Method for producing optically active azabicyclo ring derivatives, and intermediates for the production thereof.

Abstract

This disclosure relates to a method for producing optically active azabicyclo ring derivatives useful as pharmaceutical compounds, a production intermediate for the same, and a method for producing the production intermediate.

Description

[Technical Field]

[0001] This disclosure relates to a method for producing optically active azabicyclo ring derivatives useful as pharmaceutical compounds, a production intermediate for the same, and a method for producing the production intermediate. [Background technology]

[0002] As a method for producing optically active azabicyclo ring derivatives and related substances, for example, the method described in Patent Document 1 is known. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] International Publication No. 2020 / 045334 [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] The purpose of this disclosure is to provide a method for producing optically active azabicyclo ring derivatives useful as pharmaceutical compounds. [Means for solving the problem]

[0005] This disclosure provides an excellent industrial method for producing optically active azabicyclo ring derivatives represented by formula (12) in a simple, high-yielding, and inexpensive manner with fewer steps.

[0006] This disclosure provides an excellent industrial method for producing optically active azabicyclo ring derivatives represented by formula (8) in a simple, high-yield, and inexpensive manner with fewer steps.

[0007] In one embodiment, more specifically, intermediate (2) is obtained by reacting an inexpensive benzylamine derivative (1) with an inexpensive aldehyde (1a) (Step A). ​​Intermediate (3) is obtained stereoselectively by reacting the obtained intermediate (2) with 1,3-cyclohexadiene (Step B). Intermediate (3) is regioselectively and stereoselectively hydroxylated via a hydroboration-oxidation reaction to obtain intermediate (4) (Step C), and then intermediate (5) is obtained by deprotecting the amino group (Step D). The ester group of intermediate (5) is hydrolyzed to obtain intermediate (6) (Step E), and intermediate (7) is obtained by protecting the amino group of the obtained intermediate (Step F). The hydroxyl group of the obtained intermediate (7) is oxidized to obtain intermediate (8) simply, in high yield and inexpensively (Step G). Intermediate (8) is reacted with amine (8a) to obtain intermediate (9) (Step H), the carbonyl group of intermediate (9) is converted to a vinylidene group to obtain intermediate (10) (Step I), and then intermediate (11) is obtained by deprotecting the amino group of intermediate (10) (Step J). Finally, the obtained intermediate (11) is reacted with compound (11a) to obtain an optically active azabicyclo ring derivative (12). The discovered manufacturing method (manufacturing method 1) allows for the simple, high-yield, and inexpensive production of derivative (12) in a small number of steps.

[0008] In one embodiment, the present disclosure provides a method for obtaining intermediate (8) in a simple and high yield by oxidizing the hydroxyl group of intermediate (7) to obtain intermediate (8) in a step (Step G), and further provides a method for obtaining an optically active azabicyclo ring derivative (12) from intermediate (8) in high yield in just four steps (Manufacturing Method 1).

[0009] In one embodiment, more specifically, intermediate (2) is obtained by reacting an inexpensive benzylamine derivative (1) with an inexpensive aldehyde (1a) (Step A). ​​The obtained intermediate (2) is converted to intermediate (13) in high yield by reacting it with a 1,3-cyclohexadiene derivative (2a) (Step M). The obtained intermediate (13) is deprotected to obtain intermediate (14) (Step N), and then further deprotected to obtain intermediate (15), and the amino group is newly protected to produce intermediate (16) (Steps O and P). Subsequently, the ester group of intermediate (16) is hydrolyzed to obtain intermediate (8) in a simple, high-yield, and inexpensive manner (Step Q). Intermediate (8) is reacted with an amine (8a) to obtain intermediate (9) (Step H). Furthermore, the carbonyl group of intermediate (9) is converted to a vinylidene group to obtain intermediate (10) (Step I), and then the amino group in intermediate (10) is deprotected to produce intermediate (11) (Step J). Finally, the obtained intermediate (11) is reacted with compound (11a) to obtain the optically active azabicyclo ring derivative (12). The discovered manufacturing method (manufacturing method 2) allows for the simple, high-yield, and inexpensive production of derivative (12) with a small number of steps.

[0010] In one embodiment, the present disclosure provides a method for obtaining intermediate (8) in simple and high yield via a step (Step M) in which intermediate (2) is reacted with a 1,3-cyclohexadiene derivative (2a) to produce intermediate (13), and further provides a method for producing an optically active azabicyclo ring derivative (12) from intermediate (8) in high yield in just four steps (Production Method 2).

[0011] (Manufacturing method 1) [ka]

[0012] (Manufacturing method 2) [ka]

[0013] In other words, this disclosure typically provides the following:

[0014] [Section 1] Equation (12), including Step G below: [ka] [In the formula, a, b, c, and d are each independently either 1 or 2.] A method for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof: Step G: Formula (7): [ka] [In the formula, R 3 [is a protecting group for amino groups] By reacting a compound represented by (8), or a pharmaceutically acceptable salt thereof, or a solvate thereof, with an oxidizing agent in the presence of a solvent, the compound (8) is obtained. [ka] [In the formula, R 3 This is synonymous with the above. A process for producing a compound represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0015] [Section 2] The method for producing a product according to claim 1, wherein the solvent in Step G comprises an ester-based solvent and / or a halogen-based solvent.

[0016] [Section 3] The method for producing the product according to item 1, wherein the solvent in Step G is an ester-based solvent.

[0017] [Section 4] The method for producing the product according to item 1, wherein the solvent in Step G is ethyl acetate.

[0018] [Section 5] The manufacturing method according to any one of items 1 to 4, wherein in Step G, the reaction temperature is from -20°C to 50°C.

[0019] [Section 6] The manufacturing method according to any one of items 1 to 5, wherein in Step G, the reaction temperature is from 0°C to 30°C.

[0020] [Section 7] The method for producing a product according to any one of claims 1 to 6, wherein the oxidizing agent in Step G is 1-methyl-2-azaadamantane-N-oxyl, 2-hydroxy-2-azaadamantane, 9-azanoradamantane-N-oxyl, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-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-oxyl.

[0021] [Section 8] The method for producing a product according to any one of claims 1 to 6, wherein the oxidizing agent in Step G is 2,2,6,6-tetramethylpiperidine 1-oxyl.

[0022] [Section 9] The manufacturing method described in any one of items 1 to 8, further comprising Step H below: Step H: Formula (8): [ka] [In the formula, R 3 This is synonymous with the above. A compound represented by formula (8a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a condensing agent, is prepared using formula (8a): [ka] [wherein, R 4 , a, b, c and d are as defined above] react with a compound represented by the formula (9): [Chemical formula] [wherein, R 3 , R 4 , a, b, c and d are as defined above] to produce a compound represented by the formula (9), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0023] [Item 10] The production method according to Item 9, further comprising the following Step I: Step I: Formula (9): [Chemical formula] [wherein, R 3 , R 4 , a, b, c and d are as defined above] react a compound represented by the formula (9), or a pharmaceutically acceptable salt thereof, or a solvate thereof, with methyltriphenylphosphonium halide, trialkylsilylmethyl anion, or a methylsulfone derivative in the presence of a solvent and a base to produce a compound represented by the formula (10): [Chemical formula] [wherein, R 3 , R 4 , a, b, c and d are as defined above] to produce a compound represented by the formula (10), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0024] [Item 11] The production method according to Item 10, further comprising the following Step J: Step J: Formula (10): [Chemical formula] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with an acid to obtain formula (11): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0025] [Section 12] The manufacturing method according to item 11, further comprising Step K below: Step K: Equation (11): [ka] [In the formula, a, b, c, and d are the same as above.] A compound represented by formula (11a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a base, is prepared using formula (11a): [ka] [In the formula, X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl group, or methanesulfonyl group.] The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with formula (12): [ka] [In the formula, a, b, c, and d are the same as above.] Or the process of producing a pharmaceutically acceptable salt or solvate thereof.

[0026] [Section 13] The manufacturing method described in item 12, further comprising Step L below: Step L: Equation (12): [ka] [In the formula, a, b, c, and d are the same as above.] The compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, is reacted with L(+)-tartaric acid in the presence of a solvent to obtain formula (12a): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by or its solvate.

[0027] [Section 14] The manufacturing method described in any one of items 1 to 13, further comprising Step A below: Step A: Formula (1): [ka] [In the formula, R 1 C may be substituted. 1-6 It is alkyl, R 1A C may be substituted. 6-10 [Aryl] A compound represented by formula (1a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent, is subjected to the following reaction: [ka] [In the formula, R 2 C may be substituted. 1-6 It is alkyl. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with the compound represented by formula (2): [ka] [In the formula, R 1 , R 1A , and R 2This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0028] [Section 15] The manufacturing method described in item 14, further comprising Step B below: Step B: Formula (2): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with 1,3-cyclohexadiene in the presence of a solvent and an acid to obtain formula (3): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A process for producing a compound represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0029] [Section 16] The manufacturing method described in Section 15, further comprising Step C below: Step C: Formula (3): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with borane in the presence of a solvent, and then with a peroxide and a base to obtain formula (4): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0030] [Section 17] The manufacturing method described in section 16, further comprising Step D below: Step D: Formula (4): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. By reacting the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, with hydrogen in the presence of a catalyst, the protecting group on the amino group is deprotected, resulting in formula (5): [ka] [In the formula, R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0031] [Section 18] The manufacturing method described in item 17, further comprising Step E below: Step E: Formula (5): [ka] [In the formula, R 2 This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or the ester group of its solvate, is hydrolyzed to produce formula (6): [ka] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0032] [Section 19] The manufacturing method described in section 18, further comprising Step F below: Step F: Formula (6): [ka] Protect the amino group of the compound represented by formula (7): or a pharmaceutically acceptable salt thereof, or its solvate. [ka] [In the formula, R 3 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0033] [Section 20] Equation (12), including Step M below: [ka] [In the formula, a, b, c, and d are each independently either 1 or 2.] Methods for producing the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate: Step M: Formula (2): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A compound represented by formula (2a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent under acidic conditions, is prepared using formula (2a): [ka] [In the formula, R 5a , R5b , and R 5c Each of them is independent of C 1-6 Alkyl or C 6-10 [Aryl] By reacting with a compound represented by formula (13), or a pharmaceutically acceptable salt thereof, or a solvate thereof, the compound (13) is obtained. [ka] [In the formula, R 1 , R 1A , R 2 , R 5a , R 5b , and R 5c This is synonymous with the above. A process for producing a compound represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0034] [Section 21] The manufacturing method according to item 20, wherein the solvent in Step M includes a halogenated solvent.

[0035] [Section 22] The method for producing the product according to item 20, wherein the solvent in Step M comprises dichloromethane and / or chloroform.

[0036] [Section 23] The manufacturing method according to item 20, wherein the solvent in Step M comprises dichloromethane.

[0037] [Section 24] The manufacturing method according to any one of items 20 to 23, wherein in Step M, the reaction temperature is from -100°C to -30°C.

[0038] [Section 25] The manufacturing method according to any one of items 20 to 23, wherein in Step M, the reaction temperature is from -80°C to -10°C.

[0039] [Section 26] The manufacturing method according to any one of items 20 to 25, wherein the acid in the said 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.

[0040] [Item 27] The manufacturing method according to any one of items 20 to 25, wherein the acid in the said Step M is a mixture of trifluoroacetic acid and boron trifluoride - diethyl ether complex.

[0041] [Item 28] The manufacturing method according to any one of items 20 to 27, further comprising the following Step A: Step A: Formula (1): [Chemical formula] [In the formula, R 1 and R 1A are as defined above. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with the compound represented by formula (1a): [Chemical formula] [In the formula, R 2 is as defined above. to produce a compound represented by formula (2): [Chemical formula] [In the formula, R 1 , R 1A , and R 2 are as defined above. The step of manufacturing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0042] [Item 29] The manufacturing method according to any one of items 20 to 28, further comprising Step N below: Step N: Equation (13): [ka] [In the formula, R 1 , R 1A , R 2 , R 5a , R 5b , and R 5c This is synonymous with the above. The silyl enol ether group of the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, is hydrolyzed to obtain formula (14): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0043] [Section 30] The manufacturing method described in section 29, further comprising Step O below: Step O: Equation (14): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. By reacting the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, with hydrogen in the presence of a catalyst, the protecting group on the amino group is deprotected, resulting in formula (15): [ka] [In the formula, R 2 This is synonymous with the above. A process for producing a compound represented by or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0044] [Item 31] The production method according to Item 30, further comprising the following Step P: Step P: Formula (15): [Chemical formula] [wherein, R 2 is as defined above] Protecting the amino group of a compound represented by or a pharmaceutically acceptable salt thereof or a solvate thereof to obtain a compound represented by Formula (16): [Chemical formula] [wherein, R 2 and R 3 are as defined above] A process for producing a compound represented by or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0045] [Item 32] The production method according to Item 31, further comprising the following Step Q: Step Q: Formula (16): [Chemical formula] [wherein, R 3 and R 3 are as defined above] Hydrolyzing the ester group of a compound represented by or a pharmaceutically acceptable salt thereof or a solvate thereof to obtain a compound represented by Formula (8): [Chemical formula] [wherein, R 3 is as defined above] A process for producing a compound represented by or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0046] [Section 33] The manufacturing method described in item 32, further comprising Step H below: Step H: Formula (8): [ka] [In the formula, R 3 This is synonymous with the above. A compound represented by formula (8a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a condensing agent, is prepared using formula (8a): [ka] [In the formula, R 4 a, b, c, and d are synonymous with the above. By reacting with a compound represented by formula (9), or a pharmaceutically acceptable salt thereof, or a solvate thereof, the following compound can be obtained: [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0047] [Section 34] The manufacturing method described in section 33, further comprising Step I below: Step I: Formula (9) [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. By reacting a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, with methyltriphenylphosphonium halide and a base in the presence of a solvent, formula (10) is obtained: [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0048] [Section 35] The manufacturing method described in section 34, further comprising Step J below: Step J: Equation (10): [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with an acid to obtain formula (11): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0049] [Section 36] The manufacturing method according to item 35, further comprising Step K below: Step K: Equation (11): [ka] [In the formula, a, b, c, and d are the same as above.] A compound represented by formula (11a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a base, is prepared using formula (11a): [ka] [In the formula, X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl group, or methanesulfonyl group.] React with a compound represented by the formula, or a pharmaceutically acceptable salt thereof, or a solvate thereof, to obtain the formula (12):

Chemical formula

[0050] [Item 37] The production method according to Item 36, further comprising the following Step L: Step L: Formula (11):

Chemical formula

Chemical formula

[0051] [Item 38] A production method of a compound represented by the formula (8), including the following Step G:

