Bicycloheptene compound and method for producing bicycloheptene compound

Abstract

The purpose of the present disclosure is to provide a compound that is useful in a production method, said compound making it possible to solve at least one issue selected from 1) making HCN management unnecessary, 2) making heavy metals such as Co and Ni unnecessary, and 3) making a pressurized container unnecessary, when producing mirogabalin. The present disclosure relates to a bicycloheptene compound represented by formula (I). (In formula (I), X represents -CN or -C(=O)NH2. Y represents a hydrogen atom or -CO2T. T represents a hydrogen atom or a C1-3 alkyl group.)

Description

Bicycloheptene compounds and methods for producing bicycloheptene compounds

[0001] The present disclosure relates to bicycloheptene compounds and methods for producing bicycloheptene compounds, and more specifically to mirogabalin besylate and intermediates therefor, and methods for producing the same.

[0002] Mirogabalin besylate is a compound represented by the following formula (5), and is known as a therapeutic agent for neuropathic pain. Its production method is disclosed in Patent Document 1, and is shown in the following chemical formula.

[0003]

[0004] International Publication No. 2015 / 005298

[0005] Conventionally known production methods have room for improvement from the perspective of industrial production, in that they require the use of NaCN, which generates highly toxic HCN, the use of pyrophoric heavy metals such as Co and Ni, the use of a pressurized vessel for the hydrogenation reaction, etc. The present disclosure has been made in light of the above-mentioned circumstances, and its object is to provide a production method and a compound useful for said production method that can solve at least one (preferably two, more preferably three) of the following problems when producing a compound represented by formula (4) (mirogabalin) from a compound represented by formula (1z) or an analogous compound thereof: 1) no need to control HCN, 2) no need for heavy metals such as Co and Ni, and 3) no need for a pressurized vessel.

[0006] As a result of intensive research into solving the above-mentioned problems, the present inventors have found that if an intermediate is formed from a compound belonging to the bicycloheptene compound represented by a specific formula (I) (preferably, if the intermediate is formed only from compounds belonging to the formula (I)), then in producing a compound represented by formula (4) from a compound represented by formula (1z) or an analogous compound thereof, at least one (preferably two, more preferably three) of the following problems can be solved: 1) management of HCN is not required, 2) heavy metals such as Co and Ni are not required, and 3) a pressurized container is not required, and have completed the present disclosure.

[0007] That is, the present disclosure provides the following: [1] A bicycloheptene compound represented by formula (I). (In formula (I), X is —CN or —C(═O)NH ２ Y represents a hydrogen atom or —CO ２ T represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. When formula (I) has two Ts, the two Ts may be different from each other, or the two Ts may combine to form a ring.) [2] A method for producing a compound represented by formula (4), which comprises subjecting a compound represented by formula (3) below to a Hofmann rearrangement to obtain a compound represented by formula (4) below. [3] The method for producing a compound represented by formula (5), comprising: subjecting a compound represented by formula (3) to a Hofmann rearrangement in the presence of a halogenating agent and a base, wherein the halogenating agent comprises at least one selected from the group consisting of hypochlorite, hypobromite, and a hypervalent iodine compound. [4] The method for producing a compound represented by formula (5), comprising subjecting a compound represented by formula (4) obtained by the method for producing a compound represented by formula (5) to a salt formation. (In formula (5), BsOH represents benzenesulfonic acid.) [5] The compound represented by formula (3) is produced by hydrating a compound represented by formula (7) below, and the compound represented by formula (7) is produced by hydrolyzing a compound represented by formula (6) below, and the compound represented by formula (6) is produced by decarboxylating a compound represented by formula (2) below, and the compound represented by formula (2) is converted into a compound represented by formula (1) below by CH ３ The method according to [2] or [3], wherein the compound is produced by Michael addition of CN. (Wherein, Y is —CO ２T represents an alkyl group having 1 to 3 carbon atoms, and when there are two Ts, the two Ts may be different from each other or may combine to form a ring.) [6] The production method according to [5], in which the compound represented by formula (7) is hydrated by mixing with hydrogen peroxide in the presence of a base. [7] The production method according to [5] or [6], in which the compound represented by formula (6) is hydrolyzed by reacting in the presence of a base and water. [8] The production method according to any one of [5] to [7], in which the compound represented by formula (2) is decarboxylated under heating using a nucleophile, wherein the nucleophile comprises at least one selected from the group consisting of a base and a halide. [9] The compound represented by formula (3) is produced by decarboxylating, hydrolyzing, and hydrating a compound represented by formula (2) below in one pot, and the compound represented by formula (2) is converted to a compound represented by formula (1) below by CH ３ The method according to [2] or [3], wherein the compound is produced by Michael addition of CN. (Wherein, Y is —CO ２ T represents an alkyl group having 1 to 3 carbon atoms, and when there are two Ts, the two Ts may be different from each other, or the two Ts may be joined together to form a ring.)

[10] The production method according to [9], in which the compound represented by formula (2) is decarboxylated under heating in the presence of a base as a nucleophile, then hydrolyzed in the presence of a base and water, and then hydrated by mixing with hydrogen peroxide.

[0008] In this specification, the compound represented by formula (X) is also referred to as compound (X), where X varies depending on the symbol in the formula.

[0009] According to the present disclosure, an intermediate is constituted by a compound belonging to the bicycloheptene-based compound represented by the specific formula (I). Therefore, when producing a compound represented by formula (4) from a compound represented by formula (1z) or an analogous compound thereof, at least one (preferably two, more preferably three) of the following effects can be achieved: 1) no need to manage HCN, 2) no need for heavy metals such as Co and Ni, and 3) no need for a pressurized container.

[0010] The present disclosure includes a bicycloheptene-based compound (compound (I)) represented by formula (I).

[0011]

[0012] (In formula (I), X is —CN or —C(═O)NH ２ Y represents a hydrogen atom or —CO ２ T represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. When formula (I) has two Ts, the two Ts may be different from each other, or the two Ts may combine together to form a ring.

[0013] The bicycloheptene compound (I) is useful as an intermediate. Specifically, as shown below, when producing a compound represented by formula (4) from a compound represented by formula (1), the intermediate can be composed of a compound belonging to the bicycloheptene compound (I) (preferably, the intermediate can be composed solely of compounds belonging to the bicycloheptene compound (I)). As a result, at least one (preferably two, more preferably three) of the following effects can be achieved: 1) no need to manage HCN, 2) no need for heavy metals such as Co and Ni, and 3) no need for a pressurized container. Compound (4) can be converted into mirogabalin besylate (compound (5)), a known neuropathic pain treatment, by a known method.

[0014]

[0015] (In formula (1), Y is —CO ２ T represents an alkyl group having 1 to 3 carbon atoms. The two T's in formula (1) may be different from each other, or the two T's may combine to form a ring. In formula (I), X represents -CN or -C(=O)NH ２ and Y represents a hydrogen atom or —CO ２ T represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. When formula (I) has two Ts, the two Ts may be different from each other, or the two Ts may combine together to form a ring.

[0016] In the compound (1), T is preferably a linear alkyl group having 1 to 3 carbon atoms, more preferably a methyl group or an ethyl group, and even more preferably an ethyl group. In the compound (1), it is preferable that the two Ts are the same. In addition, when the two Ts are joined together to form a ring, the C—(CO ２ T) ２ Examples of the alkyl group include a Meldrum's acid ring, etc. In compound (I), when T is an alkyl group having 1 to 3 carbon atoms, the preferred embodiments thereof are the same as the preferred embodiments of T in compound (1).

[0017] As the compound (1), a compound represented by the following formula (1z) is particularly preferred.

[0018]

[0019] The compound (I) specifically includes compounds represented by the following formula (2), formula (3), formula (6), or formula (7).

[0020]

[0021] (In formula (2), Y is —CO ２ T represents an alkyl group having 1 to 3 carbon atoms, and when there are two T's, the two T's may be different from each other, or the two T's may join together to form a ring. In formula (6), T represents an alkyl group having 1 to 3 carbon atoms.

[0022] In formula (2) and formula (6), T is preferably a linear alkyl group having 1 to 3 carbon atoms, more preferably a methyl group or an ethyl group, and even more preferably an ethyl group. When there are two Ts, it is preferable that the two Ts are the same. In addition, when two Ts are taken together to form a ring, C—(CO ２ T) ２ Examples of the compound (2), the compound (3), the compound (6), and the compound (7) are particularly preferably compounds represented by the following formulas (2z), (3z), (6z), and (7z), respectively.

