with a peroxide and a base to prepare a compound of formula (4): [Chemistry 22] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

17. The method of claim 16, further comprising step D as shown below: Step D: Compounds of formula (4): [Chemistry 23] in, R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof reacts with hydrogen in the presence of a catalyst to deprotect the protecting group on the amino group to prepare the compound of formula (5): [Chemistry 24] Where R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

18. The method of claim 17, further comprising step E as shown below: Step E: Compounds of formula (5): [Chemistry 25] Where R 2 As defined above, The compound of formula (6) is prepared by hydrolyzing the ester group of its pharmaceutically acceptable salt or its solvate: [Chemistry 26] Or its pharmaceutically acceptable salt, or its solvate.

19. The method of claim 18, further comprising step F as shown below: Step F: Compounds of formula (6): [Chemistry 27] The amino group of a pharmaceutically acceptable salt or its solvate is protected to prepare a compound of formula (7): [Chemistry 28] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

20. A method for preparing a compound of formula (12) or a pharmaceutically acceptable salt thereof or a solvate thereof: [Chemistry 29] Where a, b, c, and d are independently 1 or 2. The method includes the following step M: Step M: Compounds of formula (2): [Chemistry 30] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (2a): [Chemistry 31] Where R 5a R 5b and R 5c Independently for C 1-6 Alkyl or C 6-10 Aryl, The compound of formula (13) is prepared by reacting its pharmaceutically acceptable salt or its solvate under acidic conditions in the presence of a solvent: [Chemistry 32] Where R 1 R 1A R 2 R 5a R 5b and R 5c As defined above, Or its pharmaceutically acceptable salt, or its solvate.

21. The method of claim 20, wherein the solvent in step M comprises a halogen solvent.

22. The method of claim 20, wherein the solvent in step M comprises dichloromethane and / or chloroform.

23. The method of claim 20, wherein the solvent in step M comprises dichloromethane.

24. The method according to any one of claims 20 to 23, wherein the reaction temperature in step M is from -100°C to -30°C.

25. The method according to any one of claims 20 to 23, wherein the reaction temperature in step M is -80°C to -10°C.

26. The method according to any one of claims 20 to 25, wherein the acid used in step M is methanesulfonic acid, trichloroacetic acid, dichloroacetic acid, difluoroacetic acid, trifluoroacetic acid, boron trifluoride-diethyl ether complex, or a mixture of trifluoroacetic acid and boron trifluoride-diethyl ether complex.

27. The method according to any one of claims 20 to 25, wherein the acid used in step M is a mixture of trifluoroacetic acid and boron trifluoride-diethyl ether complex.

28. The method according to any one of claims 20 to 27, further comprising step A as shown below, Step A: Compounds of formula (1): [Chemistry 33] Where R 1 and R 1A As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (1a): [Chemistry 34] Where R 2 As defined above, The compound of formula (2) is prepared by reacting its pharmaceutically acceptable salt or its solvate in the presence of a solvent: [Chemistry 35] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

29. The method according to any one of claims 20 to 28, further comprising step N as shown below: Step N: Compounds of formula (13): [Chemistry 36] Where R 1 R 1A R 2 R 5a R 5b and R 5c As defined above, The compound of formula (14) is prepared by hydrolysis of its pharmaceutically acceptable salt or its solvate's silenol ether group: [Chemistry 37] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

30. The method of claim 29, further comprising step O as shown below: Step O: Compounds of formula (14): [Chemistry 38] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof reacts with hydrogen in the presence of a catalyst to deprotect the protecting group on the amino group to prepare a compound of formula (15): [Chemistry 39] Where R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

31. The method of claim 30, further comprising step P as shown below, Step P: Compounds of formula (15): [Chemistry 40] Where R 2 As defined above, The amino group of a pharmaceutically acceptable salt or its solvate is protected to prepare a compound of formula (16): [Chemistry 41] Where R 2 and R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

32. The method of claim 31, further comprising step Q as shown below, Step Q: Compounds of formula (16): [Chemistry 42] Where R 2 and R 3 As defined above, The compound of formula (8) is prepared by hydrolyzing the ester group of its pharmaceutically acceptable salt or its solvate: [Chemistry 43] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

33. The method of claim 32, further comprising step H as shown below: Step H: Compounds of formula (8): [Chemistry 44] Where R 3 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (8a): [Chemistry 45] Where R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof or a solvate thereof, reacted in the presence of a solvent and a condensing agent to prepare a compound of formula (9): [Chemistry 46] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

