Method for producing amide compound

Abstract

Provided is a method for producing a compound represented by formula (2), said method comprising: causing a chemical reaction between a compound represented by formula (3) and a compound represented by formula (4) to obtain a compound represented by formula (1); and hydrolyzing the obtained compound represented by formula (1). (In formulae (1)-(4), R1 and R2 are each independently a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, or the like, R3 is a substituted or unsubstituted C1-6 alkyl group or the like, and Z is a t-butoxycarbonyl oxy group, a halogeno group, or a 1H-imidazol-1-yl group.)

Description

Method for producing amide compounds

[0001] The present invention relates to a method for producing an amide compound. More specifically, it relates to a method for producing an N-BOC amino acid amide compound. This application claims priority based on Japanese Patent Application No. 2023-121036, filed on July 25, 2023, the contents of which are incorporated herein by reference.

[0002] N-BOC amino acid amide compounds and amino acid amide compounds are useful compounds as intermediates for the production of pharmaceuticals and agricultural chemicals. For example, Patent Document 1 discloses that, in a production example of Compound 1-1 having acaricidal activity, t-butyl(2-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)carbamate (Compound 17: N-BOC amino acid amide compound) is obtained by a condensation reaction of N-BOC amino acid (Compound 8) with 2,2,2-trifluoroethylamine, and then 2-amino-2-methyl-N-(2,2,2-trifluoroethyl)propanamide hydrochloride (Compound 18: amino acid amide compound) is obtained by a deprotection reaction.

[0003]

[0004] International Publication No. 2019 / 198592

[0005] An object of the present invention is to provide a novel method for preparing N-BOC amino acid amide compounds.

[0006] As a result of investigations conducted to achieve the object of the present invention, the present invention has been completed, which includes the following aspects.

[0007] [1] A method for producing a compound represented by formula (2), comprising hydrolyzing a compound represented by formula (1).

[0008] In formula (1), R １ and R ２are each independently a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered heteroaryl group; R １ and R ２ may be taken together to form a substituted or unsubstituted C2-5 alkylene group. ３ is a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered heteroaryl group.

[0009] In formula (2), R １ , R ２ , and R ３ is the same as in equation (1).

[0010] [2] The production method according to [1], further comprising chemically reacting a compound represented by formula (3) with a compound represented by formula (4) to obtain a compound represented by formula (1).

[0011] In formula (3), R １ , R ２ , and R ３ is the same as in equation (1).

[0012] In formula (4), Z is a t-butoxycarbonyloxy group, a halogeno group, or a 1H-imidazol-1-yl group.

[0013] [3] The production method according to [1], further comprising: chemically reacting the compound represented by formula (3) with phosgene, diphosgene, or triphosgene to obtain a compound represented by formula (5); and chemically reacting the compound represented by formula (5) with an alkali metal t-butoxide to obtain a compound represented by formula (1).

[0014] In formula (5), R １ , R２ , and R ３ is the same as in equation (1).

[0015] [4] The production method according to [2] or [3], further comprising chemically reacting a compound represented by formula (6) with a compound represented by formula (7) to obtain a compound represented by formula (3).

[0016] In formula (6), R １ and R ２ is the same as in equation (1).

[0017] In formula (7), R ３ is the same as in formula (1). ａ is a methyl group, a trifluoromethyl group, a phenyl group, or a tolyl group.

[0018] The hydrolysis of hydantoins usually gives glycine, and similarly, the hydrolysis of 5-substituted hydantoins gives various amino acids.

[0019]

[0020] In addition, in a compound in which a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, or an i-propoxycarbonyl group is bonded to an amino group (a compound represented by formula (1a)), the following chemical reaction proceeds.

[0021] In formula (1a), R ４ is a methyl group, an ethyl group, an n-propyl group, or an i-propyl group.

[0022] On the other hand, according to the production method of the present invention, hydrolysis proceeds regioselectively due to the influence of the tert-butoxycarbonyl group (BOC group: a group known as a group that protects an amino group) in the compound represented by formula (1), and the compound represented by formula (2) can be obtained in high yield. The corresponding amino acid amide compound can be obtained by a deprotection reaction of the compound represented by formula (2). The amino acid amide compound obtained by the production method of the present invention is useful as an intermediate for producing active ingredients of pharmaceutical and agrochemicals, such as compound 1-1.

[0023]

[0024] One embodiment of the production method of the present invention comprises converting a compound represented by formula (1) (hereinafter sometimes referred to as compound (1)) into a compound represented by formula (2) (hereinafter sometimes referred to as compound (2)). Another embodiment of the production method of the present invention comprises converting a compound represented by formula (3) (hereinafter sometimes referred to as compound (3)) into compound (1), and converting compound (1) into compound (2). Another embodiment of the production method of the present invention comprises converting a compound represented by formula (6) (hereinafter sometimes referred to as compound (6)) into compound (3), converting compound (3) into compound (1), and converting compound (1) into compound (2).