[0023]

[0024] An example of a synthetic route using the compounds (2), (3), (6), and (7) can be shown in the following scheme 1. The following scheme 1 is composed of reactions R01 to R07, and each reaction number will be referred to in the description below.

[0025] [Scheme 1]

[0026] The above-mentioned scheme 1 is roughly composed of the following reaction classes 1 to 3. Reaction class 1: Compound (1) having a partial structure represented by formula (T1) is reacted with CH ３ Michael addition of CN gives -CH ２ A compound having a partial structure represented by formula (T2) containing a CN group is formed, and then -CH ２ A reaction in which a CN group is hydrated to synthesize a compound having a partial structure represented by formula (T3).

[0027] (In formula (T1), Y is —CO ２ In formulas (T2) and (T3), Y represents a hydrogen atom or —CO ２ T represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and when there are two Ts, the two Ts may be different from each other, or the two Ts may be joined together to form a ring.

[0028] Reaction Class 2: A reaction in which a compound having a partial structure represented by formula (T3) is subjected to Hofmann rearrangement to synthesize a compound having a partial structure represented by formula (U1).

[0029] (wherein Y is a hydrogen atom or —CO ２ T represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and when there are two Ts, the two Ts may be different from each other, or the two Ts may be joined together to form a ring.

[0030] Reaction Classification 3: A reaction in which a compound having a partial structure represented by formula (S1), which was introduced during the synthesis of a compound having a partial structure represented by formula (T2), is decarboxylated to form a compound having a partial structure represented by formula (S2), which is then hydrolyzed to synthesize a compound having a partial structure represented by formula (S3).

[0031] (In the formula, T represents an alkyl group having 1 to 3 carbon atoms, and when there are two Ts, the two Ts may be different from each other, or the two Ts may combine to form a ring.)

[0032] [Specific Reactions Belonging to Reaction Class 1] Reaction Class 1 specifically includes reactions in which a compound represented by formula (B1) is reacted with CH ３ The reaction includes a reaction (reaction R-B1) in which CN is subjected to Michael addition to obtain a compound represented by formula (B2), and a reaction (reaction R-B2) in which the compound represented by formula (B2) is subsequently hydrated to obtain a compound represented by formula (B3).

[0033]

[0034] (In formula (B1), Y is —CO ２ T represents an alkyl group having 1 to 3 carbon atoms. The two T's in formula (B1) may be different from each other, or the two T's may combine to form a ring. In formula (B2), Y represents a hydrogen atom or -CO ２ In formula (B3), Y represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. When formula (B2) has two Ts, the two Ts may be different from each other, or the two Ts may combine to form a ring. In formula (B3), Y represents a hydrogen atom or -CO ２ T represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. When formula (B3) has two T's, the two T's may be different from each other, or the two T's may combine together to form a ring.

[0035] The compound (B1) includes the compound (1) and the like. The compound (B2) includes the compound (2), compound (6), compound (7), and the like. The compound (B3) includes the compound (3) and the like. The reaction R-B1 includes the reaction R01 and the like. The reaction R-B2 includes the reaction R07 and the like.

[0036] (R-B1): CH ３ In the Michael addition reaction R-B1 with CN, compound (B1) is reacted with CH ３ By reacting with acetonitrile (CN), the double bond in compound (B1) is converted into an unsaturated ester having a conjugated double bond. ３ Compound (B2) is produced by stereoselective 1,4-addition of CN.

[0037] CH in reaction R-B1 ３ The amount of CN used is preferably 0.8 to 5 mol, more preferably 1.0 to 4 mol, and even more preferably 1.2 to 3 mol, relative to 1 mol of compound (B1) from the viewpoint of yield. ３ CN may also be used as a solvent, in which case CH ３ The amount of CN used is preferably within the range of the amount of the solvent used in the reaction R-B1 described below.

[0038] The base used in reaction R-B1 may be an organic base or an inorganic base, but an organic base is preferred, a strong organic base is more preferred, and an organolithium compound is even more preferred. The use of an organolithium compound can improve at least one selected from reaction rate, yield, and stereoselectivity. Examples of organolithium compounds include methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, hexyllithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), and lithium tetramethylpiperidide (LiTMP). Of these, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, and lithium tetramethylpiperidide are preferred, and n-butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, and lithium tetramethylpiperidide are more preferred. These bases may be used alone, or two or more may be used in combination.

[0039] The amount of the base used in Reaction R-B1 is preferably 0.5 to 70 mol, more preferably 1.0 to 50 mol, even more preferably 1.1 to 40 mol, and even more preferably 1.2 to 35 mol, relative to 1 mol of Compound (B1). When the amount of the base used is within the above range, the target compound can be obtained in good yield.

[0040] In reaction R-B1, it is preferable to use a solvent. The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include dipropyl ether, diisopropyl ether, dibutyl ether, dihexyl ether, butyl vinyl ether, ethyl propyl ether, cyclopentyl methyl ether, anisole, 2-methylanisole, 4-methylanisole, 2,3-dimethylanisole, 2,6-dimethylanisole, chloroanisole, anethole, phenetole, 4-methylphenetole, n-butylphenyl ether, pentylphenyl ether, benzyl ethyl ether, diphenyl ether, dibenzyl ether, veratrole, 1,2-dimethoxyethane, 1,1-diethoxyethane, 1,2-diethoxyethane, 1,2-dibutoxyethane, dimethyl acetal, t-butyl methyl ether, t-butyl ethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol di Examples of the solvent include ether solvents such as methyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, 2,3-dihydrobenzofuran, tetrahydropyran, 4-methyltetrahydropyran, cineole, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, 4-methyl-1,3-dioxane, and 4-phenyl-1,3-dioxane; hydrocarbon solvents such as toluene, xylene, hexane, heptane, cyclohexane, and methylcyclohexane; acetonitrile; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; urea solvents such as dimethylpropylene urea; and phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide. These may be used alone or in combination of two or more.The solvent used in Reaction R-B1 is preferably an ether solvent or a hydrocarbon solvent, and from the viewpoint of yield and / or stereoselectivity, it is more preferable that the solvent contains at least a polar solvent, and it is even more preferable that the solvent contains an ether solvent. As the ether solvent, an alicyclic ether solvent having a ring structure is preferable, an alicyclic ether solvent having 3 to 10 carbon atoms is more preferable, an alicyclic ether solvent having 3 to 8 carbon atoms is even more preferable, and cyclopentyl methyl ether, tetrahydrofuran, or 4-methyltetrahydropyran is even more preferable.

[0041] When a solvent is used in Reaction R-B1, the amount (volume) of the solvent used is preferably 1.0 to 50 times (vol / w), more preferably 1.5 to 40 times (vol / w), even more preferably 2.0 to 30 times (vol / w), and even more preferably 2.5 to 25 times (vol / w), the weight of Compound (B1), in terms of reaction rate and / or yield. Here, the unit of vol / w is ml / g.

[0042] Reaction R-B1 is preferably carried out in an atmosphere of an inert gas such as nitrogen.

[0043] Compound (B1) in reaction R-B1, CH ３ The method and order of adding CN and the base are not particularly limited. ３ The compound (B1) may be added to a mixture of CN, a base, and a solvent, and the compound (B1) and CH ３ A base may be added to the mixture of CN and the solvent. ３ When mixing CN and a base, from the viewpoint of reaction rate, it is recommended to add CH ３ In terms of reaction rate, the order of addition in reaction R-B1 is preferably CH ３ It is particularly preferred to add the compound (B1) to a mixture of CN, a base, and a solvent. From the viewpoint of ease of production on an industrial scale, it is also preferred to add the compound (B1) to a mixture of CN, a base, and a solvent. ３ It is particularly preferred to add a base to a mixture of CN and a solvent.

[0044] Compound (B1) in reaction R-B1, CH ３The temperature of the reaction system when CN and the base are added is preferably −100 to 10° C., more preferably −90 to 5° C., and even more preferably −80 to 0° C., from the viewpoint of reaction rate and / or yield. From the viewpoint of ease of production on an industrial scale, a temperature of −30 to 10° C. is preferred.

[0045] The reaction temperature in Reaction R-B1 is preferably −30 to 60° C., more preferably 0 to 40° C., and even more preferably 10 to 35° C., from the viewpoint of reaction rate and / or yield.

[0046] The reaction time in Reaction R-B1 may be appropriately set depending on the reaction temperature and the like, but is preferably 10 minutes to 48 hours, more preferably 15 minutes to 24 hours, from the standpoint of reaction rate and / or yield.