Chemical formula

Chemical formula

[0052] [Paragraph 39] The production method according to Paragraph 38, further comprising the following Step A:[[ID=I9]] Step A: Formula (1): [Chemical formula] [wherein, R 1 is optionally substituted C 1-6 alkyl, and R 1A is optionally substituted C 6-10 aryl] A compound represented by the formula, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with a compound represented by formula (1a): [Chemical formula] [wherein, R 2 is optionally substituted C 1-6 alkyl] to obtain a compound represented by formula (2): [Chemical formula] [wherein, R 1 , R 1A , and R 2 are as defined above] Step for producing a compound represented by the formula, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0053] [Paragraph 40] The manufacturing method described in item 39, further comprising Step B below: Step B: Formula (2): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with 1,3-cyclohexadiene in the presence of a solvent and an acid to obtain formula (3): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0054] [Section 41] The manufacturing method described in item 40, further comprising Step C below: Step C: Formula (3): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with borane in the presence of a solvent, and then with a peroxide and a base to obtain formula (4): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0055] [Section 42] The manufacturing method described in item 41, further comprising Step D below: Step D: Formula (4): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. By reacting the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, with hydrogen in the presence of a catalyst, the protecting group on the amino group is deprotected, resulting in formula (5): [ka] [In the formula, R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0056] [Section 43] The manufacturing method described in item 42, further comprising Step E below: Step E: Formula (5): [ka] [In the formula, R 2 This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or the ester group of its solvate, is hydrolyzed to produce formula (6): [ka] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0057] [Section 44] The manufacturing method described in section 43, further comprising Step F below: Step F: Formula (6): [ka] Protect the amino group of the compound represented by formula (7): or a pharmaceutically acceptable salt thereof, or its solvate. [ka] [In the formula, R 3 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0058] [Section 45] Equation (8), including Step M below: [ka] [In the formula, R 3 [is a protecting group for amino groups] Methods for producing the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate: Step M: Formula (2): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A compound represented by formula (2a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent under acidic conditions, is prepared using formula (2a): [ka] [In the formula, R 5a , R 5b , and R 5c Each of them is independent of C 1-6 Alkyl or C 6-10 [Aryl] By reacting with a compound represented by formula (13), or a pharmaceutically acceptable salt thereof, or a solvate thereof, the compound (13) is obtained. [ka] [In the formula, R 1 , R 1A , R 2 , R 5a , R 5b , and R 5c This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0059] [Section 46] The manufacturing method described in item 45, further comprising Step A below: Step A: Formula (1): [ka] [In the formula, R 1 C may be substituted. 1-6 It is alkyl, R 1A C may be substituted. 6-10 [Aryl] A compound represented by formula (1a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent, is subjected to the following reaction: [ka] [In the formula, R 2 C may be substituted. 1-6 It is alkyl. By reacting with a compound represented by formula (2), or a pharmaceutically acceptable salt thereof, or a solvate thereof, the following compound can be produced: [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0060] [Section 47] The manufacturing method according to section 45 or 46, further comprising Step N below: Step N: Equation (13): [ka] [In the formula, R 1 , R 1A , R 2 , R 5a , R 5b , and R 5c This is synonymous with the above. The silyl enol ether group of the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, is hydrolyzed to obtain formula (14): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0061] [Section 48] The manufacturing method described in item 47, further comprising Step O below: Step O: Equation (14): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. By reacting the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, with hydrogen in the presence of a catalyst, the protecting group on the amino group is deprotected, resulting in formula (15): [ka] [In the formula, R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0062] [Section 49] The manufacturing method described in section 48, further comprising Step P below: Step P: Formula (15): [ka] [In the formula, R 2 This is synonymous with the above. Protect the amino group of the compound represented by formula (16): or a pharmaceutically acceptable salt thereof, or its solvate. [ka] [In the formula, R 2 and R 3 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0063] [Section 50] The manufacturing method described in section 49, further comprising Step Q below: Step Q: Equation (16): [ka] [In the formula, R 2 and R 3 This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or the ester group of its solvate, is hydrolyzed to obtain formula (8): [ka] [In the formula, R 3 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0064] [Section 51] Equation (12), including Step H below: [ka] [In the formula, a, b, c, and d are each independently either 1 or 2.] Methods for producing the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate: Step H: Formula (8): [ka] [In the formula, R 3 This is synonymous with the above. A compound represented by formula (8a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a condensing agent, is prepared using formula (8a): [ka] [In the formula, R 4 a, b, c, and d are synonymous with the above. By reacting with a compound represented by formula (9), or a pharmaceutically acceptable salt thereof, or a solvate thereof, the following compound can be obtained: [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0065] [Section 52] The manufacturing method described in item 51, further comprising Step I below: Step I: Formula (9): [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with a methyltriphenylphosphonium halogen, a trialkylsilylmethyl anion, or a methylsulfone derivative in the presence of a solvent and a base to obtain formula (10): [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0066] [Section 53] The manufacturing method described in section 52, further comprising Step J below: Step J: Equation (10): [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with an acid to obtain formula (11): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0067] [Section 54] The manufacturing method according to item 53, further comprising Step K below: Step K: Equation (11): [ka] [In the formula, a, b, c, and d are the same as above.] A compound represented by formula (11a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a base, is prepared using formula (11a): [ka] [In the formula, X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl group, or methanesulfonyl group.] The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with formula (12): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0068] [Section 55] The manufacturing method described in item 54, further comprising Step L below: Step L: Equation (12): [ka] [In the formula, a, b, c, and d are the same as above.] The compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, is reacted with L(+)-tartaric acid in the presence of a solvent to obtain formula (12a): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by [the given symbol], or its solvate.

[0069] [Section 56] A mixture comprising 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a solvate thereof, and compound A or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0070] [Section 57] The mixture according to item 56, wherein compound A 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 measured by high-performance liquid chromatography (HPLC).

[0071] [Section 58] The mixture according to item 56, wherein compound A or a pharmaceutically acceptable salt thereof, or a solvate thereof, is present in an amount of about 0.1% or less of the mixture, as measured by high-performance liquid chromatography (HPLC).

[0072] [Section 59] The mixture according to item 56, wherein compound A 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 measured by high-performance liquid chromatography (HPLC).

[0073] [Section 60] A mixture according to any one of claims 56 to 59, further comprising compound B or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0074] [Section 61] The mixture according to item 60, wherein compound B or a pharmaceutically acceptable salt thereof, or a solvate thereof, is present in an amount of approximately 0.15% or less of the mixture, as measured by high-performance liquid chromatography (HPLC).

[0075] [Section 62] The mixture according to item 60, wherein compound B or a pharmaceutically acceptable salt thereof, or a solvate thereof, is present in an amount of about 0.1% or less of the mixture, as measured by high-performance liquid chromatography (HPLC).

[0076] [Section 63] The mixture according to item 60, 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 measured by high-performance liquid chromatography (HPLC).

[0077] [Section 64] The mixture according to claim 60, further comprising compound C or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0078] [Section 65] The mixture according to item 64, wherein compound C 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 measured by high-performance liquid chromatography (HPLC).

[0079] [Section 66] The mixture according to item 64, wherein compound C or a pharmaceutically acceptable salt thereof, or a solvate thereof, is present in an amount of about 0.1% or less of the mixture, as measured by high-performance liquid chromatography (HPLC).

[0080] [Section 67] The mixture according to item 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 measured by high-performance liquid chromatography (HPLC).

[0081] [Section 68] A mixture comprising 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a solvate thereof, and compound B or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0082] [Section 69] The mixture according to item 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 measured by high-performance liquid chromatography (HPLC).

[0083] [Section 70] The mixture according to item 68, wherein compound B or a pharmaceutically acceptable salt thereof, or a solvate thereof, is present in an amount of about 0.1% or less of the mixture, as measured by high-performance liquid chromatography (HPLC).

[0084] [Section 71] The mixture according to item 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 measured by high-performance liquid chromatography (HPLC).

[0085] [Section 72] A mixture according to any one of claims 68 to 71, further comprising compound C or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0086] [Section 73] The mixture according to item 72, wherein compound C 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 measured by high-performance liquid chromatography (HPLC).

[0087] [Section 74] The mixture according to item 72, wherein compound C or a pharmaceutically acceptable salt thereof, or a solvate thereof, is present in an amount of about 0.1% or less of the mixture, as measured by high-performance liquid chromatography (HPLC).

[0088] [Section 75] The mixture according to item 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 measured by high-performance liquid chromatography (HPLC).

[0089] [Section 76] A mixture comprising 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a solvate thereof, and compound C or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0090] [Section 77] The mixture according to item 76, wherein compound C 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 measured by high-performance liquid chromatography (HPLC).

[0091] [Section 78] The mixture according to item 76, wherein compound C or a pharmaceutically acceptable salt thereof, or a solvate thereof, is present in an amount of about 0.1% or less of the mixture, as measured by high-performance liquid chromatography (HPLC).

[0092] [Section 79] The mixture according to item 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 measured by high-performance liquid chromatography (HPLC).

[0093] [Section A1] Formula (12), manufactured by a method including Step G below: [ka] [In the formula, a, b, c, and d are each independently either 1 or 2.] Compounds represented by, or their pharmaceutically acceptable salts, or their solvates: Step G: Formula (7): [ka] [In the formula, R 3 [is a protecting group for amino groups] By reacting a compound represented by (8), or a pharmaceutically acceptable salt thereof, or a solvate thereof, with an oxidizing agent in the presence of a solvent, the compound (8) is obtained. [ka] [In the formula, R 3 This is synonymous with the above. A process for producing a compound represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0094] [Section A2] A compound described in item A1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step H below: Step H: Formula (8): [ka] [In the formula, R 3 This is synonymous with the above. A compound represented by formula (8a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a condensing agent, is prepared using formula (8a): [ka] [In the formula, R 4 a, b, c, and d are synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with the compound represented by formula (9): [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0095] [Section A3] A compound described in item A2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step I below: Step I: Formula (9): [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with methyltriphenylphosphonium halogen, trialkylsilylmethyl anion, or a methylsulfone derivative in the presence of a solvent and a base to obtain formula (10): [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0096] [Section A4] A compound described in item A3, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step J below: Step J: Equation (10): [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with an acid to obtain formula (11): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0097] [Section A5] A compound described in item A4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step K below: Step K: Equation (11): [ka] [In the formula, a, b, c, and d are the same as above.] A compound represented by formula (11a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a base, is prepared using formula (11a): [ka] [In the formula, X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl group, or methanesulfonyl group.] The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with formula (12): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0098] [Section A6] A compound described in item A5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step L below: Step L: Equation (12): [ka] [In the formula, a, b, c, and d are the same as above.] The compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, is reacted with L(+)-tartaric acid in the presence of a solvent to obtain formula (12a): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by [the given symbol], or its solvate.

[0099] [Section A7] A compound described in any one of items A1 to A6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, manufactured by a method further comprising Step A below: Step A: Formula (1): [ka] [In the formula, R 1 C may be substituted. 1-6 It is alkyl, R 1A C may be substituted. 6-10 [Aryl] A compound represented by formula (1a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent, is subjected to the following reaction: [ka] [In the formula, R 2 C may be substituted. 1-6 It is alkyl. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with the compound represented by formula (2): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0100] [Section A8] A compound described in item A7, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step B below: Step B: Formula (2): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with 1,3-cyclohexadiene in the presence of a solvent and an acid to obtain formula (3): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0101] [Section A9] A compound described in item A8, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step C below: Step C: Formula (3): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with borane in the presence of a solvent, and then with a peroxide and a base to obtain formula (4): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0102] [Section A10] A compound described in item A9, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step D below: Step D: Formula (4): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. By reacting the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, with hydrogen in the presence of a catalyst, the protecting group on the amino group is deprotected, resulting in formula (5): [ka] [In the formula, R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0103] [Section A11] A compound described in item A10, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step E below: Step E: Formula (5): [ka] [In the formula, R 2 This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or the ester group of its solvate, is hydrolyzed to produce formula (6): [ka] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0104] [Section A12] A compound described in item A11, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step F below: Step F Formula (6): [ka] Protect the amino group of the compound represented by formula (7): or a pharmaceutically acceptable salt thereof, or its solvate. [ka] [In the formula, R 3 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0105] [Section A13] Formula (12), manufactured by a method including Step M below: [ka] [In the formula, a, b, c, and d are each independently either 1 or 2.] Compounds represented by, or their pharmaceutically acceptable salts, or their solvates: Step M: Formula (2): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A compound represented by formula (2a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent under acidic conditions, is prepared using formula (2a): [ka] [In the formula, R 5a , R 5b , and R 5c Each of them is independent of C 1-6 Alkyl or C 6-10 [Aryl] By reacting with a compound represented by formula (13), or a pharmaceutically acceptable salt thereof, or a solvate thereof, the compound (13) is obtained. [ka] [In the formula, R 1 , R 1A , R 2 , R 5a , R 5b , and R 5c This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0106] [Section A14] A compound described in item A13, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step A below: Step A: Formula (1): [ka] [In the formula, R 1 and R 1A This is synonymous with the above. A compound represented by formula (1a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent, is subjected to the following reaction: [ka] [In the formula, R 2 This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with the compound represented by formula (2): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0107] [Section A15] A compound described in section A13 or A14, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step N below: Step N: Equation (13): [ka] [In the formula, R 1 , R 1A , R 2 , R 5a , R 5b , and R 5c This is synonymous with the above. The silyl enol ether group of the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, is hydrolyzed to obtain formula (14): [ka] [In the formula, R 1 , R 1A, and R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0108] [Section A16] A compound described in item A15, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step O below: Step O: Equation (14): [ka] [In the formula, R 1 , R 1A , and R 2 This is synonymous with the above. By reacting the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, with hydrogen in the presence of a catalyst, the protecting group on the amino group is deprotected, resulting in formula (15): [ka] [In the formula, R 2 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0109] [Section A17] A compound described in item A16, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step P below: Step P: Formula (15): [ka] [In the formula, R 2 This is synonymous with the above. Protect the amino group of the compound represented by formula (16): or a pharmaceutically acceptable salt thereof, or its solvate. [ka] [In the formula, R 2 and R 3 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0110] [Section A18] A compound described in item A17, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step Q below: Step Q: Equation (16): [ka] [In the formula, R 2 and R 3 This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or the ester group of its solvate, is hydrolyzed to obtain formula (8): [ka] [In the formula, R 3 This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0111] [Section A19] A compound described in item A18, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step H below: Step H: Formula (8): [ka] [In the formula, R 3 This is synonymous with the above. A compound represented by formula (8a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a condensing agent, is prepared using formula (8a): [ka] [In the formula, R 4 a, b, c, and d are synonymous with the above. By reacting with a compound represented by formula (9), or a pharmaceutically acceptable salt thereof, or a solvate thereof, the following compound can be obtained: [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0112] [Section A20] A compound described in item A19, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step I below: Step I: Formula (9): [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. By reacting a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, with methyltriphenylphosphonium halide and a base in the presence of a solvent, formula (10) is obtained: [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0113] [Section A21] A compound described in item A20, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step J below: Step J: Equation (10): [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with an acid to obtain formula (11): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0114] [Section A22] A compound described in item A21, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step K below: Step K: Equation (11): [ka] [In the formula, a, b, c, and d are the same as above.] A compound represented by formula (11a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a base, is prepared using formula (11a): [ka] [In the formula, X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl group, or methanesulfonyl group.] The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with formula (12): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0115] [Section A23] A compound described in item A22, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step L below: Step L: Equation (11): [ka] [In the formula, a, b, c, and d are the same as above.] The compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, is reacted with L(+)-tartaric acid in the presence of a solvent to obtain formula (12a): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by [the given symbol], or its solvate.

[0116] [Section A24] Formula (12), manufactured by a method including Step H below: [ka] [In the formula, a, b, c, and d are each independently either 1 or 2.] Compounds represented by, or their pharmaceutically acceptable salts, or their solvates: Step H: Formula (8): [ka] [In the formula, R 3 This is synonymous with the above. A compound represented by formula (8a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a condensing agent, is prepared using formula (8a): [ka] [In the formula, R 4 a, b, c, and d are synonymous with the above. By reacting with a compound represented by formula (9), or a pharmaceutically acceptable salt thereof, or a solvate thereof, the following compound can be obtained: [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0117] [Section A25] A compound described in item A24, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step I below: Step I: Formula (9): [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with a methyltriphenylphosphonium halogen, a trialkylsilylmethyl anion, or a methylsulfone derivative in the presence of a solvent and a base to obtain formula (10): [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0118] [Section A26] A compound described in item A25, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step J below: Step J: Equation (10): [ka] [In the formula, R 3 , R 4 a, b, c, and d are synonymous with the above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with an acid to obtain formula (11): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0119] [Section A27] A compound described in item A26, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step K below: Step K: Equation (11): [ka] [In the formula, a, b, c, and d are the same as above.] A compound represented by formula (11a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a base, is prepared using formula (11a): [ka] [In the formula, X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl group, or methanesulfonyl group.] The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with formula (12): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0120] [Section A28] A compound described in item A27, or a pharmaceutically acceptable salt thereof, or a solvate thereof, prepared by a method further comprising Step L below: Step L: Equation (12): [ka] [In the formula, a, b, c, and d are the same as above.] The compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, is reacted with L(+)-tartaric acid in the presence of a solvent to obtain formula (12a): [ka] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by [the given symbol], or its solvate.