34. The method of claim 33, further comprising step I as shown below: Step I: Make the compound of formula (9) [Chemistry 47] Where R 3 R 4 a, b, c, and d are defined as above. The compound of formula (10) is prepared by reacting its pharmaceutically acceptable salt or solvation with a halomethyltriphenylphosphonium and a base in the presence of a solvent: [Chemistry 48] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

35. The method of claim 34, further comprising step J as shown below: Step J: Compounds of formula (10): [Chemistry 49] Where R 3 R 4 a, b, c, and d are defined as above. The compound of formula (11) is prepared by reacting its pharmaceutically acceptable salt or its solvate with an acid: [Transformation 50] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

36. The method of claim 35, further comprising step K as shown below: Step K: Compounds of formula (11): [Chemistry 51] Where a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof or a solvate thereof and a compound of formula (11a): [Chemistry 52] Where X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl, or methanesulfonyl. The compound of formula (12) is prepared by reacting its pharmaceutically acceptable salt or its solvate in the presence of a solvent and a base: [Chemistry 53] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

37. The method of claim 36, further comprising step L as shown below: Step L: Compounds of formula (11): [Chemistry 54] Where a, b, c, and d are defined as above. The compound of formula (12a) is prepared by reacting its pharmaceutically acceptable salt or solvation with L(+)-tartaric acid in the presence of a solvent: [Chemistry 55] Where a, b, c, and d are defined as above. Or its solvates.

38. A method for preparing a compound of formula (8) or a pharmaceutically acceptable salt thereof or a solvate thereof: [Chemistry 56] Where R 3 It is a protecting group for amino groups. The method includes the following step G: Step G: Compounds of formula (7): [Chemistry 57] Where R 3 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof reacts with an oxidizing agent in the presence of a solvent to prepare a compound of formula (8): [Chem.58] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

39. The method of claim 38, further comprising step A as shown below: Step A: Compounds of formula (1): [Chemistry 59] Where R 1 C is an optional replacement 1-6 Alkyl, and R 1A C is an optional replacement 6-10 Aryl, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (1a): [Transformation 60] Where R 2 C is an optional replacement 1-6 alkyl, The compound of formula (2) is prepared by reacting its pharmaceutically acceptable salt or its solvate in the presence of a solvent: [Chemistry 61] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

40. The method of claim 39, further comprising step B as shown below: Step B: Compounds of formula (2): [Chemistry 62] Where R 1 R 1A and R 2 As defined above, The compound of formula (3) is prepared by reacting its pharmaceutically acceptable salt or solvation with 1,3-cyclohexadiene in the presence of a solvent and an acid: [Chemistry 63] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

41. The method of claim 40, further comprising step C as shown below: Step C: Compounds of formula (3): [Chemistry 64] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof is reacted with borane in the presence of a solvent, and then reacted with a peroxide and a base to prepare a compound of formula (4): [Chemistry 65] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

42. The method of claim 41, further comprising step D as shown below: Step D: Compounds of formula (4): [Chemistry 66] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof reacts with hydrogen in the presence of a catalyst to deprotect the protecting group on the amino group to prepare the compound of formula (5): [Chemistry 67] Where R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

43. The method of claim 42, further comprising step E as shown below: Step E: Compounds of formula (5): [Chemistry 68] Where R 2 As defined above, The compound of formula (6) is prepared by hydrolyzing the ester group of its pharmaceutically acceptable salt or its solvate: [Chemistry 69] Or its pharmaceutically acceptable salt, or its solvate.

44. The method of claim 43, further comprising step F as shown below: Step F: Compounds of formula (6): [Chemistry 70] The amino group of a pharmaceutically acceptable salt or its solvate is protected to prepare a compound of formula (7): [Chemistry 71] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

45. A method for preparing a compound of formula (8) or a pharmaceutically acceptable salt thereof or a solvate thereof: [Chemistry 72] Where R 3 It is a protecting group for amino groups. The method includes the following step M, Step M: Compounds of formula (2): [Chemistry 73] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (2a): [Chemistry 74] Where R 5a R 5b and R 5c Independently for C 1-6 Alkyl or C 6-10 Aryl, The compound of formula (13) is prepared by reacting its pharmaceutically acceptable salt or its solvate under acidic conditions in the presence of a solvent: [Chemistry 75] Where R 1 R 1A R 2 R 5a R 5b and R 5c As defined above, Or its pharmaceutically acceptable salt, or its solvate.