[0047] Compound (B2) obtained in reaction R-B1 may be separated and / or purified from the reaction mixture by a conventional separation and purification method such as extraction, column chromatography, crystallization, washing, filtration, dehydration, drying, concentration, etc. From the viewpoint of production efficiency, it is preferable to use the reaction mixture containing compound (B2) in an unpurified state in the next step (e.g., reaction R-B2). When the reaction mixture is used in an unpurified state, the yield of compound (B2) is preferably 60% or more, more preferably 80% or more.

[0048] (R-B2): Hydration Reaction In reaction R-B2, the nitrile group in compound (B2) is hydrated to an amide group to produce compound (B3).

[0049] In terms of yield, reaction R-B2 is preferably carried out by mixing compound (B2) with hydrogen peroxide in the presence of a base to carry out hydration.

[0050] The amount of hydrogen peroxide used in Reaction R-B2 is preferably 1.5 to 15 mol, more preferably 2.0 to 13 mol, even more preferably 2.2 to 11 mol, and even more preferably 2.5 to 10 mol, relative to 1 mol of Compound (B2). When the amount of hydrogen peroxide used is within the above range, the target compound can be obtained in good yield.

[0051] In Reaction R-B2 using hydrogen peroxide, it is preferable to use an aqueous solvent. The aqueous solvent refers to water or a mixed solvent of water and a polar organic solvent, and water is preferred. Examples of the polar organic solvent include alcohol-based solvents such as methanol, ethanol, propanol, butanol, pentanol, hexanol, and heptanol; ketone-based solvents such as acetone and methyl ethyl ketone; ether-based solvents such as tetrahydrofuran and dioxane; amide-based solvents such as dimethylformamide and acetamide; dimethyl sulfoxide, pyridine, and piperidine. When the aqueous solvent is a mixed solvent of water and a polar organic solvent, the concentration of the polar organic solvent is not particularly limited as long as it is equal to or lower than the solubility in water.

[0052] The amount (volume) of the aqueous solvent used is preferably 1 to 50 times (vol / w) the weight of compound (B2), more preferably 2 to 40 times (vol / w), even more preferably 3 to 30 times (vol / w), and even more preferably 5 to 25 times (vol / w), in terms of reaction rate and / or yield, where vol / w is in ml / g.

[0053] Reaction R-B2 is preferably carried out in an atmosphere of an inert gas such as nitrogen.

[0054] In the reaction R-B2 using hydrogen peroxide, it is preferable to premix the compound (B2) with a base and then react it with hydrogen peroxide, from the viewpoint of yield and / or ease of production on an industrial scale.

[0055] Examples of the base include hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; and metal carbonates such as sodium carbonate and potassium carbonate; and the like. Of these, hydroxides of alkali metals or alkaline earth metals are preferred, and sodium hydroxide and potassium hydroxide are more preferred.

[0056] The amount of the base used is preferably 0.1 to 5.0 mol, more preferably 0.5 to 4.5 mol, even more preferably 0.8 to 4.0 mol, and still more preferably 1.0 to 3.0 mol, relative to 1 mol of compound (B2), from the viewpoint of reaction rate and / or yield.

[0057] The temperature at which the compound (B2) and the base are mixed is preferably from 10 to 80°C, more preferably from 15 to 70°C, and even more preferably from 20 to 65°C, from the viewpoint of the reaction rate and / or yield.

[0058] The mixing time of compound (B2) and the base may be appropriately set depending on the reaction temperature etc., but is preferably 0.5 to 36 hours, more preferably 1 to 24 hours, from the viewpoint of reaction rate and / or yield.

[0059] The temperature of the reaction system during the addition of hydrogen peroxide is preferably from -20 to 50°C, more preferably from -10 to 40°C, and even more preferably from -5 to 30°C, from the viewpoint of reaction rate and / or yield.

[0060] The reaction temperature of the compound (B2) with hydrogen peroxide is preferably 15 to 100°C, more preferably 20 to 80°C, and even more preferably 25 to 70°C, from the viewpoint of reaction rate and / or yield.

[0061] The reaction time between compound (B2) and hydrogen peroxide may be appropriately set depending on the reaction temperature and the like, but is preferably 0.5 to 12 hours, more preferably 1 to 10 hours, from the viewpoint of reaction rate and / or yield.

[0062] Compound (B3) obtained in reaction R-B2 may be separated and / or purified from the reaction mixture by a conventional separation and purification method such as extraction, column chromatography, crystallization, washing, filtration, dehydration, drying, concentration, etc. From the viewpoint of production efficiency, it is preferable to use the reaction mixture containing compound (B3) in an unpurified state in the next step (e.g., reaction R-A1, reaction R-A2, reaction R03). When the reaction mixture is used in an unpurified state, the yield of compound (B3) is preferably 60% or more, more preferably 80% or more.

[0063] [Specific Reactions Belonging to Reaction Class 2] Reaction Class 2 specifically includes a reaction (reaction R03) in which a compound represented by formula (3) is subjected to Hofmann rearrangement to give a compound represented by formula (4).

[0064]

[0065] (R03): Hoffmann rearrangement reaction In reaction R03, compound (3) is treated with a halogenating agent and a base to convert the amide group in compound (3) into an amino group by a one-carbon reduction via an isocyanate rearrangement reaction, thereby producing compound (4). In this reaction, the configuration of compound (3) is maintained, and the target compound (4) can be produced with good optical purity and yield.

[0066] Examples of the halogenating agent used in reaction R03 include hypochlorites such as sodium hypochlorite and potassium hypochlorite; hypobromites such as sodium hypobromite and potassium hypobromite; N-halosuccinimides such as N-chlorosuccinimide, N-bromosuccinimide, and N-iodosuccinimide; N-haloisocyanuric acids such as N-chloroisocyanuric acid and N-bromoisocyanuric acid; chlorohydantoins such as 1,3-dichloro-5,5-dimethylhydantoin; 1,3-dibromo-5,5 1,3-Diiodo-5,5-dimethylhydantoin and other bromohydantoins; 1,3-Diiodo-5,5-dimethylhydantoin and other iodohydantoins; (diacetoxyiodo)benzene (DAIB), [bis(trifluoroacetoxy)iodo]benzene (PIFA), and other hypervalent iodine compounds; and halogen molecules such as chlorine, bromine, and iodine. Of these, hypochlorite, hypobromite, and hypervalent iodine compounds are preferred, and sodium hypochlorite, sodium hypobromite, DAIB, and PIFA are more preferred. The halogenating agent may be used alone or in combination of two or more.

[0067] The amount of the halogenating agent used in reaction R03 is preferably 0.3 to 20 mol, more preferably 0.5 to 10 mol, even more preferably 0.8 to 5 mol, and even more preferably 1.0 to 3 mol, relative to 1 mol of compound (3). When the amount of the halogenating agent used is within the above range, the target compound can be obtained in good yield.

[0068] The base used in reaction R03 is preferably an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, or calcium hydroxide, and more preferably sodium hydroxide. The base may be used alone or in combination of two or more kinds.

[0069] The amount of base used in reaction R03 is preferably 0.5 to 50 mol, more preferably 1.0 to 30 mol, even more preferably 1.3 to 20 mol, and even more preferably 1.5 to 10 mol, relative to 1 mol of compound (3). When the amount of base used is within the above range, the target compound can be obtained in good yield. Furthermore, the amount of base used in reaction R03 is preferably 0.5 to 20 mol, more preferably 1.0 to 10 mol, and even more preferably 1.5 to 5 mol, relative to 1 mol of the halogenating agent.

[0070] In reaction R03, it is preferable to use a solvent, and it is preferable to use an aqueous solvent as the solvent. The aqueous solvent refers to water or a mixed solvent of water and a polar organic solvent, and water is preferable. Examples of the polar organic solvent include alcohol-based solvents such as methanol, ethanol, propanol, butanol, pentanol, hexanol, and heptanol; ketone-based solvents such as acetone and methyl ethyl ketone; ether-based solvents such as tetrahydrofuran and dioxane; nitrile-based solvents such as acetonitrile and propionitrile; amide-based solvents such as dimethylformamide and acetamide; dimethyl sulfoxide, pyridine, and piperidine. When the aqueous solvent is a mixed solvent of water and a polar organic solvent, the concentration of the polar organic solvent may be any concentration that does not inhibit the reaction.

[0071] The amount (volume) of the aqueous solvent used in reaction R03 is preferably 0.8 to 100 times (vol / w) the weight of compound (B2), more preferably 1.0 to 50 times (vol / w), even more preferably 1.2 to 30 times (vol / w), and even more preferably 1.5 to 20 times (vol / w), in terms of reaction rate and / or yield, where vol / w is in ml / g.

[0072] Reaction R03 is usually preferably carried out under an atmosphere of an inert gas such as nitrogen.