[0121] In this disclosure, one or more of the above features may be provided in combination with or without expressly provided. Further embodiments and advantages of this disclosure will be apparent to those skilled in the art, by reading and understanding the detailed description below as necessary. [Effects of the Invention]

[0122] In one embodiment, according to manufacturing method 1 of the present disclosure, the number of protection and deprotection steps is reduced compared to known manufacturing methods, and a manufacturing intermediate (8) can be produced in high yield and high purity. Furthermore, an optically active azabicyclo ring derivative (12) useful as a pharmaceutical can be produced from the intermediate (8) in just four steps in high yield and high purity.

[0123] In one embodiment, according to manufacturing method 2 of the present disclosure, a manufacturing intermediate (8) can be produced using a manufacturing intermediate (2a) in even fewer steps than in manufacturing method 1, and furthermore, an optically active azabicyclo ring derivative (12) useful as a pharmaceutical can be produced from the intermediate (8) in just four steps in high yield and high purity. [Modes for carrying out the invention]

[0124] The present disclosure is described below in best form. Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Accordingly, singular articles (e.g., "a," "an," "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. In case of any conflict, this specification (including definitions) shall prevail.

[0125] Since the compounds of this disclosure may also exist in the form of solvates (e.g., hydrates), the compounds represented by 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 solvates (e.g., hydrates) of their pharmaceutically acceptable salts as needed, are also included in the compounds of this disclosure.

[0126] Compounds represented by 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 chiral carbon atoms and may exhibit geometric isomerism or axial chirality, thus existing as several stereoisomers. In this disclosure, these stereoisomers, mixtures thereof, and racemates are also included in the compounds of this disclosure.

[0127] Furthermore, one or more compounds represented by formulas (1), (1a), (2), (2a), (3), (4), (5), (6), (7), (8), (8a), (9), (10), (11), (11a), (12), (12a), (13), (14), (15), and (16) may be included. 1 H (hydrogen atom) 2 Deuterium convertibles converted to H(D: deuterium atom) are also included in the compounds represented by formulas (1), (1a), (2), (2a), (3), (4), (5), (6), (7), (8), (8a), (9), (10), (11), (11a), (12), (12a), (13), (14), (15), and (16).

[0128] Compounds represented by formulas (1), (1a), (2), (2a), (3), (4), (5), (6), (7), (8), (8a), (9), (10), (11), (11a), (12), (12a), (13), (14), (15), and (16) obtained as crystals, or their tautomers, or pharmaceutically acceptable salts thereof as needed, may have crystalline polymorphisms, which are also included in the compounds disclosed herein.

[0129] In this specification, the number of carbon atoms in the definition of a "substituent" is defined as, for example, "C 1-6 It may also be written as "C 1-6The term "alkyl" is synonymous with alkyl groups having 1 to 6 carbon atoms. Furthermore, in this specification, substituents that are not explicitly defined as "may be substituted," "may be substituted," or "substituted" refer to "unsubstituted" substituents. For example, "C 1-6 "Alkyl" refers to "unsubstituted" C 1-6 It means that it is alkyl.

[0130] In this specification, the term "group" means a monovalent group. For example, "alkyl group" means a monovalent saturated hydrocarbon group. In addition, the term "group" may be omitted in the description of substituents in this specification.

[0131] The terms used in this specification are defined below.

[0132] In this specification, the number of substituents in a group defined as “may be substituted,” “may be substituted,” or “substituted” is not particularly limited as long as substitution is possible, and can be 0, 1, or more. Furthermore, unless otherwise indicated, the definition of each group also applies when that group is a part of or a substituent of another group.

[0133] In this specification, the substituent in “may be substituted…” can be appropriately selected depending on the group being substituted. For example, “may be substituted C 1-6 "Alkyl alkyl group" means the C which may be substituted with a fluorine atom, a chlorine atom, a phenyl group, a methoxy group, and / or a hydroxyl group at any substituted position. 1-6 This refers to alkyl groups, and examples include methyl group, ethyl group, n-propyl group, isopropyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2-methoxyethyl group, and benzyl group. Preferably, it is a methyl group, ethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2-methoxyethyl group, or benzyl group.

[0134] "C 1-6"Alkyl" refers to a linear or branched saturated hydrocarbon group with 1 to 6 carbon atoms, and "C6 alkyl" refers to an alkyl group with 6 carbon atoms. The same applies to other numbers of carbon atoms. 1-6 Preferably, the alkyl group is "C 1-4 Examples include "alkyl", and more preferably "C 1-3 "Alkyl" is one example. 1-3 Specific examples of "alkyl" include, for example, methyl, ethyl, propyl, 1-methylethyl, etc. 1-4 A specific example of "alkyl" is, for example, the aforementioned "C 1-3 In addition to the examples listed for "alkyl," other examples include butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. 1-6 A specific example of "alkyl" is, for example, the aforementioned "C 1-4 In addition to the examples listed for "alkyl," other examples include pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, and hexyl.

[0135] "C 6-10 "Aryl" refers to an aromatic hydrocarbon ring group with 6 to 10 carbon atoms. 6-10 Specific examples of "aryl" include phenyl, 1-naphthyl, and 2-naphthyl.

[0136] In the reaction of this disclosure, a correlation transfer catalyst such as a tetrabutylammonium salt may be added as needed, to the extent that it does not adversely affect the reaction.

[0137] The term "base" includes both organic and inorganic bases.

[0138] Specific examples of "organic bases" include, but are not limited to, 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-ruditine, pyrimidine or pyridine, or mixtures thereof. More preferably, 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, or pyridine are mentioned. Even more preferably, 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, or pyridine are mentioned. Most preferably, sodium tert-butoxide, potassium tert-butoxide, triethylamine, or N,N-diisopropylethylamine are mentioned.

[0139] Specific examples of "inorganic bases" include, but are not limited to, ammonia, lithium hydroxide, sodium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, or cesium carbonate, or mixtures thereof. Preferably, lithium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or cesium carbonate are used. More preferably, sodium carbonate, potassium carbonate, sodium bicarbonate, or cesium carbonate are used. Most preferably, potassium carbonate is used.

[0140] The term "acid" includes both organic and inorganic acids.

[0141] "Organic acids" include organic acids and Lewis acids, and specific examples include, but are not limited to, 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), hydrogen phosphate-1,1'-binaphthyl-2,2'-diyl, hydrogen phosphate-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl, hydrogen phosphate-3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl, trifluoroborane diethyl ether complex, trimethylsilyl chloride, diethylaluminum chloride, zinc bromide, tetrachlorotitanium, magnesium bromide diethyl ether complex, or mixtures thereof. More preferably, trifluoroacetic acid, or trifluoroborane diethyl ether complex, or mixtures thereof are included.

[0142] Specific examples of "inorganic acids" include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, or sulfuric acid, or mixtures thereof. Hydrochloric acid is preferred.

[0143] An "alcohol-based solvent" refers to a compound containing one or more hydroxyl groups in its molecule, which is a liquid at the reaction temperature and has the property of dissolving or dispersing the reaction substrate. Specific examples of "alcohol-based solvents" include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, or tert-butyl alcohol. Preferably, methanol, ethanol, or 2-propanol are used. More preferably, ethanol is used.

[0144] An "amide solvent" is a compound containing one or more amide bonds in its molecule, which is a liquid at the reaction temperature and has the property of dissolving or dispersing the reaction substrate. Specific examples of "amide solvents" include N,N-dimethylacetamide, N,N-dimethylformamide, N,N-diethylformamide, N-methyl-2-pyrrolidone, tetramethylurea, or hexamethylphosphoric triamide. Preferably, N,N-dimethylformamide or N-methyl-2-pyrrolidone are used as "amide solvents." More preferably, N,N-dimethylformamide is used.

[0145] A "halogen-based solvent" refers to a compound containing one or more halogen atoms in its molecule, which is a liquid at the reaction temperature and has the property of dissolving or dispersing the reaction substrate. Specific examples of "halogen-based solvents" include dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene. Dichloromethane is preferably used as the "halogen-based solvent."

[0146] An "ether-based solvent" refers to a compound containing one or more ether bonds in its molecule, which is a liquid at the reaction temperature and has the property of dissolving or dispersing the reaction substrate. Specific examples of "ether-based solvents" include diethyl ether, tetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxane. Preferably, the "ether-based solvent" is tetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxane.

[0147] An "ester-based solvent" refers to a compound containing one or more ester bonds in its molecule, which is a liquid at the reaction temperature and has the property of dissolving or dispersing the reaction substrate. Specific examples of "ester-based solvents" include ethyl acetate and isopropyl acetate. Ethyl acetate is preferred as the "ester-based solvent."

[0148] "Protective groups for amino groups" include, for example, the protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). Specific examples of "protective groups for amino groups" include the tert-butoxycarbonyl group or the benzyloxycarbonyl group. Preferably, the tert-butoxycarbonyl group is used.

[0149] "Amino group protecting reagent" refers to a reagent used to protect an amino group. Specific examples of "amino group protecting reagents" include di-tert-butyl dicarbonate and benzyl chloroformate. Di-tert-butyl dicarbonate is preferred.

[0150] A "condensing agent" refers to a reagent used to dehydrate and condense a carboxyl group and an amino group to produce an amide group. Specific examples of "condensing agents" include, but are not limited to, 1-hydroxybenzotriazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, or mixtures thereof. Preferably, the "condensing agent" is a mixture of 1-hydroxybenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0151] Specific examples of "halogenated methyltriphenylphosphonium" include methyltriphenylphosphonium bromide and methyltriphenylphosphonium iodide. Preferably, "halogenated methyltriphenylphosphonium" is methyltriphenylphosphonium bromide.

[0152] Specific examples of "trialkylsilylmethyl anion" include trimethylsilylmethyllithium and trimethylsilylmethylmagnesium. Trimethylsilylmethyllithium is preferred as the "trialkylsilylmethyllithium" example.

[0153] Specific examples of "methylsulfone derivatives" include 1-methyl-2-(methylsulfonyl)benzimidazole and 2-(methylsulfonyl)benzothiazole. Preferably, 1-methyl-2-(methylsulfonyl)benzimidazole is used as the "methylsulfone derivative".

[0154] Specific examples of "peroxides" include hydrogen peroxide, cumene hydroperoxide, benzoyl peroxide, peracetic acid, and sodium peroxoborate (including its hydrate). Preferably, the "peroxide" is hydrogen peroxide, and sodium peroxoborate containing its hydrate. More preferably, sodium peroxoborate containing its hydrate is included.

[0155] Specific examples of "borane" include borane or 9-borabicyclo[3.3.1]nonane, and also include dimerized forms and those that form complexes with solvents. Preferably, "borane" is borane or a borane-tetrahydrofuran complex.

[0156] Specific examples of "oxidizing agents" include 1-methyl-2-azaadamantane-N-oxyl, 2-hydroxy-2-azaadamantane, 9-azanoradamantane-N-oxyl, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one, potassium 2-iodo-5-methylbenzenesulfonate, DMSO and oxalyl chloride combinations, acetic anhydride, sulfur trioxide-pyridine complex, N,N'-dicyclohexylcarbodiimide, chromium trioxide, tetrapropylammonium perruthenate, sodium hypochlorite pentahydrate, 2,2,6,6-tetramethylpiperidine 1-oxyl, and sodium periodate. Preferably, the "oxidizing agent" is 2,2,6,6-tetramethylpiperidine 1-oxyl and sodium periodate, and more preferably 2,2,6,6-tetramethylpiperidine 1-oxyl.

[0157] Specific examples of "reoxidizing agents" include oxygen, oxone, morpholine N-oxide, trichloroisocyanuric acid, sodium hypochlorite, and iodobenzene diacetate. Trichloroisocyanuric acid is preferably used as the "reoxidizing agent."

[0158] In this specification, when referring to solvents, etc., the expression "at least one independently selected from..." is understood to include a mixture of two or more of these options if two or more are selected.

[0159] As used herein, unless otherwise specified, the term “pharmaceutically acceptable salt” means a salt prepared from a pharmaceutically acceptable acid (including inorganic and organic acids). Furthermore, “a pharmaceutically acceptable salt as needed” means that it may optionally be a pharmaceutically acceptable salt; for example, in the production of intermediates, a salt that is not pharmaceutically acceptable may be used up to a certain stage. Pharmaceutically acceptable salts include, but are not limited to, acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethensulfonic acid, formic acid, fumaric acid, fluoronic acid, gluconic acid, glutamic acid, glucorenic acid, galacturonic acid, glycidic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, nitric acid, pamoic 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.

[0160] "Purification" refers to any act that increases the purity of a target substance and reduces the concentration of other substances below the concentration before the purification process. Various methods are used for purification, including precipitation, recrystallization, sublimation, distillation, solvent extraction, use of molecular sieves, and application of various chromatography techniques. Filtration using filter paper or Celite is not included in the definition of purification.

[0161] Among the compounds of this disclosure represented by formulas (1), (1a), (2), (2a), (3), (4), (5), (7), (8), (8a), (9), (10), (11), (11a), (12), (12a), (13), (14), (15), and (16), R 1 , R 1A , R 2 , R 3 , R 4 , R 5a , R 5b , R 5c Of a, b, c, and d, the following are preferred, but are not limited to the following ranges.

[0162] R 1 A preferred embodiment is C 1-3 Alkyl compounds are examples. R 1 A more preferred embodiment is a methyl group.

[0163] R 1A A preferred embodiment is C 6-10 Aryl is one example. R 1A A more preferred embodiment is a phenyl group.

[0164] R 2 A preferred embodiment is C 1-3 Alkyl compounds are examples. R 2 A more preferred embodiment is the ethyl group.

[0165] R 3 Preferred embodiments include a tert-butoxycarbonyl group or a benzyloxycarbonyl group. R 3 A more preferred embodiment is a tert-butoxycarbonyl group.

[0166] R 4 Preferred embodiments include a tert-butoxycarbonyl group or a benzyloxycarbonyl group. R 4A more preferred embodiment is a tert-butoxycarbonyl group.

[0167] R 5a , R 5b and R 5c A preferred embodiment of this is that each is independent of C 1-4 Examples include alkyl or phenyl groups. R 5a , R 5b and R 5c More preferred embodiments include, independently, a methyl group or a phenyl group. R 5a , R 5b and R 5c A more preferred embodiment is a methyl group.

[0168] A preferred embodiment of a, b, c, and d is, independently, 1 or 2.

[0169] Preferred embodiments of a and c are, independently, 1 or 2. A more preferred embodiment of a and c is 1.

[0170] Preferred embodiments of b and d are, independently, 1 or 2. A more preferred embodiment of b and d is 2.

[0171] Preferred embodiments of X include fluorine, chlorine, bromine, iodine, a p-toluenesulfonyl group, or a methanesulfonyl group. A more preferred embodiment of X is chlorine, bromine, or a p-toluenesulfonyl group. A more preferred embodiment of X is chlorine.