46. ​​The method of claim 45, further comprising step A as shown below: Step A: Compounds of formula (1): [Chemistry 76] Where R 1 C is an optional replacement 1-6 Alkyl, and R 1A C is an optional replacement 6-10 Aryl, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (1a): [Chemistry 77] Where R 2 C is an optional replacement 1-6 alkyl, The compound of formula (2) is prepared by reacting its pharmaceutically acceptable salt or its solvate in the presence of a solvent: [Chemistry 78] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

47. The method according to claim 45 or 46, further comprising step N as shown below: Step N: Compound of formula (13) [Chemistry 79] Where R 1 R 1A R 2 R 5a R 5b and R 5c As defined above, The compound of formula (14) is prepared by hydrolysis of its pharmaceutically acceptable salt or its solvate's silenol ether group: [Chemistry 80] Where R 1 R 1A and R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

48. The method of claim 47, further comprising step O as shown below: Step O: Compounds of formula (14): [Chemistry 81] Where R 1 R 1A and R 2 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof reacts with hydrogen in the presence of a catalyst to deprotect the protecting group on the amino group to prepare a compound of formula (15): [Chemistry 82] Where R 2 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

49. The method of claim 48, further comprising step P as shown below, Step P: Compounds of formula (15): [Chemistry 83] Where R 2 As defined above, The amino group of a pharmaceutically acceptable salt or its solvate is protected to prepare a compound of formula (16): [Chemistry 84] Where R 2 and R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

50. The method of claim 49, further comprising step Q as shown below, Step Q: Compounds of formula (16): [Chemistry 85] Where R 2 and R 3 As defined above, The compound of formula (8) is prepared by hydrolyzing the ester group of its pharmaceutically acceptable salt or its solvate: [Chemistry 86] Where R 3 As defined above, Or its pharmaceutically acceptable salt, or its solvate.

51. A method for preparing a compound of formula (12) or a pharmaceutically acceptable salt thereof or a solvate thereof: [Chemistry 87] Where a, b, c, and d are independently 1 or 2. The method includes step H as shown below. Step H: Compounds of formula (8): [Chemistry 88] Where R 3 As defined above, Or a pharmaceutically acceptable salt thereof or a solvate thereof with a compound of formula (8a): [Chemistry 89] Where R 4 a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof or a solvate thereof, reacted in the presence of a solvent and a condensing agent to prepare a compound of formula (9): [Chemistry 90] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

52. The method of claim 51, further comprising step I as shown below: Step I: Make the compound of formula (9) [Chemistry 91] Where R 3 R 4 a, b, c, and d are defined as above. The compound of formula (10) is prepared by reacting its pharmaceutically acceptable salt or solvation with a halomethyltriphenylphosphonium, trialkylsilylmethyl anion or methyl sulfone derivative in the presence of a solvent and a base. [Chemistry 92] Where R 3 R 4 a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

53. The method of claim 52, further comprising step J as shown below: Step J: Compounds of formula (10): [Chemistry 93] Where R 3 R 4 a, b, c, and d are defined as above. The compound of formula (11) is prepared by reacting its pharmaceutically acceptable salt or its solvate with an acid: [Chemistry 94] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

54. The method of claim 53, further comprising step K as shown below: Step K: Compounds of formula (11): [Chemistry 95] Where a, b, c, and d are defined as above. Or a pharmaceutically acceptable salt thereof or a solvate thereof and a compound of formula (11a): [Chemistry 96] Where X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl, or methanesulfonyl. The compound of formula (12) is prepared by reacting its pharmaceutically acceptable salt or its solvate in the presence of a solvent and a base: [Chemistry 97] Where a, b, c, and d are defined as above. Or its pharmaceutically acceptable salt, or its solvate.

55. The method of claim 54, further comprising step L as shown below: Step L: Compounds of formula (12): [Chem. 98] Where a, b, c, and d are defined as above. The compound of formula (12a) is prepared by reacting its pharmaceutically acceptable salt or solvation with L(+)-tartaric acid in the presence of a solvent: [Chemistry 99] Where a, b, c, and d are defined as above. Or its solvates.

56. A mixture comprising 5-fluoro-2-[(4-{7-[(1 S ,3 S 4 R )-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]non-2-ylpyrimidin-5-yl)oxy- N , N -Di(propyl-2-yl)benzamide or a pharmaceutically acceptable salt thereof or a solvation thereof, and compound A or a pharmaceutically acceptable salt thereof or a solvation thereof.

57. The mixture according to claim 56, wherein compound A or a pharmaceutically acceptable salt thereof or a solvate thereof, as determined by high performance liquid chromatography (HPLC), is present in an amount of about 0.15% or less of the mixture.

58. The mixture according to claim 56, wherein compound A or a pharmaceutically acceptable salt thereof or a solvate thereof, as determined by high performance liquid chromatography (HPLC), is present in an amount of about 0.1% or less of the mixture.