[0073] The reaction temperature in reaction R03 is preferably −20 to 50° C., more preferably −10 to 40° C., and even more preferably −5 to 35° C., from the viewpoint of reaction rate and / or yield. The reaction temperature may be, and is preferably, changed during the reaction. For example, it is preferable to initially carry out the reaction at a low temperature, and then to raise the temperature and carry out the reaction. Specifically, it is preferable to initially carry out the reaction at a temperature of −20° C. or higher and 10° C. or lower (preferably −10° C. or higher and 6° C. or lower), and then to carry out the reaction at a temperature higher than 10° C. and 50° C. or lower (preferably 15° C. or higher and 40° C. or lower).

[0074] The reaction time in Reaction R03 may be appropriately set depending on the reaction temperature, etc., but from the viewpoint of the reaction rate and / or yield, it is preferably 0.5 to 48 hours, more preferably 1 to 24 hours, and even more preferably 2 to 18 hours. When the reaction temperature is changed during the reaction, it is preferable to carry out the reaction at a low temperature of, for example, -20°C or higher and 10°C or lower for 0.1 to 10 hours, and then raise the temperature to 10°C or higher and 50°C or lower for 0.5 to 30 hours.

[0075] Compound (4) obtained in reaction R03 may be separated and / or purified from the reaction mixture by a conventional separation and purification method such as extraction, column chromatography, crystallization, washing, filtration, dehydration, drying, concentration, etc. From the viewpoint of production efficiency, it is preferable to use the reaction mixture containing compound (4) in an unpurified state in the next step (reaction R04). When the reaction mixture is used in an unpurified state, the yield of compound (4) is preferably 60% or more, more preferably 80% or more.

[0076] [Specific Reactions Belonging to Reaction Classification 3] Specifically, reaction class 3 includes a reaction of decarboxylating a compound represented by formula (A1) to give a compound represented by formula (A2) (reaction R-A1), and a reaction of hydrolyzing a compound represented by formula (A2) to give a compound represented by formula (A3) (reaction R-A2).

[0077]

[0078] (In formulas (A1) to (A3), X is —CN or —C(═O)NH ２ Y represents a hydrogen atom or —CO ２T represents an alkyl group having 1 to 3 carbon atoms. The two T's in formula (A1) may be different from each other, or the two T's may join together to form a ring. There are two types of compounds represented by formula (A2): a compound obtained by decarboxylation of a compound represented by formula (A1), and a raw material for hydrolysis to obtain a compound represented by formula (A3). Both X's may be the same, or X's in both may be different from each other.

[0079] The compound (A1) includes the compound (2) and the like. The compound (A2) includes the compound (6) and the like. The compound (A3) includes the compounds (3), (7) and the like. The reaction R-A1 includes the reaction R05 and the like. The reaction R-A2 includes the reaction R06 and the like.

[0080] (R-A1): Decarboxylation Reaction In the reaction R-A1, the carboxylic acid ester group represented by Y in the compound (A1) is eliminated to produce the compound (A2).

[0081] In terms of yield, reaction R-A1 is preferably carried out by decarboxylating compound (A1) using a nucleophilic agent under heating.

[0082] Examples of the nucleophilic agent include bases and halides. Examples of the base include alkali metal or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and cesium hydroxide, with sodium hydroxide, potassium hydroxide, and cesium hydroxide being more preferred. Examples of the halide include alkali metal chlorides such as lithium chloride and sodium chloride, with lithium chloride being preferred.

[0083] When a base is used as the nucleophile, the amount of the base used in Reaction R-A1 is preferably 0.3 to 30 mol, more preferably 0.5 to 15 mol, even more preferably 0.8 to 10 mol, and even more preferably 1.0 to 5 mol, relative to 1 mol of Compound (A1). When the amount of the base used is within the above range, the target compound can be obtained in good yield.

[0084] When a halide is used as the nucleophile, the amount of the halide used in Reaction R-A1 is preferably 1.0 to 50 mol, more preferably 1.5 to 30 mol, even more preferably 2.0 to 20 mol, and even more preferably 2.5 to 15 mol, relative to 1 mol of Compound (A1). When the amount of the halide used is within the above range, the target compound can be obtained in good yield.

[0085] In Reaction R-A1, it is preferable to use a solvent, and examples of the solvent include water; alcohol solvents such as methanol, ethanol, propanol, butanol, pentanol, hexanol, and heptanol; ketone solvents such as acetone and methyl ethyl ketone; ether solvents such as tetrahydrofuran and dioxane; amide solvents such as dimethylformamide and acetamide; sulfoxide solvents such as dimethyl sulfoxide; pyridine and piperidine. These solvents may be used alone or in combination of two or more. In the case of decarboxylation using a base as the nucleophile, water and alcohol solvents are preferred, and water and alcohol solvents having 1 to 4 carbon atoms are more preferred. In the case of decarboxylation using a halide as the nucleophile, water and sulfoxide solvents are preferred, and water and dimethyl sulfoxide are more preferred.

[0086] The amount (volume) of the solvent used in Reaction R-A1 is preferably 1.0 to 80 times (vol / w) the weight of Compound (A1), more preferably 3.0 to 60 times (vol / w), even more preferably 4.0 to 50 times (vol / w), and even more preferably 5.0 to 40 times (vol / w), in terms of reaction rate and / or yield, where vol / w is in ml / g.

[0087] Reaction R-A1 is preferably carried out in an atmosphere of an inert gas such as nitrogen.

[0088] The method for adding the base as a nucleophile is not particularly limited, but it is preferable to add a mixture of the base and the solvent dropwise to a mixture of compound (A1) and the solvent. The time for adding the base dropwise is, for example, preferably 0.1 to 18 hours, more preferably 0.5 to 12 hours, and even more preferably 1.0 to 8 hours. From the viewpoint of reaction rate and / or yield, the temperature for adding the base is preferably 40 to 110°C, more preferably 45 to 100°C, and even more preferably 50 to 90°C, and is particularly preferably the reflux temperature of the solvent.

[0089] In the reaction R-A1 using a base as a nucleophile, the reaction temperature is preferably 40 to 150° C., more preferably 45 to 130° C., even more preferably 50 to 100° C., and particularly preferably the reflux temperature of the solvent, from the viewpoint of reaction rate and / or yield. By carrying out the reaction R-A1 under reflux conditions, the ease of production is further improved.

[0090] The reaction time in Reaction R-A1 using a base as a nucleophile may be appropriately set depending on the reaction temperature, etc., but is preferably 1 to 96 hours, more preferably 5 to 84 hours, from the viewpoint of reaction rate and / or yield.

[0091] The reaction temperature in Reaction R-A1 using a halide as a nucleophile is preferably 60 to 200°C, more preferably 80 to 180°C, and even more preferably 90 to 170°C, from the viewpoint of reaction rate and / or yield.

[0092] The reaction time in Reaction R-A1 using a halide as a nucleophile may be appropriately set depending on the reaction temperature, etc., but is preferably 1.0 to 48 hours, more preferably 1.5 to 36 hours, from the viewpoint of reaction rate and / or yield.

[0093] Compound (A2) obtained in reaction R-A1 may be separated and / or purified from the reaction mixture by a conventional separation and purification method such as extraction, column chromatography, crystallization, washing, filtration, dehydration, drying, concentration, etc. From the viewpoint of production efficiency, it is preferable to use the reaction mixture containing compound (A2) in an unpurified state in the next step (e.g., reaction R-A2). When the reaction mixture is used in an unpurified state, the yield of compound (A2) is preferably 60% or more, more preferably 80% or more.

[0094] (R-A2): Hydrolysis Reaction In reaction R-A2, —CO ２ T is hydrolyzed to -CO ２ As H, compound (A3) is produced.

[0095] Reaction R-A2 is preferably carried out by reacting compound (A2) in the presence of a base and water, and is usually preferably carried out in an inert gas atmosphere such as nitrogen.

[0096] The base is preferably an alkali metal or alkaline earth metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or calcium hydroxide, more preferably lithium hydroxide, sodium hydroxide, or potassium hydroxide, and even more preferably potassium hydroxide.

[0097] The amount of the base used in Reaction R-A2 is preferably 0.3 to 50 mol, more preferably 0.5 to 20 mol, even more preferably 0.8 to 10 mol, and even more preferably 1.0 to 5 mol, relative to 1 mol of Compound (A2). When the amount of the base used is within the above range, the target compound can be obtained in good yield.