[0172] Examples of compounds represented by formula (1) include (1-A) below. (1-A) R 1 However, C 1-3 It is alkyl, R1A However, C 6-10 It is Ariel. The compound of formula (1), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0173] Among the compounds represented by formula (1), preferred embodiments include (1-B) below. (1-B) R 1 It is a methyl group, R 1A However, it is a phenyl group. The compound of formula (1), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0174] The following (1a-A) are examples of compounds represented by formula (1a). (1a-A) R 2 However, C 1-3 It is alkyl. The compound of formula (1a), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0175] Among the compounds represented by formula (1a), preferred embodiments include the following (1a-B). (1a-B) R 2 However, it is an ethyl group, The compound of formula (1a), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0176] Examples of compounds represented by formula (2) include (2-A) below. (2-A) R 1 and R 2 However, each is independent of C 1-3 It is alkyl, R 1A However, C 6-10 It is Ariel. The compound of formula (2), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0177] Among the compounds represented by formula (2), preferred embodiments include (2-B) below. (2-B) R 1 However, it is a methyl group, R 2 However, it is an ethyl group, R 1A However, it is a phenyl group. The compound of formula (2), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0178] The following (2a-A) are examples of compounds represented by formula (2a). (2a-A) R 5a , R 5b and R 5c However, each is independent of C 1-4 It is an alkyl or phenyl group. The compound of formula (2a), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0179] Among the compounds represented by formula (2a), preferred embodiments include (2a-B) below. (2a-B) R 5a , R 5b and R 5c However, it is a methyl group. The compound of formula (2a), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0180] Examples of compounds represented by formula (3) include (3-A) below. (3-A) R 1 and R 2 However, each is independent of C 1-3 It is alkyl, R 1A However, C 6-10 It is Ariel. The compound of formula (3), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0181] Among the compounds represented by formula (3), preferred embodiments include (3-B) below. (3-B) R 1 However, it is a methyl group, R 2 However, it is an ethyl group, R 1A However, it is a phenyl group. The compound of formula (3), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0182] Examples of compounds represented by formula (4) include (4-A) below. (4-A) R 1 and R 2 However, each is independent of C 1-3 It is alkyl, R 1A However, C 6-10 It is Ariel. The compound of formula (4), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0183] Among the compounds represented by formula (4), preferred embodiments include (4-B) below. (4-B) R 1 However, it is a methyl group, R 2 However, it is an ethyl group, R 1A However, it is a phenyl group. The compound of formula (4), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0184] Examples of compounds represented by formula (5) include (5-A) below. (5-A) R 2 C 1-3 It is alkyl. The compound of formula (5), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0185] Among the compounds represented by formula (5), preferred embodiments include (5-B) below. (5-B) R 2 However, it is an ethyl group, The compound of formula (5), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0186] Examples of compounds represented by formula (7) include (7-A) below. (7-A) R 3 However, it is a tert-butoxycarbonyl group. The compound of formula (7), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0187] Examples of compounds represented by formula (8) include (8-A) below. (8-A) R 3 However, it is a tert-butoxycarbonyl group. The compound of formula (8), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0188] The following (8a-A) are examples of compounds represented by formula (8a). (8a-A) a, b, c, and d are each independently either 1 or 2. R 4 However, it is a tert-butoxycarbonyl group. The compound of formula (8a), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0189] Among the compounds represented by formula (8a), preferred embodiments include (8a-B) below. (8a-B) a and c are 1, b and d are 2, R 4 However, it is a tert-butoxycarbonyl group. The compound of formula (8a), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0190] Examples of compounds represented by formula (9) include (9-A) below. (9-A) a, b, c, and d are each independently either 1 or 2. R 3 and R 4 However, it is a tert-butoxycarbonyl group. The compound of formula (9), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0191] Among the compounds represented by formula (9), preferred embodiments include (9-B) below. (9-B) a and c are 1, b and d are 2, R 3 and R 4 However, it is a tert-butoxycarbonyl group. The compound of formula (9), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0192] Examples of compounds represented by formula (10) include (10-A) below. (10-A) a, b, c, and d are each independently either 1 or 2. R 3 and R 4 However, it is a tert-butoxycarbonyl group. The compound of formula (10), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0193] Among the compounds represented by formula (10), preferred embodiments include (10-B) below. (10-B) a and c are 1, b and d are 2, R 3 and R 4 However, it is a tert-butoxycarbonyl group. The compound of formula (10), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0194] Examples of compounds represented by formula (11) include (11-A) below. (11-A) a, b, c, and d are each independently either 1 or 2. The compound of formula (11), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0195] Among the compounds represented by formula (11), preferred embodiments include (11-B) below. (11-B) a and c are 1, b and d are 2. The compound of formula (11), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0196] The following (11a-A) are examples of compounds represented by formula (11a). (11a-A) X is chlorine, bromine, or a p-toluenesulfonyl group. The compound of formula (11a), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0197] Among the compounds represented by formula (11a), preferred embodiments include (11a-B) below. (11a-B) X is chlorine. The compound of formula (11a), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0198] Examples of compounds represented by formula (12) include (12-A) below. (12-A) a, b, c, and d are each independently either 1 or 2. The compound of formula (12), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0199] Among the compounds represented by formula (12), preferred embodiments include (12-B) below. (12-B) a and c are 1, b and d are 2. The compound of formula (12), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0200] The following (12a-A) are examples of compounds represented by formula (12a). (12a-A) a, b, c, and d are each independently either 1 or 2. The compound of formula (12a), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0201] Among the compounds represented by formula (12a), preferred embodiments include (12a-B) below. (12a-B) a and c are 1, b and d are 2. The compound of formula (12a), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0202] Examples of compounds represented by formula (13) include (13-A) below. (13-A) R 1 However, C 1-3 It is alkyl, R 1A However, C 6-10 It is Ariel, R 5a , R 5b and R 5c However, each is independent of C 1-4 It is alkyl. The compound of formula (13), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0203] Among the compounds represented by formula (13), preferred embodiments include (13-B) below. (13-B) R 1 However, it is a methyl group, R 1A However, it is a phenyl group, R 5a , R 5b and R 5c However, it is a methyl group. The compound of formula (13), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0204] Examples of compounds represented by formula (14) include (14-A) below. (14-A) R 1 and R 2 However, each is independent of C 1-3 It is alkyl, R 1A However, C 6-10 It is Ariel. The compound of formula (14), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0205] Among the compounds represented by formula (14), preferred embodiments include (14-B) below. (14-B) R 1 However, it is a methyl group, R 2 However, it is an ethyl group, R 1A However, it is a phenyl group. The compound of formula (14), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0206] Examples of compounds represented by formula (15) include (15-A) below. (15-A) R 2 However, C 1-3 It is alkyl. The compound of formula (15), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0207] Among the compounds represented by formula (15), preferred embodiments include (15-B) below. (15-B) R 2 However, it is an ethyl group, The compound of formula (15), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0208] Examples of compounds represented by formula (16) include (16-A) below. (16-A) R 2 However, C 1-3 It is alkyl, R 3 However, it is a tert-butoxycarbonyl group. The compound of formula (16), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0209] Among the compounds represented by formula (16), preferred embodiments include (16-B) below. (16-B) R 2 However, it is an ethyl group, R 3 However, it is a tert-butoxycarbonyl group. The compound of formula (16), or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0210] The present invention will now be described in more detail with reference to preferred embodiments, but the technical scope of the present invention is not limited to these preferred embodiments. Furthermore, modifications may be made without departing from the scope of this disclosure. Note that the compound names shown in the following preferred embodiments do not necessarily conform to IUPAC nomenclature.

[0211] The following describes methods for producing compounds of (1), (1a), (2), (2a), (3), (4), (5), (6), (7), (8), (8a), (9), (10), (11), (11a), (12), (12a), (13), (14), (15), and (16) relating to this disclosure, or their tautomers, stereoisomers, mixtures thereof, or racemates, or pharmaceutically acceptable salts thereof, or solvates thereof as needed (these are used as intermediates for the production of optically active azabicyclo ring derivatives (formula (12))). Optically active azabicyclo ring derivatives of formula (12) and their intermediates can be produced from known compounds by the following production methods and similar methods, or by synthesis methods well known to those skilled in the art. They can also be produced by combining these methods as appropriate.

[0212] Furthermore, the compounds obtained in each step can be used in the next reaction either as a reaction solution or as a composition. However, they can also be isolated from the reaction mixture according to conventional methods and easily purified by separation methods such as recrystallization, distillation, and chromatography.

[0213] In the following reactions, the symbols of the compounds have the same meaning as above unless otherwise specified.

[0214] The manufacturing method of this disclosure is described below. Starting materials not described below can be manufactured by commercially available methods, methods known to those skilled in the art, or similar methods.

[0215] (Manufacturing method 1) [ka]

[0216] (Manufacturing method 2) [ka] (In the formula, R 1 , R 1A , R 2 , R 3 , R 4 , R5a , R 5b , R 5c (a, b, c, and d are synonymous with item 1 and / or other items.)

[0217] Steps A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, and Q will be described below with reference to preferred embodiments, but this disclosure is not limited to these.

[0218] Step A [ka] (In the formula, R 1 , R 1A and R 2 This is synonymous with item 1 and / or other items.

[0219] This process involves reacting a compound represented by formula (1) with a compound represented by formula (1a) in a solvent to obtain a compound represented by formula (2).

[0220] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include halogenated solvents, preferably dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene, and more preferably dichloromethane.

[0221] The amount of solvent used in this process is typically 2 to 20 parts by weight, preferably 5 to 20 parts by weight, and more preferably 8 to 15 parts by weight, per 1 weight of the compound represented by formula (1).

[0222] The amount of compound represented by formula (1a) used is typically 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, more preferably 1.0 to 2.0 equivalents, and most preferably 1.0 to 1.2 equivalents, relative to 1 equivalent of the compound represented by formula (1).

[0223] The reaction time is typically 0.5 to 12 hours, preferably 0.5 to 8 hours.

[0224] The reaction temperature is typically -30°C to 120°C, preferably -30°C to 130°C, more preferably -30°C to 50°C, and even more preferably -20°C to 30°C.

[0225] A desiccant may be added as an additive to accelerate the reaction, preferably in an amount of 1.0 to 5.0 parts by weight per 1 weight of the compound represented by formula (1a). Examples of desiccants include sodium sulfate, magnesium sulfate, and molecular sieves. Sodium sulfate is more preferred.

[0226] R 1 and R 2 Preferably, as defined above.

[0227] Instead of the compound represented by formula (1a), the compounds represented by formulas (1a-B) and (1a-C), obtained by the following method, can be used. [ka] (In the formula, R 2 (This is synonymous with item 1 and / or other items.)

[0228] This process involves oxidizing the compound represented by formula (1a-A) in a solvent to obtain compounds represented by formulas (1a-B) and (1a-C).

[0229] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include halogenated solvents or mixed solvents of halogenated solvents and water, preferably dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, or mixed solvents of these halogenated solvents and water, and more preferably dichloromethane or a mixed solvent of dichloromethane and water.

[0230] The oxidizing agents used in this process include 2,2,6,6-tetramethylpiperidine 1-oxyl, 1-methyl-2-azaadamantane-N-oxyl, 2-hydroxy-2-azaadamantane, 9-azanoradamantane-N-oxyl, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-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, and sodium periodate, with sodium periodate being preferred.

[0231] The amount of solvent used in this process is typically 2 to 20 parts by weight, preferably 5 to 20 parts by weight, and more preferably 8 to 15 parts by weight, per 1 weight of the compound represented by formula (1a-A).

[0232] The amount of oxidizing agent used in this process is typically 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, and more preferably 1.0 to 1.5 equivalents, relative to one equivalent of the compound represented by formula (1a-A).

[0233] The reaction time is typically 1 to 48 hours, preferably 5 to 36 hours, and more preferably 12 to 24 hours.

[0234] The reaction temperature is typically 0°C to 50°C, preferably 5°C to 40°C, and more preferably 10°C to 30°C.

[0235] R 2 Preferably, as defined above.

[0236] Step B [ka] (In the formula, R 1, R 1A and R 2 This is synonymous with item 1 and / or other items.

[0237] This process involves reacting a compound represented by formula (2) with 1,3-cyclohexadiene in the presence of a solvent and an acid to obtain a compound represented by formula (3).

[0238] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include halogenated solvents, preferably dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene, and more preferably dichloromethane.

[0239] The acid used in this process is an organic acid, preferably trifluoroacetic acid, or a trifluoroborane-diethyl ether complex or a mixture thereof, and more preferably a mixture of trifluoroacetic acid and a trifluoroborane-diethyl ether complex.

[0240] The amount of solvent used in this step is typically 2 to 20 parts by weight, preferably 3 to 10 parts by weight, and more preferably 4 to 8 parts by weight, per 1 weight of the compound represented by formula (2).

[0241] The amount of 1,3-cyclohexadiene used in this process is typically 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, more preferably 1.0 to 2.0 equivalents, and most preferably 1.0 to 1.6 equivalents, relative to 1 equivalent of the compound represented by formula (2).

[0242] The amount of acid used in this step is typically 0.3 to 3.0 equivalents, preferably 0.5 to 2.0 equivalents, more preferably 0.5 to 1.5 equivalents, and most preferably 0.8 to 1.2 equivalents, relative to 1 equivalent of the compound represented by formula (2).

[0243] The reaction time is typically 0.5 to 24 hours, preferably 5 to 20 hours.

[0244] The reaction temperature is typically -80°C to 60°C, preferably -70°C to 50°C, and more preferably -70°C to 30°C.

[0245] R 1 and R 2 Preferably, as defined above.

[0246] Step C [ka] (In the formula, R 1 , R 1A and R 2 This is synonymous with item 1 and / or other items.

[0247] This process involves reacting the compound represented by formula (3) with borane in the presence of a solvent, and then reacting it with a peroxide and a base to obtain the compound represented by formula (4).

[0248] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include ether-based solvents, preferably diethyl ether, tetrahydrofuran, and methyl tert-butyl ether, and more preferably methyl tert-butyl ether.

[0249] The borane used in this process may be borane or 9-borabicyclo[3.3.1]nonane, and may also be dimerized or complex with a solvent, with borane-tetrahydrofuran complex being a preferred example.

[0250] The base used in this process is an inorganic base, preferably lithium hydroxide, sodium hydroxide, or potassium hydroxide, and more preferably sodium hydroxide.

[0251] The peroxides used in this process include hydrogen peroxide, cumene hydroperoxide, benzoyl peroxide, peracetic acid, and sodium peroxoborate (including its hydrate), preferably hydrogen peroxide and sodium peroxoborate (including its hydrate), and more preferably sodium peroxoborate (including its hydrate).

[0252] The amount of solvent used in this process is typically 1 to 20 parts by weight, preferably 1 to 10 parts by weight, and more preferably 1 to 2 parts by weight, per unit weight of the compound represented by formula (3).

[0253] The amount of borane used in this process is typically 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, more preferably 1.0 to 2.0 equivalents, and most preferably 1.0 to 1.6 equivalents, relative to one equivalent of the compound represented by formula (3).

[0254] The amount of peroxide used in this process is typically 1.0 to 20.0 equivalents, preferably 1.0 to 10.0 equivalents, and more preferably 1.0 to 6.0 equivalents, relative to one equivalent of the compound represented by formula (3).

[0255] The reaction time is typically 0.5 to 24 hours, preferably 3 to 20 hours.

[0256] The reaction temperature is typically -50°C to 50°C, preferably -40°C to 40°C, and more preferably -30°C to 30°C.

[0257] R 1 and R 2 Preferably, as defined above.

[0258] Step D [ka] (In the formula, R 1 , R1A and R 2 This is synonymous with item 1 and / or other items.

[0259] This process involves reacting the compound represented by formula (4) with hydrogen in the presence of a solvent and a catalyst to obtain the compound represented by formula (5).

[0260] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include alcoholic solvents, preferably ethanol and methanol, and more preferably methanol.

[0261] The catalyst used in this process is preferably Pd / C.

[0262] The amount of solvent used in this process is typically 2 to 20 parts by weight, preferably 2 to 10 parts by weight, and more preferably 2 to 5 parts by weight, per 1 weight of the compound represented by formula (4).

[0263] The amount of catalyst used in this process is typically 1.0 to 30.0 parts by weight, preferably 5.0 to 20.0 parts by weight, and more preferably 7.0 to 15.0 parts by weight, per 1 weight of the compound represented by formula (4).

[0264] The reaction time is typically 0.5 to 48 hours, preferably 12 to 30 hours.

[0265] The reaction temperature is typically 0°C to 60°C, preferably 10°C to 50°C, and more preferably 15°C to 40°C.

[0266] R 1 and R 2 Preferably, as defined above.

[0267] Step E [ka] (In the formula, R 2 (This is synonymous with item 1 and / or other items.)

[0268] This process involves reacting the compound represented by formula (5) with a base in the presence of a solvent to obtain the compound represented by formula (6).

[0269] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include ether-based solvents, preferably tetrahydrofuran and 1,4-dioxane, and more preferably dioxane.

[0270] The base used in this process is preferably sodium hydroxide or potassium hydroxide, and more preferably sodium hydroxide. The base may also be used as an aqueous solution.

[0271] The amount of solvent used in this process is typically 2 to 20 parts by weight, preferably 5 to 15 parts by weight, and more preferably 8 to 15 parts by weight, per 1 weight of the compound represented by formula (5).