59. The mixture according to claim 56, wherein compound A or a pharmaceutically acceptable salt thereof or a solvate thereof, as determined by high performance liquid chromatography (HPLC), is present in an amount of about 0.05% or less of the mixture.

60. The mixture according to any one of claims 56 to 59, further comprising compound B or a pharmaceutically acceptable salt thereof or a solvation thereof.

61. The mixture according to claim 60, wherein compound B or a pharmaceutically acceptable salt thereof or a solvate thereof, as determined by high performance liquid chromatography (HPLC), is present in an amount of about 0.15% or less of the mixture.

62. The mixture of claim 60, wherein compound B or a pharmaceutically acceptable salt thereof or a solvate thereof, as determined by high performance liquid chromatography (HPLC), is present in an amount of about 0.1% or less of the mixture.

63. The mixture according to claim 60, wherein compound B or a pharmaceutically acceptable salt thereof or a solvate thereof, as determined by high performance liquid chromatography (HPLC), is present in an amount of about 0.05% or less of the mixture.

64. The mixture according to claim 60, further comprising compound C or a pharmaceutically acceptable salt thereof or a solvation thereof.

65. The mixture according to claim 64, wherein compound C or a pharmaceutically acceptable salt thereof or a solvate thereof, as determined by high performance liquid chromatography (HPLC), is present in an amount of about 0.15% or less of the mixture.

66. The mixture according to claim 64, wherein compound C or a pharmaceutically acceptable salt thereof or a solvate thereof, as determined by high performance liquid chromatography (HPLC), is present in an amount of about 0.1% or less of the mixture.

67. The method of claim 64, wherein compound C or a pharmaceutically acceptable salt thereof or a solvate thereof is present in an amount of about 0.06% or less of the mixture, as determined by high performance liquid chromatography (HPLC).

68. A mixture comprising 5-fluoro-2-[(4-{7-[(1 S ,3 S 4 R )-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]non-2-ylpyrimidin-5-yl)oxy- N , N -Di(propyl-2-yl)benzamide or a pharmaceutically acceptable salt thereof or a solvation thereof, and compound B or a pharmaceutically acceptable salt thereof or a solvation thereof.

69. The mixture according to claim 68, wherein compound B or a pharmaceutically acceptable salt thereof or a solvate thereof is present in an amount of about 0.15% or less of the mixture as determined by high performance liquid chromatography (HPLC).

70. The mixture of claim 68, wherein compound B or a pharmaceutically acceptable salt thereof or a solvate thereof, as determined by high performance liquid chromatography (HPLC), is present in an amount of about 0.1% or less of the mixture.

71. The mixture according to claim 68, wherein compound B or a pharmaceutically acceptable salt thereof or a solvate thereof is present in an amount of about 0.05% or less of the mixture as determined by high performance liquid chromatography (HPLC).

72. The mixture according to any one of claims 68 to 71, further comprising compound C or a pharmaceutically acceptable salt thereof or a solvation thereof.

73. The mixture according to claim 72, wherein compound C or a pharmaceutically acceptable salt thereof or a solvate thereof, as determined by high performance liquid chromatography (HPLC), is present in an amount of about 0.15% or less of the mixture.

74. The mixture according to claim 72, wherein compound C or a pharmaceutically acceptable salt thereof or a solvate thereof, as determined by high performance liquid chromatography (HPLC), is present in an amount of about 0.1% or less of the mixture.

75. The mixture according to claim 72, wherein compound C or a pharmaceutically acceptable salt thereof or a solvate thereof is present in an amount of about 0.06% or less of the mixture as determined by high performance liquid chromatography (HPLC).

76. A mixture comprising 5-fluoro-2-[(4-{7-[(1 S ,3 S 4 R )-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]non-2-ylpyrimidin-5-yl)oxy- N , N -Di(propyl-2-yl)benzamide or a pharmaceutically acceptable salt thereof or a solvation thereof, and compound C or a pharmaceutically acceptable salt thereof or a solvation thereof.

77. The mixture according to claim 76, wherein compound C or a pharmaceutically acceptable salt thereof or a solvate thereof, as determined by high performance liquid chromatography (HPLC), is present in an amount of about 0.15% or less of the mixture.

78. The mixture according to claim 76, wherein compound C or a pharmaceutically acceptable salt thereof or a solvate thereof, as determined by high performance liquid chromatography (HPLC), is present in an amount of about 0.1% or less of the mixture.

79. The mixture according to claim 76, wherein compound C or a pharmaceutically acceptable salt thereof or a solvate thereof is present in an amount of about 0.06% or less of the mixture as determined by high performance liquid chromatography (HPLC).

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