[0098] In Reaction R-A2, it is preferable to use a solvent, and it is preferable to use an aqueous solvent as the solvent. The aqueous solvent refers to water or a mixed solvent of water and a polar organic solvent. Examples of the polar organic solvent include alcohol-based solvents such as methanol, ethanol, propanol, butanol, pentanol, hexanol, and heptanol; ketone-based solvents such as acetone and methyl ethyl ketone; ether-based solvents such as tetrahydrofuran and dioxane; amide-based solvents such as dimethylformamide and acetamide; dimethyl sulfoxide, pyridine, and piperidine, with alcohol-based solvents being preferred. When the aqueous solvent is a mixed solvent of water and a polar organic solvent, the concentration of the polar organic solvent may be any concentration that does not inhibit the reaction.

[0099] The amount (volume) of the solvent used in Reaction R-A2 is preferably 0.8 to 100 times (vol / w) the weight of Compound (A2), more preferably 1.0 to 80 times (vol / w), even more preferably 1.2 to 60 times (vol / w), and even more preferably 1.5 to 40 times (vol / w), in terms of reaction rate and / or yield, where vol / w is in ml / g.

[0100] When reaction R-A2 is carried out successively after reaction R-A1, reaction R-A2 may be carried out using the solvent and / or base as a nucleophile used in reaction R-A1, or a solvent and / or base may be added to the reaction system.

[0101] The reaction temperature in Reaction R-A2 is preferably 0 to 110°C, more preferably 5 to 100°C, and even more preferably 10 to 90°C, from the viewpoint of reaction rate and / or yield, and may be the reflux temperature of the solvent.

[0102] The reaction time in Reaction R-A2 may be appropriately set depending on the reaction temperature and the like, but from the viewpoint of the reaction rate and / or yield, it is preferably 0.1 to 48 hours, more preferably 0.5 to 36 hours, and even more preferably 1 to 12 hours.

[0103] Compound (A3) obtained in reaction R-A2 may be separated and / or purified from the reaction mixture by a conventional separation and purification method such as extraction, column chromatography, crystallization, washing, filtration, dehydration, drying, concentration, etc. From the viewpoint of production efficiency, the reaction mixture containing compound (A3) is preferably used in the next step (reaction R04) without purification. When the reaction mixture is used without purification, the yield of compound (A3) is preferably 60% or more, more preferably 80% or more.

[0104] Compound (1) first undergoes the first reaction (reaction R-B1; Michael addition reaction) belonging to reaction class 1. After the series of reactions belonging to reaction class 1 is completed, a reaction belonging to reaction class 2 occurs. Furthermore, after the first reaction (reaction R-B1; Michael addition reaction) belonging to reaction class 1, a reaction belonging to reaction class 3 becomes possible.

[0105] A preferred combination of reaction classes 1 to 3 is as shown in Scheme 1 above, which includes Route 1, in which compound (1) is converted to compound (3), and Route 2, in which compound (5) is produced from compound (3) via compound (4) following Route 1. In addition, in all the reaction steps from Route 1 to Route 2, any reactions may be carried out together in one pot. By carrying out the one-pot process, production efficiency can be improved.

[0106] [Route 1] Route 1 is a method for adding CH ３ This route involves producing compound (2) by Michael addition of CN (reaction R01), decarboxylating the resulting compound (2) to produce compound (6) (reaction R05), hydrolyzing the resulting compound (6) to produce compound (7) (reaction R06), and hydrating the resulting compound (7) to produce compound (3) (reaction R07).

[0107]

[0108] (Wherein, Y is —CO ２ T represents an alkyl group having 1 to 3 carbon atoms, and when there are two Ts, the two Ts may be different from each other, or the two Ts may be joined together to form a ring.

[0109] In Route 1, compounds (7) and (3) may or may not be isolated as solids (preferably crystals) from the reaction mixture. Isolation can increase the purity of the compounds. When isolating, it is preferable to isolate at least compound (3). Furthermore, the fewer the number of isolations, the shorter the working time, and compounds (3), (4), (5), etc. can be produced more efficiently.

[0110] [Route 2] Route 2 is a route in which compound (3) is subjected to Hofmann rearrangement to produce compound (4) (reaction R03), and the resulting compound (4) is converted into a salt to produce compound (5) (reaction R04).

[0111]

[0112]

[0113] (In formula (5), BsOH represents benzenesulfonic acid.)

[0114] In the reaction R04, compound (5) is produced by forming a salt of compound (4) in the presence of an organic acid (benzenesulfonic acid).

[0115] The amount of the organic acid used in reaction R04 is preferably 0.90 to 1.20 mol, more preferably 0.95 to 1.15 mol, and even more preferably 1.00 to 1.10 mol, relative to 1 mol of compound (4). When the amount of the organic acid used is within the above range, the target compound can be obtained in good yield.

[0116] In reaction R04, a solvent is preferably used. The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include water, anisole, t-butyl methyl ether, acetone, acetonitrile, etc., with water and anisole being preferred. These solvents may be used alone or in combination of two or more.

[0117] When a solvent is used in reaction R04, the amount (volume) of the solvent used is preferably 1.0 to 100 times (vol / w), more preferably 3.0 to 80 times (vol / w), even more preferably 5.0 to 70 times (vol / w), and even more preferably 7.0 to 60 times (vol / w), the weight of compound (4), in terms of reaction rate and / or yield. Here, the unit of vol / w is ml / g.

[0118] Reaction R04 is usually preferably carried out under an atmosphere of an inert gas such as nitrogen.

[0119] The reaction temperature in reaction R04 is preferably −15 to 40° C., more preferably −10 to 35° C., and even more preferably −5 to 30° C., from the viewpoint of reaction rate and / or yield.

[0120] The reaction time in reaction R04 may be appropriately set depending on the reaction temperature and the like, but is preferably 0.1 to 48 hours, more preferably 0.5 to 24 hours, from the standpoint of reaction rate and / or yield.

[0121] In Route 2, compound (4) may or may not be isolated as a solid (preferably crystals) from the reaction mixture by a conventional separation and purification method, but isolation is preferred. In Route 2, compound (5) is preferably isolated as a solid (preferably crystals) from the reaction mixture by a conventional separation and purification method. Isolation can increase the purity of the obtained compound. Furthermore, the fewer the number of isolations, the shorter the working time, allowing compounds (4), (5), etc. to be produced more efficiently.

[0122] [One-pot Route 1] An example of carrying out multiple reactions in one pot is, for example, combining the reactions from compound (2) to compound (3) (reactions R05, R06, and R07) in Route 1. Route 1 including this one-pot portion specifically involves adding CH ３ This is a route in which compound (2) is produced by Michael addition of CN (reaction R01), and the resulting compound (2) is then decarboxylated, hydrolyzed, and hydrated in this order in one pot to produce compound (3) (reaction R02).

[0123]

[0124] (Wherein, Y is —CO ２ T represents an alkyl group having 1 to 3 carbon atoms, and when there are two Ts, the two Ts may be different from each other, or the two Ts may be joined together to form a ring.

[0125] In reaction R02, compound (2) is decarboxylated under heating in the presence of a base as a nucleophile, and then, if necessary, the solvent is changed to an aqueous solvent, and the compound is hydrolyzed in the presence of a base and water, followed by hydration by adding hydrogen peroxide, to produce compound (3). According to reaction R02, decarboxylation, hydrolysis, and hydration are carried out in the same reactor (one-pot) without isolating the product during the process, allowing compound (3) to be produced efficiently and simply.

[0126] Reaction R02 is usually preferably carried out under an atmosphere of an inert gas such as nitrogen.

[0127] The solvent used in reaction R02 is preferably an aqueous solvent. The aqueous solvent refers to water or a mixed solvent of water and a polar organic solvent, and the polar organic solvent is preferably an alcoholic solvent such as methanol, ethanol, propanol, butanol, pentanol, hexanol, or heptanol. Only an alcoholic solvent may be used during decarboxylation, but in this case, it is preferable to convert the solvent in the reaction system to an aqueous solvent by adding water and then concentrating under reduced pressure before hydrolysis.

[0128] The base used in the decarboxylation and hydrolysis in reaction R02 is preferably an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, or calcium hydroxide, more preferably sodium hydroxide or potassium hydroxide, and even more preferably potassium hydroxide. The base used in the decarboxylation and hydrolysis places the reaction system under basic conditions, allowing the subsequent hydration to be carried out efficiently.

[0129] The amount of base used in reaction R02 is preferably 0.1 to 70 mol, more preferably 0.5 to 50 mol, even more preferably 0.8 to 40 mol, and even more preferably 1.0 to 35 mol, per 1 mol of compound (1) in terms of reaction rate and / or yield. The base may be added during reaction R02, for example, after decarboxylation and before hydrolysis.