[0272] The amount of base used in this process is typically 1.0 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, and more preferably 1.0 to 1.5 equivalents, per equivalent of the compound represented by formula (5).

[0273] The reaction time is typically 0.5 to 24 hours, preferably 1 to 10 hours, and more preferably 2 to 5 hours.

[0274] The reaction temperature is typically 0°C to 60°C, preferably 0°C to 40°C, and more preferably 5°C to 30°C.

[0275] R 2 Preferably, as defined above.

[0276] Step F [ka] (In the formula, R 3 (This is synonymous with item 1 and / or other items.)

[0277] This process involves reacting a compound represented by formula (6) with an amino group protecting reagent in the presence of a solvent to obtain a compound represented by formula (7).

[0278] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include ether-based solvents, preferably tetrahydrofuran and 1,4-dioxane, and more preferably dioxane.

[0279] The amino group protecting reagent used in this process is preferably di-tert-butyl dicarbonate or benzyloxycarbonyl chloride, and more preferably di-tert-butyl dicarbonate.

[0280] The amount of solvent used in this process is typically 2 to 20 parts by weight, preferably 5 to 15 parts by weight, and more preferably 8 to 15 parts by weight, per 1 weight of the compound represented by formula (6).

[0281] The amount of amino group protecting reagent used in this process is typically 1.0 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, and more preferably 1.0 to 1.5 equivalents, per equivalent of the compound represented by formula (6).

[0282] The reaction time is typically 0.5 to 48 hours, preferably 5 to 36 hours, and more preferably 12 to 24 hours.

[0283] The reaction temperature is typically -20°C to 50°C, preferably -10°C to 40°C, and more preferably 0°C to 30°C.

[0284] R 3Preferably, as defined above.

[0285] Step G [ka] (In the formula, R 3 (This is synonymous with item 1 and / or other items.)

[0286] This process involves reacting the compound represented by formula (7) with an oxidizing agent and a reoxidizing agent in the presence of a solvent to obtain the compound represented by formula (8).

[0287] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include ester-based solvents and halogen-based solvents, preferably ester-based solvents, and more preferably ethyl acetate.

[0288] The oxidizing agents used in this process include 2,2,6,6-tetramethylpiperidine 1-oxyl, 1-methyl-2-azaadamantane-N-oxyl, 2-hydroxy-2-azaadamantane, 9-azanoradamantane-N-oxyl, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-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, and sodium hypochlorite pentahydrate, with 2,2,6,6-tetramethylpiperidine 1-oxyl being preferred.

[0289] The reoxidizing agents used in this process are preferably trichloroisocyanuric acid, sodium hypochlorite, iodobenzene diacetate, air, oxygen, oxone, and N-morpholine oxide, and more preferably trichloroisocyanuric acid.

[0290] The amount of solvent used in this process is typically 2 to 80 parts by weight, preferably 10 to 70 parts by weight, and more preferably 20 to 60 parts by weight, per 1 weight of the compound represented by formula (7).

[0291] The amount of oxidizing agent used in this process is typically 0.01 to 0.2 equivalents, preferably 0.01 to 0.1 equivalents, and more preferably 0.01 to 0.08 equivalents, relative to one equivalent of the compound represented by formula (7).

[0292] The amount of reoxidizing agent used in this process is typically 0.3 to 2.0 equivalents, preferably 0.3 to 1.5 equivalents, and more preferably 0.3 to 1.0 equivalent, per equivalent of the compound represented by formula (7).

[0293] The reaction time is typically 0.5 to 15 hours, preferably 1 to 12 hours, and more preferably 1 to 8 hours.

[0294] The reaction temperature is typically -20°C to 50°C, preferably -10°C to 30°C, and more preferably -10°C to 10°C.

[0295] R 3 Preferably, as defined above.

[0296] Step H [ka] (In the formula, a, b, c, d, R 3 and R 4 This is synonymous with item 1 and / or other items.

[0297] This process involves reacting a compound represented by formula (8) with a compound represented by formula (8a) in the presence of a solvent, a base, and a condensing agent to obtain a compound represented by formula (9).

[0298] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include amide solvents, preferably N,N-dimethylformamide and N-methyl-2-pyrrolidone, and more preferably N,N-dimethylformamide.

[0299] The base used in this process is an organic base, preferably triethylamine, diisopropylethylamine, or pyridine, more preferably triethylamine or N,N-diisopropylethylamine, and most preferably triethylamine.

[0300] The condensing agents used in this process are thionyl chloride, diphenyl phosphate azide, propylphosphonic anhydride, 1,1-carbonyl diimidazole, 1H-benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate, {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylammonium hexafluorophosphate, O-(7-azabenzotriazole-1-yl)-N,N,N'N'-the Examples include tramethyluronium hexafluorophosphate, 1-hydroxyazabenzotriazole, 1-hydroxybenzotriazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, or mixtures thereof, with a preferred example being a mixture of 1-hydroxybenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0301] The amount of solvent used in this process is typically 2 to 20 parts by weight, preferably 5 to 15 parts by weight, and more preferably 7 to 12 parts by weight, per 1 weight of the compound represented by formula (8).

[0302] The amount of compound represented by formula (8a) used is typically 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, more preferably 1.0 to 2.0 equivalents, and most preferably 1.0 to 1.5 equivalents, relative to 1 equivalent of the compound represented by formula (8).

[0303] The amount of base used in this process is typically 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, more preferably 1.0 to 2.0 equivalents, and most preferably 1.0 to 1.6 equivalents, relative to 1 equivalent of the compound represented by formula (8).

[0304] The amount of condensing agent used in this process is typically 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, more preferably 1.0 to 2.0 equivalents, and most preferably 1.0 to 1.6 equivalents, relative to 1 equivalent of the compound represented by formula (8).

[0305] The reaction time is typically 0.5 to 24 hours, preferably 0.5 to 5 hours, and more preferably 0.5 to 2 hours.

[0306] The reaction temperature is typically 0°C to 60°C, preferably 0°C to 40°C, and more preferably 10°C to 30°C.

[0307] R 3 and R 4 Preferably, as defined above.

[0308] Step I [ka] (In the formula, a, b, c, d, R 3 and R 4 This is synonymous with item 1 and / or other items.

[0309] This process involves reacting a compound represented by formula (9) with methyltriphenylphosphonium halide in the presence of a solvent and a base to obtain a compound represented by formula (10).

[0310] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include ether-based solvents, preferably diethyl ether, tetrahydrofuran, and methyl tert-butyl ether, and more preferably tetrahydrofuran.

[0311] The base used in this process is an inorganic base, preferably sodium tert-butoxide, potassium tert-butoxide, or sodium methoxide, and more preferably sodium tert-butoxide or potassium tert-butoxide.

[0312] Examples of methyltriphenylphosphonium halides used in this process include methyltriphenylphosphonium bromide and methyltriphenylphosphonium iodide, with methyltriphenylphosphonium bromide being preferred.

[0313] The amount of solvent used in this process is typically 2 to 30 parts by weight, preferably 5 to 20 parts by weight, and more preferably 8 to 15 parts by weight, per 1 weight of the compound represented by formula (9).

[0314] The amount of methyltriphenylphosphonium halogen used in this process is typically 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, more preferably 1.0 to 3.0 equivalents, and most preferably 1.5 to 2.5 equivalents, relative to 1 equivalent of the compound represented by formula (9).

[0315] The amount of base used in this process is typically 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, more preferably 1.0 to 3.0 equivalents, and most preferably 1.5 to 2.0 equivalents, relative to 1 equivalent of the compound represented by formula (9).

[0316] The reaction time is typically 0.5 to 24 hours, preferably 0.5 to 6 hours, and more preferably 1 to 3 hours.

[0317] The reaction temperature is typically 0°C to 100°C, preferably 10°C to 60°C, and more preferably 10°C to 40°C.

[0318] R 3 and R 4 Preferably, as defined above.

[0319] Step J [ka] (In the formula, a, b, c, d, R 3 and R 4 This is synonymous with item 1 and / or other items.

[0320] This process involves reacting a compound represented by formula (10) with an acid in the presence of a solvent to obtain a compound represented by formula (11).

[0321] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include ether-based solvents, preferably diethyl ether, tetrahydrofuran, and methyl tert-butyl ether, and more preferably tetrahydrofuran.

[0322] The acid used in this process is preferably hydrochloric acid, hydrobromic acid, or trifluoroacetic acid, and more preferably hydrochloric acid.

[0323] The amount of acid used in this process is typically 1.0 to 20.0 equivalents, preferably 5.0 to 15.0 equivalents, and more preferably 7.0 to 12.0 equivalents, relative to one equivalent of the compound represented by formula (10).

[0324] The reaction time is typically 0.5 to 24 hours, preferably 0.5 to 6 hours, and more preferably 1 to 5 hours.

[0325] The reaction temperature is typically 0°C to 100°C, preferably 10°C to 80°C, and more preferably 20°C to 50°C.

[0326] Step K [ka] (In the formula, a, b, c, d, and X are synonymous with term 1 and / or other terms.)

[0327] This process involves reacting a compound represented by formula (11) with a compound represented by formula (11a) in the presence of a solvent and a base to obtain a compound represented by formula (12).

[0328] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include ether-based solvents and acetonitrile, with acetonitrile being preferred.

[0329] The base used in this process is an organic base, preferably triethylamine, diisopropylethylamine, or pyridine, more preferably triethylamine or N,N-diisopropylethylamine, and most preferably triethylamine.

[0330] The amount of solvent used in this process is typically 2 to 20 parts by weight, preferably 2 to 10 parts by weight, and more preferably 2 to 6 parts by weight, per 1 weight of the compound represented by formula (11).

[0331] The amount of base used in this process is typically 1.0 to 30.0 equivalents, preferably 5.0 to 25.0 equivalents, and more preferably 10.0 to 20.0 equivalents, per equivalent of the compound represented by formula (11).

[0332] The amount of compound represented by formula (11a) used is typically 0.5 to 3.0 equivalents, preferably 0.6 to 1.5 equivalents, and more preferably 0.6 to 1.2 equivalents, per equivalent of the compound represented by formula (11).

[0333] The reaction time is typically 0.5 to 48 hours, preferably 5 to 48 hours, and more preferably 10 to 48 hours.

[0334] The reaction temperature is typically -20°C to 60°C, preferably -10°C to 30°C, and more preferably -5°C to 20°C.

[0335] Step L [ka] (In the formula, a, b, c, and d are synonymous with term 1 and / or other terms.)

[0336] This process involves reacting the compound represented by formula (12) with L(+)-tartaric acid in the presence of a solvent to obtain the compound represented by formula (12a).

[0337] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include alcoholic solvents or mixed solvents of alcoholic solvents and water, preferably methanol, ethanol, 2-propyl alcohol, or mixed solvents of these alcoholic solvents and water, and more preferably ethanol or mixed solvents of ethanol and water.

[0338] The amount of alcohol-based solvent used in this process is typically 2 to 30 parts by weight, preferably 5 to 20 parts by weight, and more preferably 8 to 15 parts by weight, per 1 weight of the compound represented by formula (12).

[0339] The amount of water used in this process is typically 0.01 to 2 parts by weight, preferably 0.05 to 1.5 parts by weight, and more preferably 0.05 to 1 part by weight, per unit weight of the compound represented by formula (12).

[0340] The amount of L(+)-tartaric acid used in this process is typically 0.5 to 2.0 equivalents, preferably 0.7 to 1.5 equivalents, and more preferably 1.0 to 1.5 equivalents, relative to 1 equivalent of the compound represented by formula (12).

[0341] The reaction time is typically 0.5 to 5 hours, preferably 0.5 to 3 hours, and more preferably 0.5 to 2 hours.

[0342] The reaction temperature is typically 0°C to 80°C, preferably 20°C to 70°C, and more preferably 40°C to 70°C.

[0343] Step M [ka] (In the formula, R 1 , R 2 , R 5a , R 5b and R 5c This is synonymous with item 1 and / or other items.

[0344] This process involves reacting a compound represented by formula (2) with a compound represented by formula (2a) in the presence of a solvent and an acid to obtain a compound represented by formula (13).

[0345] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include halogenated solvents, preferably dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene, and more preferably dichloromethane.

[0346] The acid used in this process is an organic acid, preferably trifluoroacetic acid, or a trifluoroborane-diethyl ether complex or a mixture thereof, and more preferably a mixture of trifluoroacetic acid and a trifluoroborane-diethyl ether complex.

[0347] The amount of solvent used in this process is typically 2 to 20 parts by weight, preferably 3 to 10 parts by weight, and more preferably 3 to 8 parts by weight, per 1 weight of the compound represented by formula (2).

[0348] The amount of compound represented by formula (2a) used is typically 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, more preferably 1.0 to 2.0 equivalents, and most preferably 1.0 to 1.5 equivalents, relative to 1 equivalent of the compound represented by formula (2).

[0349] The amount of acid used in this process is typically 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, more preferably 1.0 to 2.0 equivalents, and most preferably 1.0 to 1.5 equivalents, relative to one equivalent of the compound represented by formula (2).

[0350] The reaction time is typically 0.5 to 24 hours, preferably 0.5 to 10 hours, and more preferably 0.5 to 5 hours.

[0351] The reaction temperature is typically -100°C to 30°C, preferably -90°C to 20°C, and more preferably -80°C to 10°C.

[0352] R 1 , R 2 , R5a , R 5b and R 5c Preferably, as defined above.

[0353] Step N [ka] (In the formula, R 1 , R 2 , R 5a , R 5b and R 5c This is synonymous with item 1 and / or other items.

[0354] This process involves hydrolyzing the compound represented by formula (13) with water to obtain the compound represented by formula (14).

[0355] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include halogenated solvents, preferably dichloromethane, chloroform, 1,2-dichloroethane, and chlorobenzene, and more preferably dichloromethane.

[0356] The amount of solvent used in this process is typically 2 to 20 parts by weight, preferably 3 to 10 parts by weight, and more preferably 3 to 8 parts by weight, per 1 weight of the compound represented by formula (13).

[0357] The amount of water used in this process is typically 1.0 to 100.0 equivalents, preferably 5.0 to 50.0 equivalents, and more preferably 5.0 to 30.0 equivalents, per equivalent of the compound represented by formula (13).

[0358] The reaction time is typically 0.5 to 5 hours, preferably 0.5 to 3 hours, and more preferably 0.5 to 2 hours.

[0359] The reaction temperature is typically -50°C to 50°C, preferably -20°C to 20°C, and more preferably -10°C to 10°C.

[0360] R 1 , R 2 , R 5a , R 5b and R 5c Preferably, as defined above.

[0361] Step O and P [ka] (In the formula, R 1 , R 2 and R 3 This is synonymous with item 1 and / or other items.

[0362] This process involves reacting the compound represented by formula (14) with hydrogen in the presence of a solvent, a catalyst, and an amino group protecting reagent to obtain the compound represented by formula (16) via the compound represented by formula (15).

[0363] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include alcoholic solvents, preferably ethanol and methanol, and more preferably ethanol.

[0364] The catalyst used in this process is preferably Pd / C.

[0365] The amino group protecting reagent used in this process is preferably di-tert-butyl dicarbonate.

[0366] The amount of solvent used in this process is typically 0.01 to 2.0 parts by weight, preferably 0.01 to 1.0 parts by weight, and more preferably 0.01 to 0.5 parts by weight, per 1 weight of the compound represented by formula (14).

[0367] The amount of catalyst used in this process is typically 1.0 to 30.0 parts by weight, preferably 5.0 to 20.0 parts by weight, and more preferably 7.0 to 15.0 parts by weight, per 1 weight of the compound represented by formula (14).

[0368] The amount of amino group protecting reagent used in this process is typically 1.0 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, and more preferably 1.0 to 1.5 equivalents, per equivalent of the compound represented by formula (14).

[0369] The reaction time is typically 0.5 to 12 hours, preferably 1 to 8 hours, and more preferably 2 to 6 hours.

[0370] The reaction temperature is typically 0°C to 60°C, preferably 10°C to 50°C, and more preferably 15°C to 40°C.