[0130] The reaction conditions in reaction R02, such as the reaction temperature and reaction time for decarboxylation, hydrolysis, and hydration, and the amount of hydrogen peroxide used in hydration, can be determined by referring to the above-mentioned reactions R-A1, R-A2, and R-B2, respectively.

[0131] In the one-pot example of Route 1, compound (3) may be isolated as a solid (preferably crystals) from the reaction mixture by a conventional separation and purification method, or may not be isolated. Isolation can increase the purity of the compound. Furthermore, the fewer the isolation times, the shorter the working time, allowing compounds (3), (4), (5), etc. to be produced more efficiently.

[0132] This application claims the benefit of priority based on Japanese Patent Application No. 2024-134379, filed on August 9, 2024. The entire contents of the specification of Japanese Patent Application No. 2024-134379, filed on August 9, 2024, are incorporated herein by reference.

[0133] The present disclosure will be explained in more detail below with reference to examples. However, the present disclosure is not limited to the examples below, and it is possible to carry out the present disclosure with appropriate modifications within the scope of the above-mentioned and below-mentioned aims, and all such modifications are included within the technical scope of the present disclosure. The reaction schemes of the examples are outlined below. Unless otherwise specified, the reactions were carried out under a nitrogen atmosphere.

[0134]

[0135] In the following examples, each compound was measured by high performance liquid chromatography (HPLC) and the content, yield, etc. were calculated. The HPLC conditions were as follows: Apparatus: LC-2050C (Shimadzu Corporation) Column: COSMOSIL 5C18-AR-II (4.6 mm I.D. x 250 mm) (Nacalai Tesque) Column temperature: 40°C Flow rate: 1.4 ml / min Detection wavelength: 210 nm Injection volume: 10 μl Mobile phase A: 0.1 wt% phosphoric acid aqueous solution Mobile phase B: acetonitrile Gradient conditions: Time (min) Mobile phase A (%) Mobile phase B (%) 0 50 50 3.20 30 70 9.20 30 70 14.00 0 100 18.79 0 100 18.80 50 50 25.00 50 50 Retention time: compound (a); 5.186 minutes, compound (1z); 9.560 minutes, compound (2z); 9.204 minutes, diastereomer of compound (2z); 8.970 minutes , Compound (6z); 7.575 minutes, Compound (7z); 4.318 minutes, Compound (3z); 2.906 minutes, Compound (4); 1.575 minutes, Compound (5); 2.393 minutes.

[0136] In the following examples, the structure of each compound was confirmed by nuclear magnetic resonance (NMR) analysis. １ H NMR and １３ C NMR was performed using chloroform-d containing 0.03% tetramethylsilane (99.8% D; manufactured by Kanto Chemical Co., Ltd.). １ (CDCl ３ ), or methanol-d ４ (CD ３ OD-d ４ ) as a solvent, and was measured at room temperature using a JEOL 500SS spectrometer (JNM-ECA500; manufactured by JEOL Ltd.).

[0137] (Reference Example 1: Production of compound (1z))

[0138] A solution of tetraisopropyl orthotitanate (3.50 mL, 11.8 mmol) in cyclopentyl methyl ether (32.0 mL) was added to TiCl ４ (3.52 mL, 32.3 mmol) was added dropwise at 20°C. After stirring at 10°C for 30 minutes, diethyl malonate (4.93 mL, 32.3 mmol) was added at 10°C. After stirring at 5°C for 15 minutes, (1R,5S)-3-ethyl-Bicyclo[3.2.0]hept-3-en-6-one (weighed value: 4.00 g, pure content: 3.96 g, content: 99.0 wt%, chemical purity: 98.8 area%, 29.4 mmol; compound (a)) was added at 5°C. After stirring at 30°C for 3 hours, the reaction mixture was heated at 5°C under H ２ 20 mL of HCl was added. The organic phase was separated and diluted with 3.8% HCl (8 mL) and 3.0% NaHCO. ３ (0.060w / w in H ２ The organic phase was concentrated under reduced pressure and dried in vacuo at 25° C. for 18 hours to obtain the compound represented by formula (1z) as a red oil (yield: 8.07 g, pure content: 7.59 g, content: 92.4 wt %, chemical purity: 94.5 area %, 27.3 mmol, yield: 93.8%).

[0139] The compound represented by formula (1z) １ H NMR, １３Identification data by C NMR was as follows: １ H-NMR (CDCl ３ ):δ 5.37-5.35 (m, 1H), 4.29-4.23 (m, 1H), 4.26 (qd, J=7.2, 1.4Hz, 2H), 4.21 (qd, J=7.2, 0.9Hz, 2H), 3.32 (ddd, J = 18.9, 8.6, 3.7Hz, 1H), 2.95-2.89 (m, 1H), 2.72 (ddd, J = 18.9 , 5.8, 3.7Hz, 1H), 2.66 (dd, J = 16.8, 8.2Hz, 1H), 2.22 (dd, J = 16.8, 3.4Hz, 1H), 2.11 ( q, J = 7.5Hz, 2H), 1.33 (t, J = 7.2Hz, 3H), 1.28 (t, J = 7.2Hz, 3H), 1.07 (t, J = 7.5Hz, 3H); １３ C NMR (CDCl ３ ): δ 176.1 (1C), 164.5 (1C), 164.2 (1C), 148.8 (1C), 121.0 (1CH), 118.2 (1C), 60.6 (1CH ２ ), 60.6 (1CH ２ ), 58.3 (1CH), 42.7 (1CH ２ ), 39.7 (1CH ２ ), 32.7 (1CH), 24.3 (1CH ２ ), 14.22 (1CH ３ ), 14.20 (1CH ３ ), 12.2 (1CH ３ )

[0140] Example 1: Preparation of compound (2z)

[0141] Acetonitrile (0.937 mL, 18.0 mmol) was added to a solution of n-butyllithium (1.6 M in hexane, 11.2 mL, 18.0 mmol) in tetrahydrofuran (36 mL) at −78° C. After stirring for 30 minutes, the compound represented by formula (1z) (weighed value: 3.60 g, pure content: 3.33 g, content: 92.4 wt %, chemical purity: 94.5 area%, 12.0 mmol) was added dropwise at −78° C. After stirring at 25° C. for 1 hour (conversion: 100%, yield: 102.6%), saturated aqueous ammonium chloride solution (18 mL) was added to the reaction mixture at 25° C. The organic and aqueous phases were separated, and the separated aqueous phase was dissolved in CH ２ Cl ２ The extract was extracted twice with 18 mL of hexane, and the combined organic phase was concentrated under reduced pressure. The resulting mixture was then vacuum dried at 25°C for 18 hours to obtain the compound represented by formula (2z) as a red oil (yield: 4.17 g, pure content: 3.57 g, content: 85.6 wt%, chemical purity: 89.7 area%, 1.47 mmol, yield: 91.1%). The conversion rate was measured by HPLC and calculated using the following formula: Conversion rate (%) = (peak area of ​​compound (2z) + peak area of ​​diastereomer of compound (2z)) / (peak area of ​​compound (1z) + peak area of ​​compound (2z) + peak area of ​​diastereomer of compound (2z)).

[0142] The compound represented by formula (2z) １ H NMR, １３ Identification data by C NMR was as follows: １ H-NMR (CDCl ３): δ 5.28-5.26 (m, 1H), 4.22 (qd, J = 7.2, 3, 4Hz, 2H), 4.28 (q, J = 7.2Hz, 2H), 3.71 (s, 1H), 3.30 (br s, 1H), 3.08-3.02 (m, 1H), 3.01 (d, J = 2.9Hz, 2H), 2.54 (dd, J = 16.6, 8.0Hz, 1H), 2.31 (ddd, J = 13.0, 8.9, 2.7Hz, 1H), 2.19-2.12 (m , 2H), 2.07 (d, J=16.6Hz, 1H), 1.70 (dd, J=13.0, 7.5Hz, 1H), 1.2 9 (t, J=7.0Hz, 3H), 1.26 (t, J=7.0Hz, 3H), 1.09 (t, J=7.5Hz, 3H); １３ C NMR (CDCl ３ ): δ 168.0 (1C), 167.8 (1C), 151.8 (1C), 121.0 (1CH), 118.9 (1C), 61.52 (1CH ２ ), 61.47 (1CH ２ ), 55.7 (1CH), 55.1 (1CH), 43.7 (1C), 42.6 (1CH ２ ), 37.9 (1CH ２ ), 31.4 (1CH), 24.5 (1CH ２ ), 24.4 (1CH ２ ), 14.01 (1CH ３ ), 13.99 (1CH ３ ), 12.4 (1CH ３ )

[0143] Example 2: Preparation of Compound (2z) To a solution of acetonitrile (1.33 mL, 25.4 mmol) in tetrahydrofuran (5 mL) was added the compound represented by formula (1z) (weighed value: 500 mg, pure content: 442 mg, content: 88.3 wt%, chemical purity: 97.9 area%, 1.59 mmol) at −20° C. Then, n-butyllithium (1.6 M in hexane, 1.98 mL, 3.17 mmol) was added at −20° C. After stirring at 25° C. for 1 hour (conversion: 97.3%, yield: 92.9%), saturated aqueous ammonium chloride solution (2.5 mL) was added to the reaction mixture at 25° C. The organic and aqueous phases were separated, and the separated aqueous phase was dissolved in CH ２ Cl ２The extract was combined with the previous organic phase and concentrated under reduced pressure, and then vacuum dried at 25°C for 18 hours to obtain the compound represented by formula (2z) above as a red oil (yield: 615 mg, pure content: 448 mg, content: 72.9 wt%, chemical purity: 77.7 area%, 1.40 mmol, yield: 89.1%).

[0144] (Example 3; Production of compound (6z))

[0145] A compound represented by formula (2z) (weighed value: 3.42 g, pure content: 2.36 g, content: 68.9 wt %, chemical purity: 59.4 area %, 7.39 mmol) in dimethyl sulfoxide (DMSO) (34.2 mL) was dissolved in LiCl (2.73 g, 64.3 mmol) and H ２ 0 (1.16 g, 64.3 mmol) was added at room temperature. After stirring at 150°C for 4 hours, the reaction mixture was cooled to room temperature. ２ After adding 0 (17.1 mL) at room temperature, the reaction mixture was extracted three times with methyl tert-butyl ether (MTBE; 34.2 mL). The combined organic phase was concentrated under reduced pressure and dried in vacuo at 25°C to obtain a residue. The residue was purified by silica gel column chromatography (EPCL-W-Prep 2XY A-Type (Yamazen); Universal Column Premium cartridge (Yamazen); Rf = 0.27, n-hexane: EtOAc = 9:1) to obtain the compound represented by formula (6z) as a red oil (yield: 1.43 g, pure content: 1.38 g, content: 96.5 wt%, chemical purity: 96.1 area%, 15.8 mmol, yield: 75.8%).

[0146] The compound represented by formula (6z) １ H NMR, １３ Identification data by C NMR was as follows: １ H-NMR (CDCl ３): δ 5.29-5.27 (m, 1H), 4.12 (qd, J=7.2, 2.3Hz, 2H), 3.13 (br s, 1H), 2.92-2.86 (m, 1H), 2.82 (s, 2H), 2.51 (d, J = 2.3Hz, 2H), 2.50 (dd, J = 16.4, 8.7Hz, 1H), 2.17-2.11 (m , 3H), 2.04 (d, J = 16.4Hz, 1H), 1.57 (dd, J = 13.0, 7.5Hz, 1H), 1.26 (t, J = 7.2Hz, 3H), 1.08 (t, J = 7.5Hz, 1H); １３ C NMR (CDCl ３ ): δ 171.4 (1C), 150.7 (1C), 121.2 (1CH), 118.7 (1C), 60.4 (1CH ２ ), 54.4 (1CH), 42.2 (1CH ２ ), 41.6 (1C), 38.8 (1CH ２ ), 37.9 (1CH ２ ), 31.0 (1CH), 27.3 (1CH ２ ), 24.4 (1CH ２ ), 14.2 (1CH ３ ), 12.4 (1CH ３ )

[0147] (Example 4: Production of compound (7z) and compound (3z))

[0148] The compound represented by formula (6z) (yield: 1.43 g, pure content: 1.38 g, content: 95.5 wt %, chemical purity: 96.1 area %, 5.59 mmol) ２ To a solution of 10 mL of HCl (10% solution) was added NaOH (20% solution, 2.23 g, 11.2 mmol) at room temperature. After stirring at 60° C. for 23 hours (yields: compound (6z): 0.0%, compound (7z): 91.4%, compound (3z): 3.4%), the reaction mixture was cooled to room temperature. The reaction mixture was diluted with H O at room temperature. ２ O ２aq. (30% solution, 2.85 g, 25.1 mmol) was added, and the mixture was stirred at 50° C. for 5 hours (yields: compound (6z): 0.0%, compound (7z): 0.0%, compound (3z): 92.7%). The reaction mixture was then cooled to room temperature. 6 M hydrochloric acid (2.0 mL) was added to the reaction mixture at room temperature to separate the organic and aqueous phases. The separated aqueous phase was then dissolved in CH ２ Cl ２ The organic phase was combined with the previous organic phase, concentrated under reduced pressure, and vacuum dried at 25° C. for 5 hours to obtain the compound represented by formula (3z) above as a yellow solid (yield: 1.16 g, pure content: 1.11 g, content: 96.1 wt %, chemical purity: 95.9 area %, 4.68 mmol, yield: 84.7%).

[0149] The compound represented by formula (7z) １ H NMR, １３ Identification data by C NMR was as follows: １ H-NMR (CD ３ OD-d ４ ): δ 5.36-5.35 (m, 1H), 3.11 (br s, 1H), 2.95-2.87 (m, 1H), 2.91 (s, 2H), 2.51 (dd, J = 16.5, 8.0Hz, 1H), 2.45 (d, J = 4.5Hz, 2H), 2.17-2.11 (m , 1H), 2.17 (q, J = 7.5Hz, 2H), 2.07 (d, J = 16.5Hz, 1H), 1.57 (dd, J = 12.6, 7.5Hz, 1H), 1.11 (t, J = 7.5Hz, 3H); １３ C NMR (CD ３ OD-d ４ ): δ 174.8 (1C), 151.6 (1C), 122.7 (1CH), 120.0 (1C), 55.8 (1CH), 43.0 (1CH ２ ), 42.6 (1C), 39.8 (1CH ２ ), 38.9 (1CH ２ ), 32.2 (1CH), 27.5 (1CH ２ ), 25.3 (1CH ２ ), 12.8 (1CH ３ )

[0150] The compound represented by formula (3z) １ H NMR,１３ Identification data by C NMR was as follows: １ H-NMR (CD ３ OD-d ４ ): δ 5.39-5.38 (m, 1H), 3.16 (br s, 1H), 2.87-2.81 (m, 1H), 2.67 (d, J = 14.0Hz, 1H), 2.63 (d, J = 14.0Hz, 1H), 2.51 (s, 2H), 2.48 (dd, J = 16.3, 7.7Hz, 1H), 2.21 (dd d, J = 12.3, 8.8, 2.6 Hz, 1H), 2.15 (q, J = 7.5 Hz, 2H), 2.03 (d, J = 16 .3Hz, 1H), 1.49 (dd, J=12.3, 7.5Hz, 1H), 1.10 (t, J=7.5Hz, 3H); １３ C NMR (CD ３ OD-d ４ ): δ 177.4 (1C), 176.2 (1C), 150.7 (1C), 123.6 (1CH), 56.5 (1CH), 44.1 (1CH ２ ), 43.1 (1CH ２ +1C), 40.3 (1CH ２ ), 39.5 (1CH ２ ), 32.4 (1CH), 25.4 (1CH ２ ), 12.9 (1CH ３ )

[0151] (Example 5; Production of Compound (6z) and Compound (7z))

[0152] To a solution of the compound represented by formula (2z) (weighed value: 584 mg, pure content: 500 mg, content: 85.6 wt%, chemical purity: 89.7 area%, 1.57 mmol) in EtOH (10 mL), a solution of KOH (106 mg, 1.88 mmol) in EtOH (2.0 mL) was added at reflux temperature over 4 hours. After stirring for 72 hours, the reaction mixture was cooled to 25°C. The yields of the reaction mixture were compound (2z): 0.0%, compound (6z): 49.9%, and compound (7z): 49.2%.