[0371] R 1 , R 2 and R 3 Preferably, as defined above.

[0372] Step Q [ka] (In the formula, R 2 and R 3 This is synonymous with item 1 and / or other items.

[0373] This process involves reacting a compound represented by formula (16) with a base in the presence of a solvent to obtain a compound represented by formula (8).

[0374] The solvent used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include alcoholic solvents, preferably ethanol and methanol, and more preferably methanol.

[0375] The base used in this process is preferably sodium hydroxide or potassium hydroxide, and more preferably sodium hydroxide. The base may also be used as an aqueous solution.

[0376] The amount of solvent used in this process is typically 2 to 50 parts by weight, preferably 5 to 40 parts by weight, and more preferably 8 to 35 parts by weight, per 1 weight of the compound represented by formula (16).

[0377] The amount of base used in this process is typically 1.0 to 10.0 equivalents, preferably 2.0 to 8.0 equivalents, and more preferably 3.0 to 6.0 equivalents, per equivalent of the compound represented by formula (16).

[0378] The reaction time is typically 0.5 to 24 hours, preferably 1 to 10 hours, and more preferably 3 to 8 hours.

[0379] The reaction temperature is typically 0°C to 80°C, preferably 20°C to 70°C, and more preferably 30°C to 60°C.

[0380] R 2 and R 3 Preferably, as defined above.

[0381] The order in which reagents and other substances are added is not limited to those listed above.

[0382] The present invention will be described in more detail below with reference to examples and embodiments, but these are not intended to limit the present invention. Compound identification was performed by elemental analysis, mass spectrometry, high-performance liquid chromatography-mass spectrometry (LCMS), infrared absorption (IR) spectrometry, nuclear magnetic resonance (NMR) spectrometry, high-performance liquid chromatography (HPLC), etc.

[0383] The table below shows the RT values ​​obtained by analyzing each compound under the HPLC conditions shown in the table below. TIFF2026525467000189.tif108157 TIFF2026525467000190.tif104157 TIFF2026525467000191.tif104157 TIFF2026525467000192.tif78157

[0384] In this specification, the following abbreviations may be used. 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-oxyl WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HOBt: 1-hydroxybenzotriazole wt%: weight% v / w stands for volume / weight, and indicates the ratio of volume to weight of the substrate. RT: retention time RRT: Relative Retention Time In NMR, the symbols used are s for single line, d for double line, t for triple line, q for quadruple line, and m for multiple line. The room temperature is between 10°C and 30°C. [Examples]

[0385] The present invention will now be described in more detail with reference to the following examples and reference examples, but the technical scope of the present invention is not limited thereto. Furthermore, modifications may be made without departing from the scope of this disclosure. Note that the compound names shown in the following examples and reference examples do not necessarily follow IUPAC nomenclature.

[0386] Example 1: Preparation of (R,E)-2-((1-phenylethyl)imino)ethyl acetate [ka]

[0387] (R)-1-phenylethane-1-amine (compound 1, 3000 g) was dissolved in DCM (11925 g) under a nitrogen atmosphere. Na2SO4 (3000 g) was added to the solution. The resulting suspension mixture was cooled to -20 to -10°C. 2-ethyl oxoethyl acetate (5160 g, 50% toluene solution) was added dropwise to the suspension at -20 to -10°C. The resulting mixture was heated to 15 to 25°C and stirred thoroughly for 2 to 4 hours. The reaction mixture was filtered, and the resulting filter cake was washed with DCM (6000 g). The filtrate (compound 2, DCM solution considered to be 100% yield, theoretical amount of compound 2: 5080 g) was used directly in the next step.

[0388] Example 1A: Preparation of (R,E)-2-((1-phenylethyl)imino)ethyl acetate [ka]

[0389] 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 amounts while stirring vigorously. 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. The filtrates were combined (Entry 1), 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 reduced pressure 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).

[0390] Example 2: Preparation of (1S,3S,4R)-2-((R)-1-phenylethyl)-2-azabicyclo[2.2.2]octa-5-ene-3-carboxylate ethyl [ka]

[0391] The filtrate from the previous step (containing 5.08 kg of ethyl acetate ((R,E)-2-((1-phenylethyl)imino)ethyl compound 2) was stirred under air and cooled to -60 to -50°C. TFA (2.84 kg), BF3·OEt2 (effective amount 3.50 kg, 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 hours. The reaction mixture was then heated to 10 to 20°C and stirred thoroughly for 10 to 15 hours. The reaction mixture was diluted with DCM (7.92 kg) and quenched with NaHCO3 (37.24 kg, 10% aqueous solution). An additional DCM (15.24 kg) was then added and the mixture was stirred. The lower organic layer was collected and concentrated to 4-6 v / w under reduced pressure below 45°C. Then toluene (26.52 kg) was added, and the mixture was concentrated to 4-6 v / w under reduced pressure at 60°C. Toluene (26.52 kg) was added, and the mixture was concentrated to 8-10 v / w and stirred at 55-60°C for 1 hour. The resulting mixture was cooled to 35-45°C and stirred for 16 hours to obtain a suspension. The mixture was filtered, and the wet cake was washed with MTBE (7.52 kg) to obtain a crude product containing 15% isomers as a white solid (mixture of salts). The solid was dissolved in DCM (30.48 kg). NaHCO3 (20.32 kg, 10% aqueous solution) was added little by little, and the resulting solution was adjusted to pH 8-9 at 15-25°C and stirred for 1 hour. The organic layer was collected, and the aqueous layer was extracted with DCM (15.24 kg). The organic layers were combined and concentrated under reduced pressure to obtain crude compound 3 as a mixture of free bases of the isomers. purification Purification using silica gel pads: Crude compound 3 (free base 308 g) was dissolved in n-heptane (616 g) to obtain a clear solution. Silica gel (616 g) was placed in a Buchner funnel and packed with silica gel. The crude compound 3 / n-heptane solution was filtered through a silica gel pad. The pad was then washed with eluent n-heptane (8 kg). The filtrate was concentrated to obtain compound 3 (243 g) with 99% purity and a recovery rate (yield) of 78.9%.

[0392] Example 3: Preparation of (1S,3S,4S)-5-hydroxy-2-((R)-1-phenylethyl)-2-azabicyclo[2.2.2]octane-3-carboxylate ethyl [ka]

[0393] (1S,3S,4R)-2-((R)-1-phenylethyl)-2-azabicyclo[2.2.2]octa-5-ene-3-carboxylate ethyl (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 resulting mixture was stirred for 4 to 6 hours and then monitored by HPLC. Purified water (848 g) was added dropwise at below 10°C. NaBO3-4H2O (327 g) was added gradually as a solid under stirring at 0 to 10°C. The resulting mixture was stirred at 0 to 10°C for 14 to 18 hours and then monitored by HPLC. The mixture was quenched at 30°C or below with sodium sulfite (20% aqueous solution, 892 g) and diluted with ethyl acetate (455 g). The reaction mixture was filtered, and the resulting cake was washed with ethyl acetate (202 g). The filtrate was placed in a separatory funnel. The organic upper layer was collected and dried with Na₂SO₄ (404 g), and the remaining Na₂SO₄ was removed. The drying agent was removed by filtration, and the solid was washed with ethyl acetate (404 g). The filtrate was concentrated to 4-5 v / w under reduced pressure at 45°C to obtain crude (1S,3S,4S)-5-hydroxy-2-((R)-1-phenylethyl)-2-azabicyclo[2.2.2]octane-3-carboxylate ethyl (compound 4) as a pale yellow solution. This crude product solution was used directly in the next step at 100% yield.

[0394] Example 4: Preparation of (1S,3S,4S)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate ethyl [ka]

[0395] To a solution of (1S,3S,4S)-5-hydroxy-2-((R)-1-phenylethyl)-2-azabicyclo[2.2.2]octane-3-carboxylate ethyl (compound 4, 6.08 kg solution, containing 1.49 kg), 10% Pd / C (0.19 kg, 65% hydrate) was added under inert conditions. The reaction mixture was reacted at 20-30°C for 16-24 hours under a hydrogen atmosphere of 0.5-0.8 MPa. The reaction mixture was filtered through a Celite pad (0.6 kg). The filtered cake was washed with ethyl acetate (1.49 kg), and the filtrate was concentrated to obtain crude product 4. The crude product was used directly in the next step as 100% yield.

[0396] Example 5: Preparation of (1S,3S,4S)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid [ka]

[0397] (1S,3S,4S)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-ethyl 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 purified water (1.05 kg), and the upper organic layer was removed as liquid waste. The lower aqueous layer containing compound 5 was mixed with 1,4-dioxane (1.05 kg) and cooled to 10-15°C. Then, 30% NaOH aqueous solution (154.13 g) was added dropwise to the reaction mixture at 0-20°C. The reaction mixture was stirred at 10-20°C for 3-4 hours 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 5-20°C. The reaction mixture was stirred at 10-20°C for 16-20 hours and then cooled to 0-10°C. A pre-mixed solvent (810 g of HCl, 90 g of MeOH) was added. The pH was adjusted to 1-3 at 0-10°C using 4.0 M aqueous hydrochloric acid (351.25 g). Solid NaCl (314.9 g) was added. The organic layer was collected, and the aqueous layer was extracted three times with the mixed solvent (810 g of HCl, 90 g of MeOH). The organic layer was collected and dried with Na2SO4 (418.8 g). The resulting mixture was filtered, and the resulting 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 hours, then cooled to 5-10°C to obtain a suspension. The suspension was filtered, and the resulting cake was washed with n-heptane (284.78 g). The resulting wet cake was dried to obtain 116.9 g of compound 7 in a yield of 41.03%.

[0398] Example 6: Preparation of (1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carboxylic acid [ka]

[0399] (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 with ethyl acetate (500 g). The mixture was cooled to -5 to 5°C. TEMPO (1.45 g) was added in one addition, followed by solid TCCA (32.1 g) in several additions at -5 to 5°C. The reaction mixture was stirred at -5 to 5°C for 4 to 6 hours to allow complete conversion. The reaction mixture was diluted with ethyl acetate (1500 g), and the resulting suspension was filtered through a Celite pad (30 g). The resulting cake was washed with ethyl acetate (100 g). The filtrate was quenched at 0 to 10°C with FeSO4 solution (102.5 g FeSO4-7H2O / 187 g purified water). The aqueous layer was removed, and the organic layer was dried with Na₂SO₄ (100 g) at 20–30°C for 14–18 hours. The reaction mixture was filtered, and the resulting cake was washed with HCl (100 g). The filtrate was concentrated under reduced pressure to 2–3 v / w at 45°C to obtain a suspension. n-heptane (204 g, 6 v / w) was added to further induce precipitation. The resulting mixture was filtered, and the cake product was washed with n-heptane. The wet cake was dried under reduced pressure at 35–45°C to obtain compound 8 (45.37 g) in yield 91.4% and purity 97.5% (HPLC).

[0400] Example 7A: Preparation of (1S,3S,4S)-3-[2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate tert-butyl [ka]

[0401] Compound 8 (20 g, 74.27 mmol) and HOBt H2O (11.60 g, 1.02 eq.) were placed in a 1 L five-necked separable flask. DMF (60 mL, 3 v / w) was added to the mixture at 25 ± 5 °C. The resulting mixture was cooled to 0 ± 5 °C. A solution of WSC HCl (15.66 g, 1.1 eq.) in DMF (60 mL, 3 v / w) and water (10 mL, 0.5 v / w) was added to the mixture at 0 ± 5 °C. The resulting mixture was stirred at 0 ± 5 °C for 1 hour. A solution of 2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl (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 at least 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 filtered cake was dried under reduced pressure at 60±5°C to obtain compound 9 (33.61 g) as a nearly white crystalline powder. Yield 94.8% (97.9 HPLC area%, analyzed by Method 1). 1 H-NMR (CDCl3) δ: 4.79 and 4.73 (total 1H, each m), 4.70 and 4.55 (total 1H, each m), 3.73-3.25 (total 8H, m), 2.67-2.29 (total 4H, m), 2.01-1.50 (total 7H, m) 1.50-1.41 (total 12H, m), 1.39 (6H, s).

[0402] Example 7B: Preparation of (1S,3S,4S)-3-[2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl]-5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate tert-butyl [ka]

[0403] Compound 8 (1000 g, 3.71 mol) and HOBt H2O (580 g, 1.02 eq.) were placed in a 20 L separable flask. DMF (3 L, 3 v / w) was added to the mixture at 25 ± 5 °C. The resulting mixture was cooled to 0 ± 5 °C. A solution of 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 resulting mixture was stirred at 0 ± 5 °C for 1 hour. A solution of 2,7-diazaspiro[3.5]nonane-2-carboxylate tert-butyl (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 resulting reaction mixture was stirred for 2 hours. The reaction mixture was heated to 25±5°C and then stirred for at least 12 hours. Water (4.5 L, 4.5 v / w) was added to the mixture at 25±5°C. The resulting mixture was stirred at 25±5°C for 2 hours. The precipitate was collected by filtration and then washed three times with water (3 L, 3 v / w). The filtered cake was dried under reduced pressure at 60±5°C to obtain compound 9 (1695 g) as a nearly white crystalline powder. Yield 95.6% (98.7% HPLC area, analyzed by Method 1). 1 H-NMR (CDCl3) δ: 4.79 and 4.73 (total 1H, each m), 4.70 and 4.55 (total 1H, each m), 3.73-3.25 (total 8H, m), 2.67-2.29 (total 4H, m), 2.01-1.50 (total 7H, m) 1.50-1.41(total 12H, m), 1.39 (6H, s).

[0404] Example 8A: Preparation of ((1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octan-3-yl)(2,7-diazaspiro[3.5]nonane-7-yl)methanone dihydrochloride [ka]

[0405] PPh3MeBr (46.37 g, 1.55 eq.) was placed in a 1 L five-neck separable flask. THF (240 mL, 6 v / w) was added to the flask at 20 ± 5 °C. t BuOK (14.10 g, 1.50 eq.) was added to the mixture at 20±5°C. The resulting mixture was stirred at 20±5°C for 1 hour. A solution of compound 9 (40 g, 83.752 mmol) in THF (240 mL, 6 v / w) was added to the mixture at 20±5°C. The resulting reaction mixture was stirred at 20±5°C for 17.5 hours. Concentrated hydrochloric acid (48.8 mL, 7 eq.) was added to the mixture at 20±5°C. The resulting 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 then washed three times with THF (120 mL, 3 v / w). The filtered cake was dried under reduced pressure at 50±5°C to obtain compound 11 (36.66 g) as a nearly white crystalline powder. Yield 87.5%, measured by quantitative NMR. 94.6% HPLC area, analyzed using Method 2. 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).

[0406] Example 8B: Preparation of ((1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octan-3-yl)(2,7-diazaspiro[3.5]nonane-7-yl)methanone dihydrochloride [ka]

[0407] PPh3MeBr (637 g, 1.55 eq.) was placed in a 10 L five-neck separable flask. THF (3.3 L, 6 v / w) was added to the flask at 20 ± 5 °C. t BuOK (194 g, 1.50 eq.) was added to the mixture at 20±5°C. The resulting mixture was stirred at 20±5°C for 1 hour. A solution of compound 9 (550 g, 1.15 mol) in THF (3.3 L, 6 v / w) was added to the mixture at 20±5°C. The resulting reaction mixture was stirred at 20±5°C for 18 hours. Concentrated hydrochloric acid (816 g, 7 eq.) was added to the mixture at 20±5°C. The resulting 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 then washed three times with THF (2750 mL, 5 v / w). The filtered cake was dried under reduced pressure at 50±5°C to obtain compound 11 (277 g) as a nearly white crystalline powder. Yield 87.3%, measured by quantitative NMR. 86.4% HPLC area, analyzed by Method 2. 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).

[0408] Example 9A: Preparation of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide [ka]

[0409] Compound 11 (6.27 g, 0.018 mol) was placed in a 300 mL five-neck separable 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 resulting reaction mixture was stirred at 5 ± 5 °C for 0.5 hours. A solution of 2-((4-chloropyrimidine-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 resulting suspension at 5±5°C. The resulting reaction mixture was stirred at 5±5°C for 23 hours. The precipitate was collected by filtration and then washed with cooled MeCN (20 mL, 4 v / w). The resulting filter cake was filter-dried at room temperature for at least 1 hour. 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 obtain compound 12 (8.74 g) as a nearly white crystalline powder. Yield 82.2% (99.2% HPLC area, analyzed by Method 3). Compound 12 (8.0 g, 13.542 mmol) was placed in a 200 mL five-neck separable flask. MeCN (30 mL, 3.75 v / w) and water (10 mL, 1.25 v / w) were added to the flask. The resulting 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 resulting mixture was stirred at 60±5°C for 1 hour. The mixture was cooled to 20±5°C over 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 filtered cake was dried under reduced pressure at 50±5°C to obtain compound 12 (7.63 g) as a nearly white crystalline powder. Yield 95.4% (99.8% HPLC area, analyzed by Method 3). 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).

[0410] Example 9B: Preparation of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide [ka]

[0411] Compound 11 (233.5 g, 0.848 mol) was placed in a 10 L separable 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 resulting reaction mixture was stirred at 5±5°C for 0.5 hours. The mixture was cooled to 5±5°C. A solution of 2-[(4-chloropyrimidine-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 resulting suspension at 5±5°C. The resulting reaction mixture was stirred at 5±5°C for 24 hours. The precipitate was collected by filtration and then washed with cooled MeCN (934 mL, 4 v / w). The resulting filter cake was filtered dry at room temperature for at least 1 hour. The filtered cake was re-slurried with water (3735 mL, 16 v / w) and then stirred for 3 hours. The precipitate was collected by filtration and then washed twice with water (1868 mL, 8 v / w). The filtered cake was dried under reduced pressure at 60±5°C to obtain compound 12 (446 g) as a nearly white crystalline powder. Yield 89.1% (98.8% HPLC area, analyzed by Method 3). Compound 12 (400 g, 0.677 mol) was placed in a 10 L separable flask. MeCN (1500 mL, 3.75 v / w) and water (500 mL, 1.25 v / w) were added to the flask. The resulting 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 resulting mixture was stirred at 60±5°C for 2 hours. The mixture was cooled to 40±5°C over 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 resulting mixture was stirred at 40±5°C for 1 hour. The mixture was cooled to 20±5°C over 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 filtered cake was dried under reduced pressure at 60±5°C to obtain compound 12 (347 g) as a nearly white crystalline powder. Yield 86.9% (99.6% HPLC area, analyzed by Method 3). 1 H-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).

[0412] Example 10A: Preparation of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide mono-L-tartrate [ka]

[0413] 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 resulting mixture was heated to 40±5°C. The resulting 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 resulting 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 resulting mixture was stirred at 60±5°C for 2 hours. The resulting 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 filtered cake was dried under reduced pressure at 50±5°C to obtain compound 13 (3.47 g) as a white crystalline powder. Yield 92.3% (99.9% HPLC area, analyzed by Method 3). 1 H-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).

[0414] Example 10B: Preparation of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide mono-L-tartrate [ka]

[0415] Compound 12 (10 g, 16.93 mmol) was placed in a 300 mL separable flask. EtOH (65 mL, 6.5 v / w) was added to the flask. The resulting 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 resulting 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 resulting 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 filtered cake was dried under reduced pressure at 50±5°C to obtain compound 13 (11.79 g) as a white crystalline powder. Yield 94.0%.

[0416] Table 1 shows the impurity profiles. The purity of the target compound using Method 3 was 99.9%, with 0.05% of compound A and 0.05% of compound B present as impurities. On the other hand, the purity of the target compound using Method 4 was 99.8%, with 0.06% of compound C and less than 0.05% of the enantiomer present as impurities. Relative retention time (RRT) refers to the relative ratio of the measured retention time to the retention time of the target compound (compound 12). [Table 1]

[0417] Compound 13 (12.6 g, 17.01 mmol) was placed in a 300 mL five-neck separable flask. EtOH (50 mL, 4 v / w) and water (8.1 mL, 0.65 v / w) were added to the flask. The resulting 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 resulting 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, 1.2 v / w). The filtered cake was dried under reduced pressure at 50±5°C to obtain compound 13 (11.1 g) as a white crystalline powder. Yield 88.2% (99.9% HPLC area, analyzed by Method 3, 100% ee, analyzed by Method 4). 1 H-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).

[0418] Example 11: Preparation of (1S,3S,4S)-5-oxo-2-((R)-2-phenylethyl)-2-azabicyclo[2.2.2]octane-3-carboxylate ethyl [ka]

[0419] To a solution of compound 2 (assuming 1.17 g, 4.87 mmol) in dichloroethane (5 ml), TFA (0.38 ml, 4.97 mmol) and BF3-OEt2 (0.62 ml, 4.97 mmol) were added at -78°C and the mixture was stirred for 15 minutes. 2-(trimethylsilyloxy)-1,3-cyclohexadiene (940 mg, 5.34 mmol) was added (using 0.25 ml of dichloromethane twice for washing, and added slowly while maintaining the temperature below -50°C), the mixture was stirred for 2 hours, then slowly warmed (over approximately 30 minutes), water (1 ml) was added at 0°C, and stirring was continued for 15 minutes. The reaction mixture was neutralized by adding aqueous NaHCO3 (25 ml) and extracted with ethyl acetate (20 ml). The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation, and (after refrigeration) the concentrate was purified the following day by silica gel column chromatography (30 g neutral silica; eluent was ethyl acetate / hexane in a ratio of 1 / 19-1 / 3) to obtain compound 15 (634 mg, 43.2%, pale yellow liquid, containing impurities). LC-MS; [M+H] + 302.0

[0420] Example 12: Preparation of 2-(tert-butyl)3-ethyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate [ka]

[0421] 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) were added and stirred under a hydrogen atmosphere at room temperature for 4 hours. The mixture was then filtered through Celite 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; elution solvent was ethyl acetate / hexane in a ratio of 1 / 15-1 / 4) to obtain compound 16 (306 mg, 49%, colorless viscous liquid). LC-MS; [M+H] + 298.0 [ka] TIFF2026525467000212.tif132136

[0422] Example 13: Preparation of (1S,3S,4S)-2-(tert-butoxycarbonyl)-5-oxo-2-azabicyclo[2.2.2]octane-3-carboxylic acid [ka]

[0423] To a methanol (11 mL) solution of compound 16 (306 mg, 1.02 mmol), 1.0 ml of 5N 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 with 2N HCl aqueous solution. The solvent was partially removed by concentration and extracted with chloroform. The organic layer 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; eluent was chloroform / methanol in a ratio of 1 / 0-12.5 / 1). 1 ml of chloroform was added to the concentrate (203 mg). 4 ml of hexane was slowly added and the mixture was stirred for 30 minutes. The resulting 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). LC-MS; [MH] - 298.0 [ka] TIFF2026525467000215.tif125160

[0424] Comparative Example 1: For the production of the target compound of the present invention, the production method disclosed in WO 2020 / 045334 can be summarized as follows, as Comparative Example 1. [ka]

[0425] 1. Comparison of manufacturing method 1 of the present invention and manufacturing method 1 of comparative example 1 "Manufacturing Method 1" as defined herein differs from the manufacturing method of Comparative Example 1 above in that Manufacturing Method 1 produces compound (12) from compound (7) in 5 steps, whereas Manufacturing Method 1 produces compound 13A (corresponding to compound (12) in Manufacturing Method 1) from compound 7A (corresponding to compound (7) in Manufacturing Method 1) in 6 steps. Specifically, Manufacturing Method 1 of Comparative Example 1 includes steps to protect and deprotect the carboxylic acid in Steps 7 and 10, but these are unnecessary in Manufacturing Method 1 of this disclosure. Furthermore, in this disclosure, compound (12) can be produced from compound (7) with a total yield of 61%, whereas in Comparative Example 1, the total yield of compound (13A) from compound (7A) is only 31%. Therefore, the manufacturing method 1 of the present disclosure does not require the additional protection and deprotection steps that are essential in Comparative Example 1. As a result, the experimental procedure in the manufacturing method 1 of the present disclosure is simpler because there are almost no liquid-liquid extraction or purification steps using silica gel columns, and the total yield is more than twice that of Comparative Example 1. Therefore, the manufacturing method 1 of the present disclosure makes it possible to produce a larger amount of the desired intermediate 12 and to produce the target compound.

[0426] 2. Comparison of manufacturing method 2 of the present invention and manufacturing method 1 of comparative example The "Manufacturing Method 2" as defined herein differs from the manufacturing method of Comparative Example 1 above in that Manufacturing Method 2 produces compound (12) from compound (1) in 10 steps, whereas the manufacturing method of Comparative Example 1 produces compound 13A (corresponding to compound (12) in Manufacturing Method 2) from compound 1A (corresponding to compound (1) in Manufacturing Method 2) in 12 steps. Specifically, in Manufacturing Method 2 herein, compound (13) having a trimethylsilyloxy group is produced in Step M, and the trimethylsilyloxy group can be hydrolyzed to form a carbonyl group, so compound (14) can be produced efficiently without requiring an oxidation reaction. Using the manufacturing method of this disclosure, compound (12) can be produced from compound (1) with a total yield of 7%, whereas in the manufacturing method of Comparative Example 1, the total yield of compound (13A) from compound (1A) is only 3%. Therefore, the manufacturing method 2 of this disclosure does not require the oxidation reaction, which is an essential step in Comparative Example 1. As a result, the experimental procedure in manufacturing method 2 of this disclosure is simpler because there are almost no liquid-liquid extraction or purification steps using silica gel columns, and the total yield is more than twice that of Comparative Example 1. Therefore, manufacturing method 2 of this disclosure makes it possible to produce the target compound with exceptional efficiency.

[0427] Comparative Example 2: For the production of the target compound of the present invention, in addition to Comparative Example 1, the production method disclosed in WO 2020 / 045334 can be summarized as follows as Comparative Example 2. [ka]

[0428] 3. Comparison of manufacturing methods 1 of the present invention and 2 of comparative examples The "Manufacturing Method 1" of this disclosure and the manufacturing method of Comparative Example 2 have the same number of reaction steps from the starting materials. However, the manufacturing method of Comparative Example 2 requires alcohol oxidation using Swern oxidation, which requires extremely low temperature conditions. Furthermore, the reaction generates dimethyl sulfide, which has a malodorous odor, and carbon monoxide, which is extremely toxic, making it unsuitable as an industrial manufacturing method. On the other hand, Manufacturing Method 1 of this disclosure uses TEMPO oxidation in Step G, and this oxidation reaction can be carried out at around room temperature. Since it does not generate dimethyl sulfide or carbon monoxide, which are problematic in the manufacturing method of Comparative Example 2, it is extremely desirable as an industrial manufacturing method. Regarding the introduction of the diazaspiro ring moiety in the target compound, in the production method of Comparative Example 2, Step 14 is performed before the hydroxyl group on the azabicyclo ring is oxidized to a ketone, whereas in production method 1 of the present invention, Step H is performed after the hydroxyl group on the azabicyclo ring is oxidized to a ketone. The hydroxyl group here can cause a mixture of stereoisomers. Therefore, by introducing the structurally complex diazaspiro ring moiety after oxidizing the structurally troublesome hydroxyl group to a ketone, production method 1 of the present invention can reduce the complexity of its purification and analysis. Therefore, the manufacturing method 1 of this disclosure does not require the industrially inappropriate oxidation reaction that is problematic in the manufacturing method of Comparative Example 2, and can oxidize alcohols under mild conditions. Furthermore, the manufacturing method 1 of this disclosure requires almost no liquid-liquid extraction or purification using silica gel columns, making the experimental procedure simple. In addition, by changing the timing of introduction of the diazaspiro ring portion, the complexity of purification and analysis can be reduced compared to the manufacturing method of Comparative Example 2. Therefore, the target compound can be produced with remarkable effect according to the manufacturing method 1 of this disclosure.

[0429] 4. Comparison of manufacturing method 2 of the present invention and manufacturing method 2 of comparative example The "Manufacturing Method 2" as defined herein differs from the manufacturing method of Comparative Example 2 above in that Manufacturing Method 2 produces compound (12) from compound (1) in 10 steps, whereas the manufacturing method of Comparative Example 2 produces compound 13A (corresponding to compound (12) in Manufacturing Method 2) from compound 1A (corresponding to compound (1) in Manufacturing Method 2) in 11 steps. Specifically, in Manufacturing Method 2 herein, compound (13) having a trimethylsilyloxy group is produced in Step M, and the trimethylsilyloxy group can be hydrolyzed to form a carbonyl group, so compound (14) can be produced efficiently without requiring an oxidation reaction. Using the manufacturing method of this disclosure, compound (12) can be produced from compound (1) with a total yield of 7%, whereas in the manufacturing method of Comparative Example 2, the total yield of compound (14A) from compound (1A) is only 5%. Furthermore, in the production method 2 of this disclosure, formula (13) has an enol ether, and this portion does not have stereoisomers due to the hydroxyl group portion, as in compound (7A) of Comparative Example 2. Therefore, the production method 2 of the present invention can reduce the complexity of its purification and analysis. Therefore, the manufacturing method 2 of this disclosure does not require the oxidation reaction, which is an essential step in Comparative Example 2. As a result, the experimental procedure in manufacturing method 2 of this disclosure is simpler because it involves fewer liquid-liquid extraction or purification steps using silica gel columns, reducing the complexity of purification and analysis, and the total yield is more than twice that of Comparative Example 2. Accordingly, manufacturing method 2 of the present invention makes it possible to produce the target compound with remarkable effect.

Claims

1. Equation (12), including Step G below: 【Chemistry 1】 [In the formula, a, b, c, and d are each independently either 1 or 2.] A method for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof: Step G: Formula (7): 【Chemistry 2】 [In the formula, R ３ [is a protecting group for amino groups] By reacting a compound represented by (8), or a pharmaceutically acceptable salt thereof, or a solvate thereof, with an oxidizing agent in the presence of a solvent, the compound (8) is obtained. 【Transformation 3】 [In the formula, R ３ This is synonymous with the above. A process for producing a compound represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

2. The manufacturing method according to claim 1, wherein the solvent in Step G comprises an ester-based solvent and / or a halogen-based solvent.

3. The manufacturing method according to claim 1, wherein the solvent in Step G includes an ester-based solvent.

4. The manufacturing method according to claim 1, wherein the solvent in Step G contains ethyl acetate.

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

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

7. The manufacturing method according to any one of claims 1 to 6, wherein the oxidizing agent in Step G is 1-methyl-2-azaadamantane-N-oxyl, 2-hydroxy-2-azaadamantane, 9-azanoradamantane-N-oxyl, 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-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-oxyl.

8. The manufacturing method according to any one of claims 1 to 6, wherein the oxidizing agent in Step G is 2,2,6,6-tetramethylpiperidine 1-oxyl.

9. The manufacturing method according to any one of claims 1 to 8, further comprising Step H below: Step H: Formula (8): 【Chemistry 4】 [In the formula, R ３ This is synonymous with the above. A compound represented by formula (8a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a condensing agent, is prepared using formula (8a): 【Transformation 5】 [In the formula, R ４ a, b, c, and d are the same as above. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted to produce formula (9): 【Transformation 6】 [In the formula, R ３ , R ４ a, b, c, and d are the same as above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

10. The manufacturing method according to claim 9, further comprising Step I below: Step I: Formula (9): 【Transformation 7】 [In the formula, R ３ , R ４ a, b, c, and d are the same as above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with methyltriphenylphosphonium halogen, trialkylsilylmethyl anion, or a methylsulfone derivative in the presence of a solvent and a base to obtain formula (10): 【Transformation 8】 [wherein, R ３ , R ４ , a, b, c and d are as defined above] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

11. The manufacturing method according to claim 10, further comprising Step J below: Step J: Formula (10): 【Chemistry 9】 [In the formula, R ３ , R ４ a, b, c, and d are the same as above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with an acid to obtain formula (11): 【Chemistry 10】 [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

12. The manufacturing method according to claim 11, further comprising Step K below: Step K: Formula (11): 【Chemistry 11】 [In the formula, a, b, c, and d are the same as above.] A compound represented by formula (11a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a base, is prepared using formula (11a): 【Chemistry 12】 [In the formula, X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl group, or methanesulfonyl group] The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted to produce formula (12): 【Chemistry 13】 [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

13. The manufacturing method according to claim 12, further comprising Step L below: Step L: Formula (12): 【Chemistry 14】 [In the formula, a, b, c, and d are the same as above.] A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with L(+)-tartaric acid in the presence of a solvent to obtain formula (12a): 【Chemistry 15】 [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by or its solvate.