[0153] (Example 6; Production of compound (3z))

[0154] To a solution of the compound represented by formula (2z) (weighed value: 4.05 g, pure content: 3.47 g, content: 85.6 wt%, chemical purity: 89.7 area%, 10.9 mmol) in EtOH (55.5 mL), a solution of KOH aq. (5.6% aqueous solution, 730 mg, 13.0 mmol) in EtOH (15.6 mL) was added at reflux temperature over 4 hours. After stirring for 72 hours (yields; compound (2z): 0.0%, compound (6z): 39.9%, compound (7z): 62.7%), the reaction mixture was cooled to 25 °C. The reaction mixture was heated at 25 °C for 1 hour. ２ After adding 13.9 mL of HCl, the reaction mixture was concentrated under reduced pressure (30°C, 50 mmHg) to obtain an aqueous solution (total weight: 24.4 g). To the reaction mixture (aqueous solution), KOH aq. (20% aqueous solution, 1.22 g, 21.7 mmol) was added at 25°C. After stirring at 25°C for 3 hours (yields: compound (6z): 0.0%, compound (7z): 98.4%), the reaction mixture was cooled to 0°C. The reaction mixture was then heated at 0°C with H ２ O ２ Aq. (30% solution, 2.58 g, 76.0 mmol) was added. After stirring at 60 °C for 3 hours (yield: compound (7z): 1.0%, compound (3z): 92.8%), the reaction mixture was cooled to 25 °C. Toluene (20.3 mL) was added to this mixture at 25 °C to separate the organic and aqueous phases. HCl aq. (17.5% solution, 2.35 mL) was added to the separated aqueous phase at room temperature, and the mixture was extracted three times with ethyl acetate (40.5 mL) and combined with the previous organic phase. The organic phase thus obtained was concentrated under reduced pressure and dried in vacuo at 25 °C for 18 hours to obtain the compound represented by formula (3z) as a viscous yellow oil (yield: 3.20 g, pure content: 2.17 g, content: 67.5 wt%, chemical purity: 81.7 area%, 12.5 mmol, yield: 84.4%).

[0155] (Example 7; Production of compound (4))

[0156] H of the compound represented by formula (3z) (weighed value: 1.00 g, pure content: 675 mg, content: 67.5 wt %, chemical purity: 81.7 area %, 5.59 mmol) ２ 0 (3 mL) suspension was added to NaOH aq. (20% in H ２0, 8.53 mmol) and NaClO.5H ２ 0 (561 mg, 3.41 mmol) was added at 0° C. After stirring at 0° C. for 1 hour, the reaction mixture was warmed to 25° C. After stirring at 25° C. for 3 hours (conversion: 100%, yield: 92.4%), the reaction mixture was cooled to 0° C. HCl (17.5 wt % in H ２ HCl (1.78 g) was added until the pH reached 6, resulting in a precipitate. Next, NaCl (1.04 g, 17.8 mmol) was added to the reaction mixture. After stirring at 0°C for 1 hour, the resulting slurry solution was filtered. The resulting wet crystals were washed twice with ice-cooled water (2 mL) and vacuum-dried at 40°C for 20 hours to obtain the compound represented by formula (4) as white crystals (yield: 483 mg, purity: 465 mg, content: 96.2 wt%, chemical purity: 88.8 area%, 2.22 mmol, yield: 78.4%).

[0157] The compound represented by formula (4) １ H NMR, １３ Identification data by C NMR was as follows: １ H-NMR (CD ３ OD-d ４ ): δ 5.37-5.35 (m, 1H), 3.17 (d, J = 13.2Hz, 1H), 3.13 (d, J = 13.2Hz, 1H), 3.09 (br s, 1H), 2.87-2.81 (m, 1H), 2.50-2.45 (m, 1H), 2.49 (d, J = 16.0Hz, 1H), 2.45 (d, J = 16.0Hz, 1H), 2.14 (q, J = 7.5Hz, 2H), 2.07-2.02 (m, 2H), 1.46 (dd, J = 12.3, 7.5Hz, 1H), 1.09 (t, J = 7.5Hz, 3H); １３ C NMR (CD ３ OD-d ４ ): δ 180.3 (1C), 151.0 (1C), 122.8 (1CH), 53.7 (1CH), 48.5 (1CH ２ ), 46.1 (1CH ２ ), 43.3 (1C), 43.0 (1CH ２ ), 37.8 (1CH ２ ), 32.3 (1CH), 25.4 (1CH ２), 12.8 (1CH ３ )

[0158] (Example 8: Production of compound (5))

[0159] To a suspension of the compound represented by formula (4) (weighed value: 100 mg, pure content: 96.2 mg, content: 96.2 wt%, chemical purity: 88.8 area%, 0.460 mmol) in anisole (4.0 mL), a solution of besylic acid (79.5 mg, 0.483 mmol) in anisole (0.40 mL) was added at 25 ° C. The reaction mixture was cooled to 0 ° C. After stirring at 0 ° C. for 1 hour, the resulting suspension was filtered. The resulting wet crystals were washed once with acetone (0.50 mL) and vacuum dried at 40 ° C. for 20 hours to obtain the compound represented by formula (5) as white crystals (yield: 111 mg, pure content: 113 mg, content: 101.7 wt%, chemical purity: 99.1 area%, 0.303 mmol, yield: 65.9%).

[0160] The compound represented by formula (5) １ H NMR, １３ Identification data by C NMR was as follows: １ H-NMR (CD ３ OD-d ４ ): δ 7.85-7.82 (m, 2H), 7.46-7.41 (m, 3H), 5.32 (s, 1H), 3.34 (d, J = 13.2Hz, 1H), 3.29 (d, J = 13.2Hz, 1H), 3.13 (br s, 1H), 2.91-2.84 (m, 1H), 2.52 (dd, J=16.0, 6.9Hz, 1H), 2.51 (s, 2H), 2.20-2.13 (m , 3H), 2.09 (d, J = 16.0Hz, 1H), 1.50 (dd, J = 12.6, 7.5Hz, 1H), 1.11 (t, J = 7.5Hz, 3H); １３ C NMR (CD ３ OD-d ４ ): δ 175.5 (1C), 152.1 (1C), 146.3 (1C), 131.3 (1CH), 129.3 (2CH), 126.9 (2CH), 122.0 (1CH), 53.7 (1CH), 47.7 (1CH ２ ), 43.2 (1CH ２), 42.9 (1C), 38.5 (1CH ２ ), 37.3 (1CH ２ ), 32.4 (1CH), 25.3 (1CH ２ ), 12.8 (1CH ３ )

[0161] The present disclosure is useful for the preparation of mirogabalin besylate.

Claims

1. A bicycloheptene compound represented by formula (I): (In formula (I), X is —CN or —C(═O)NH ２ Y represents a hydrogen atom or —CO ２ T represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. When formula (I) has two Ts, the two Ts may be different from each other, or the two Ts may combine together to form a ring.

2. A method for producing a compound represented by formula (4), comprising subjecting a compound represented by formula (3) below to Hofmann rearrangement to give a compound represented by formula (4) below.

3. The production method according to claim 2, wherein the compound represented by formula (3) is subjected to a Hoffmann rearrangement in the presence of a halogenating agent and a base, wherein the halogenating agent comprises at least one selected from the group consisting of hypochlorite, hypobromite, and hypervalent iodine compounds.

4. A method for producing a compound represented by formula (5), which comprises converting a compound represented by formula (4) obtained by the method according to claim 2 or 3 into a salt to produce a compound represented by formula (5). (In formula (5), BsOH represents benzenesulfonic acid.) 5. The compound represented by formula (3) is produced by hydrating a compound represented by formula (7) below, and the compound represented by formula (7) is produced by hydrolyzing a compound represented by formula (6) below, and the compound represented by formula (6) is produced by decarboxylating a compound represented by formula (2) below, and the compound represented by formula (2) is converted into a compound represented by formula (1) below by CH ３ The method according to claim 2 or 3, wherein the compound is produced by Michael addition of CN. (Wherein, Y is —CO ２ T represents an alkyl group having 1 to 3 carbon atoms, and when there are two Ts, the two Ts may be different from each other, or the two Ts may be joined together to form a ring.

6. The method according to claim 5, wherein the compound represented by formula (7) is hydrated by mixing with hydrogen peroxide in the presence of a base.

7. The method according to claim 5, wherein the compound represented by formula (6) is hydrolyzed by reacting it in the presence of a base and water.

8. The production method according to claim 5, wherein the compound represented by formula (2) is decarboxylated under heating using a nucleophilic agent, wherein the nucleophilic agent comprises at least one selected from the group consisting of a base and a halide.

9. The compound represented by formula (3) is produced by one-pot decarboxylation, hydrolysis, and hydration of a compound represented by formula (2): ３ The method according to claim 2 or 3, wherein the compound is produced by Michael addition of CN. (Wherein, Y is —CO ２ T represents an alkyl group having 1 to 3 carbon atoms, and when there are two Ts, the two Ts may be different from each other, or the two Ts may be joined together to form a ring.

10. The method according to claim 9, wherein the compound represented by formula (2) is decarboxylated under heating in the presence of a base as a nucleophile, then hydrolyzed in the presence of a base and water, and then hydrated by mixing with hydrogen peroxide.

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