14. The manufacturing method according to any one of claims 1 to 13, further comprising Step A below: Step A: Formula (1): 【Chemistry 16】 [In the formula, R １ C may be substituted. １－６ It is alkyl, R １Ａ C may be substituted. ６-１０ [It is Ariel] A compound represented by formula (1a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent, is subjected to the following reaction: 【Chemistry 17】 [In the formula, R ２ C may be substituted. １－６ It is alkyl. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted to produce formula (2): [Chemistry 18] [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

15. The manufacturing method according to claim 14, further comprising Step B below: Step B: Formula (2): 【Chemistry 19】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with 1,3-cyclohexadiene in the presence of a solvent and an acid to obtain formula (3): 【Chemistry 20】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. A process for producing a compound represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

16. The manufacturing method according to claim 15, further comprising Step C below: Step C: Formula (3): 【Chemistry 21】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with borane in the presence of a solvent, and then with a peroxide and a base to obtain formula (4): 【Chemistry 22】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

17. The manufacturing method according to claim 16, further comprising Step D below: Step D: Formula (4): 【Chemistry 23】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. By reacting the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, with hydrogen in the presence of a catalyst, the protecting group on the amino group is deprotected, resulting in formula (5): 【Chemistry 24】 [In the formula, R ２ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

18. The manufacturing method according to claim 17, further comprising Step E below: Step E: Formula (5): 【Chemistry 25】 [In the formula, R ２ This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or the ester group of its solvate, is hydrolyzed to produce formula (6): 【Chemistry 26】 A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

19. The manufacturing method according to claim 18, further comprising Step F below: Step F: Formula (6): 【Chemistry 27】 Protect the amino group of the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, as in formula (7): 【Chemistry 28】 [In the formula, R ３ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

20. Formula (12), including Step M below: 【Chemistry 29】 [In the formula, a, b, c, and d are each independently either 1 or 2.] Methods for producing the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate: Step M: Formula (2): 【Transformation 30】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. A compound represented by formula (2a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent under acidic conditions, is prepared using formula (2a): 【Chemistry 31】 [In the formula, R ５ａ , R ５ｂ , and R ５ｃ Each of them is independent of C １－６ Alkyl or C ６-１０ [It is Ariel] By reacting with a compound represented by formula (13), or a pharmaceutically acceptable salt thereof, or a solvate thereof, the compound (13) is obtained. 【Chemistry 32】 [In the formula, R １ , R １Ａ , R ２ , R ５ａ , R ５ｂ , and R ５ｃ This is synonymous with the above. A process for producing a compound represented by , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

21. The manufacturing method according to claim 20, wherein the solvent in Step M includes a halogenated solvent.

22. The manufacturing method according to claim 20, wherein the solvent in Step M comprises dichloromethane and / or chloroform.

23. The manufacturing method according to claim 20, wherein the solvent in Step M contains dichloromethane.

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

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

26. The manufacturing method according to any one of claims 20 to 25, wherein the acid in Step M is methanesulfonic acid, trichloroacetic acid, dichloroacetic acid, difluoroacetic acid, trifluoroacetic acid, trifluoroborane diethyl ether complex, or a mixture of trifluoroacetic acid and trifluoroborane diethyl ether complex.

27. The manufacturing method according to any one of claims 20 to 25, wherein the acid in Step M is a mixture of trifluoroacetic acid and a trifluoroborane diethyl ether complex.

28. The manufacturing method according to any one of claims 20 to 27, further comprising Step A below: Step A: Formula (1): 【Transformation 33】 [In the formula, R １ and R １Ａ This is synonymous with the above. A compound represented by formula (1a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent, is subjected to the following reaction: 【Transformation 34】 [In the formula, R ２ This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted to produce formula (2): 【Chemistry 35】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

29. The manufacturing method according to any one of claims 20 to 28, further comprising Step N below: Step N: Formula (13): 【Transformation 36】 [In the formula, R １ , R １Ａ , R ２ , R ５ａ , R ５ｂ , and R ５ｃ This is synonymous with the above. The silyl enol ether group of the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, is hydrolyzed to obtain formula (14): 【Chemistry 37】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

30. The manufacturing method according to claim 29, further comprising Step O below: Step O: Formula (14): 【Transformation 38】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. By reacting the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, with hydrogen in the presence of a catalyst, the protecting group on the amino group is deprotected, resulting in formula (15): 【Chemistry 39】 [In the formula, R ２ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

31. The manufacturing method according to claim 30, further comprising Step P below: Step P: Formula (15): 【Chemistry 40】 [In the formula, R ２ This is synonymous with the above. Protecting the amino group of the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, formula (16): 【Chemistry 41】 [In the formula, R ２ and R ３ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

32. The manufacturing method according to claim 31, further comprising Step Q below: Step Q: Formula (16): 【Chemistry 42】 [In the formula, R ２ and R ３ This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or the ester group of its solvate, is hydrolyzed to obtain formula (8): 【Chemistry 43】 [In the formula, R ３ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

33. The manufacturing method according to claim 32, further comprising Step H below: Step H: Formula (8): 【Chemistry 44】 [In the formula, R ３ This is synonymous with the above. A compound represented by formula (8a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a condensing agent, is prepared using formula (8a): 【Chemistry 45】 [In the formula, R ４ a, b, c, and d are the same as above. By reacting with a compound represented by formula (9), or a pharmaceutically acceptable salt thereof, or a solvate thereof, the following compound is obtained: 【Chemistry 46】 [In the formula, R ３ , R ４ a, b, c, and d are the same as above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

34. The manufacturing method according to claim 33, further comprising Step I below: Step I: Formula (9) 【Chemistry 47】 [In the formula, R ３ , R ４ a, b, c, and d are the same as above. By reacting a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, with methyltriphenylphosphonium halide and a base in the presence of a solvent, formula (10) is obtained: 【Chemistry 48】 [In the formula, R ３ , R ４ a, b, c, and d are the same as above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

35. The manufacturing method according to claim 34, further comprising Step J below: Step J: Formula (10): 【Chemistry 49】 [In the formula, R ３ , R ４ a, b, c, and d are the same as above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with an acid to obtain formula (11): [Transformation 50] [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

36. The manufacturing method according to claim 35, further comprising Step K below: Step K: Formula (11): 【Chemistry 51】 [In the formula, a, b, c, and d are the same as above.] A compound represented by formula (11a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a base, is prepared using formula (11a): 【Chemistry 52】 [In the formula, X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl group, or methanesulfonyl group] The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted to produce formula (12): 【Chemistry 53】 [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

37. The manufacturing method according to claim 36, further comprising Step L below: Step L: Formula (11): 【Chemistry 54】 [In the formula, a, b, c, and d are the same as above.] A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with L(+)-tartaric acid in the presence of a solvent to obtain formula (12a): 【Transformation 55】 [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by [the given symbol], or its solvate.

38. Equation (8), including Step G below: 【Transformation 56】 [In the formula, R ３ [is a protecting group for amino groups] Methods for producing the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate: Step G: Formula (7): 【Chemistry 57】 [wherein, R ３ is as defined above] A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with an oxidizing agent in the presence of a solvent to obtain formula (8): 【Chemistry 58】 [In the formula, R ３ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

39. The manufacturing method according to claim 38, further comprising Step A below: Step A: Formula (1): 【Chemistry 59】 [In the formula, R １ C may be substituted. １－６ It is alkyl, R １Ａ C may be substituted. ６-１０ [It is Ariel] A compound represented by formula (1a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent, is subjected to the following reaction: 【Transformation 60】 [wherein, R ２ is optionally substituted C １－６ alkyl] The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted to produce formula (2): 【Chemistry 61】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

40. The manufacturing method according to claim 39, further comprising Step B below: Step B: Formula (2): 【Transformation 62】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with 1,3-cyclohexadiene in the presence of a solvent and an acid to obtain formula (3): 【Transformation 63】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

41. The manufacturing method according to claim 40, further comprising Step C below: Step C: Formula (3): 【Chemistry 64】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with borane in the presence of a solvent, and then with a peroxide and a base to obtain formula (4): 【Transformation 65】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

42. The manufacturing method according to claim 41, further comprising Step D below: Step D: Formula (4): 【Chemical Formula 66】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. By reacting the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, with hydrogen in the presence of a catalyst, the protecting group on the amino group is deprotected, resulting in formula (5): 【Transformation 67】 [In the formula, R ２ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

43. The manufacturing method according to claim 42, further comprising Step E below: Step E: Formula (5): 【Transformation 68】 [In the formula, R ２ This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or the ester group of its solvate, is hydrolyzed to produce formula (6): 【Transformation 69】 A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

44. The manufacturing method according to claim 43, further comprising Step F below: Step F: Formula (6): 【Transformation 70】 Protect the amino group of the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, as in formula (7): 【Chemistry 71】 [In the formula, R ３ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

45. Formula (8), including Step M below: 【Chemistry 72】 [In the formula, R ３ [is a protecting group for amino groups] Methods for producing the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate: Step M: Formula (2): 【Transformation 73】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. A compound represented by formula (2a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent under acidic conditions, is prepared using formula (2a): 【Chemistry 74】 [In the formula, R ５ａ , R ５ｂ , and R ５ｃ Each of them is independent of C １－６ Alkyl or C ６-１０ [It is Ariel] By reacting with a compound represented by formula (13), or a pharmaceutically acceptable salt thereof, or a solvate thereof, the following compound is obtained: 【Chemistry 75】 [In the formula, R １ , R １Ａ , R ２ , R ５ａ , R ５ｂ , and R ５ｃ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

46. The manufacturing method according to claim 45, further comprising Step A below: Step A: Formula (1): 【Transformation 76】 [In the formula, R １ C may be substituted. １－６ It is alkyl, R １Ａ C may be substituted. ６-１０ [It is Ariel] A compound represented by formula (1a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent, is subjected to the following reaction: 【Chemical 77】 [In the formula, R ２ C may be substituted. １－６ It is alkyl. By reacting with a compound represented by formula (2), or a pharmaceutically acceptable salt thereof, or a solvate thereof, the following compound is produced: 【Transformation 78】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

47. The manufacturing method according to claim 45 or 46, further comprising Step N below: Step N: Formula (13): 【Transformation 79】 [In the formula, R １ , R １Ａ , R ２ , R ５ａ , R ５ｂ , and R ５ｃ This is synonymous with the above. The silyl enol ether group of the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, is hydrolyzed to obtain formula (14): 【Chemistry 80】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

48. The manufacturing method according to claim 47, further comprising Step O below: Step O: Formula (14): 【Chemistry 81】 [In the formula, R １ , R １Ａ , and R ２ This is synonymous with the above. By reacting the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, with hydrogen in the presence of a catalyst, the protecting group on the amino group is deprotected, resulting in formula (15): 【Chemistry 82】 [In the formula, R ２ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

49. The manufacturing method according to claim 48, further comprising Step P below: Step P: Formula (15): 【Chemistry 83】 [In the formula, R ２ This is synonymous with the above. Protecting the amino group of the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate, formula (16): 【Chemical 84】 [In the formula, R ２ and R ３ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

50. The manufacturing method according to claim 49, further comprising Step Q below: Step Q: Formula (16): 【Chemical 85】 [In the formula, R ２ and R ３ This is synonymous with the above. The compound represented by, or a pharmaceutically acceptable salt thereof, or the ester group of its solvate, is hydrolyzed to obtain formula (8): 【Chemical 86】 [In the formula, R ３ This is synonymous with the above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

51. Formula (12), including Step H below: 【Chemistry 87】 [In the formula, a, b, c, and d are each independently either 1 or 2.] Methods for producing the compound represented by, or a pharmaceutically acceptable salt thereof, or its solvate: Step H: Formula (8): 【Chemical 88】 [In the formula, R ３ This is synonymous with the above. A compound represented by formula (8a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a condensing agent, is prepared using formula (8a): 【Chemistry 89】 [In the formula, R ４ a, b, c, and d are the same as above. By reacting with a compound represented by formula (9), or a pharmaceutically acceptable salt thereof, or a solvate thereof, the following compound is obtained: [Chemical 90] [In the formula, R ３ , R ４ a, b, c, and d are the same as above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

52. The manufacturing method according to claim 51, further comprising Step I below: Step I: Formula (9): 【Chemistry 91】 [In the formula, R ３ , R ４ a, b, c, and d are the same as above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with a methyltriphenylphosphonium halogen, a trialkylsilylmethyl anion, or a methylsulfone derivative in the presence of a solvent and a base to obtain formula (10): 【Chemistry 92】 [In the formula, R ３ , R ４ a, b, c, and d are the same as above. A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

53. The manufacturing method according to claim 52, further comprising Step J below: Step J: Formula (10): 【Chemistry 93】 [In the formula, R ３ , R ４ a, b, c, and d are the same as above. A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with an acid to obtain formula (11): 【Chemical 94】 [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

54. The manufacturing method according to claim 53, further comprising Step K below: Step K: Formula (11): 【Chemical 95】 [In the formula, a, b, c, and d are the same as above.] A compound represented by formula (11a), or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the presence of a solvent and a base, is prepared using formula (11a): 【Chemistry 96】 [In the formula, X is fluorine, chlorine, bromine, iodine, p-toluenesulfonyl group, or methanesulfonyl group] The compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted to produce formula (12): 【Chemistry 97】 [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

55. The manufacturing method according to claim 54, further comprising Step L below: Step L: Formula (12): 【Chem.98】 [In the formula, a, b, c, and d are the same as above.] A compound represented by, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is reacted with L(+)-tartaric acid in the presence of a solvent to obtain formula (12a): 【Chem.99】 [In the formula, a, b, c, and d are the same as above.] A process for producing a compound represented by [the given symbol], or its solvate.

56. A mixture comprising 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a solvate thereof, and compound A or a pharmaceutically acceptable salt thereof, or a solvate thereof.

57. The mixture according to claim 56, wherein compound A 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 measured by high-performance liquid chromatography (HPLC).

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

59. The mixture according to claim 56, wherein compound A 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 measured by high-performance liquid chromatography (HPLC).

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

61. The mixture according to claim 60, 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 measured by high-performance liquid chromatography (HPLC).

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

63. The mixture according to claim 60, 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 measured by high-performance liquid chromatography (HPLC).

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

65. The mixture according to claim 64, wherein compound C 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 measured by high-performance liquid chromatography (HPLC).

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

67. The mixture according to 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 measured by high-performance liquid chromatography (HPLC).

68. A mixture comprising 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a solvate thereof, and compound B or a pharmaceutically acceptable salt thereof, or a solvate 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 measured by high-performance liquid chromatography (HPLC).

70. 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 0.1% or less of the mixture, as measured by high-performance liquid chromatography (HPLC).

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 measured 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 solvate thereof.

73. 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 0.15% or less of the mixture, as measured by high-performance liquid chromatography (HPLC).

74. 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 0.1% or less of the mixture, as measured by high-performance liquid chromatography (HPLC).

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 measured by high-performance liquid chromatography (HPLC).

76. A mixture comprising 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide or a pharmaceutically acceptable salt thereof, or a solvate thereof, and compound C or a pharmaceutically acceptable salt thereof, or a solvate thereof.

77. 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 0.15% or less of the mixture, as measured by high-performance liquid chromatography (HPLC).

78. 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 0.1% or less of the mixture, as measured by high-performance liquid chromatography (HPLC).

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 measured by high-performance liquid chromatography (HPLC).

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