[0025] In the present invention, the term "unsubstituted" refers to only the core group. When the name of the core group alone is used without the term "substituted," it means "unsubstituted" unless otherwise specified. On the other hand, the term "substituted" means that any hydrogen atom in the core group is substituted with a group (substituent) of the same or different structure as the core group. Therefore, a "substituent" is another group bonded to the core group. There may be one substituent, or there may be two or more substituents. The two or more substituents may be the same or different. A term such as "C1-6" indicates that the core group has 1 to 6 carbon atoms, for example. This number of carbon atoms does not include the number of carbon atoms in the substituent. For example, a butyl group having an ethoxy group as a substituent is classified as a C2 alkoxy C4 alkyl group. The "substituent" is not particularly limited as long as it is chemically permissible and achieves the effects of the present invention.

[0026] Examples of groups that can serve as "substituents" include: C1-6 alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, and n-hexyl; C2-6 alkenyl groups such as vinyl, 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, and 2-methyl-2-propenyl; C2-6 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 1-methyl-2-propynyl;

[0027] C3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups; phenyl groups; 3- to 6-membered heterocyclyl groups;

[0028] C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, and t-butoxy groups; C6-10 aryloxy groups such as phenoxy and naphthoxy groups; 5- to 6-membered heteroaryloxy groups such as thiazolyloxy and pyridyloxy groups;

[0029] C1-6 alkoxycarbonyl groups such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, and a t-butoxycarbonyl group;

[0030] Halogeno groups such as a fluoro group, a chloro group, a bromo group, and an iodo group; C1-6 haloalkyl groups such as a chloromethyl group, a chloroethyl group, a trifluoromethyl group, a 1,2-dichloro-n-propyl group, a 1-fluoro-n-butyl group, and a perfluoro-n-pentyl group; C1-6 haloalkoxy groups such as a trifluoromethoxy group, a 2-chloro-n-propoxy group, and a 2,3-dichlorobutoxy group;

[0031] a formylamino group; a C1-6 alkylcarbonylamino group such as an acetylamino group, a propanoylamino group, a butyrylamino group, or an i-propylcarbonylamino group; a C1-6 alkoxycarbonylamino group such as a methoxycarbonylamino group, an ethoxycarbonylamino group, an n-propoxycarbonylamino group, or an i-propoxycarbonylamino group; an unsubstituted or substituted aminocarbonyl group such as an aminocarbonyl group, a dimethylaminocarbonyl group, a phenylaminocarbonyl group, or an N-phenyl-N-methylaminocarbonyl group;

[0032] C1-6 alkylthio groups such as methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio, s-butylthio, and t-butylthio; C1-6 haloalkylthio groups such as trifluoromethylthio and 2,2,2-trifluoroethylthio; C1-6 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, and t-butylsulfonyl; C1-6 haloalkylsulfonyl groups such as trifluoromethylsulfonyl and 2,2,2-trifluoroethylsulfonyl;

[0033] Cyano group; nitro group.

[0034] In addition, any hydrogen atom in these "substituents" may be substituted with a group of a different structure. In this case, examples of the substituent include a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 haloalkoxy group, a halogeno group, a cyano group, and a nitro group.

[0035] Furthermore, the above-mentioned "3- to 6-membered heterocyclyl group" contains 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring-constituting atoms. The heterocyclyl group may be either monocyclic or polycyclic. In a polycyclic heterocyclyl group, as long as at least one ring is a heterocycle, the remaining rings may be saturated alicyclic, unsaturated alicyclic, or aromatic. Examples of the "3- to 6-membered heterocyclyl group" include 3- to 6-membered saturated heterocyclyl groups, 5- to 6-membered heteroaryl groups, and 5- to 6-membered partially unsaturated heterocyclyl groups.

[0036] Examples of the 3- to 6-membered saturated heterocyclyl group include an aziridinyl group, an epoxy group, a pyrrolidinyl group, a tetrahydrofuranyl group, a thiazolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a dioxolanyl group, and a dioxanyl group.

[0037] Examples of the 5-membered heteroaryl group include a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a triazolyl group, an oxadiazolyl group, a thiadiazolyl group, and a tetrazolyl group.

[0038] Examples of 6-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl groups. Examples of 5-membered partially unsaturated heterocyclyl groups include pyrrolinyl, dihydrofuranyl, imidazolinyl, pyrazolinyl, oxazolinyl, and isoxazolinyl groups. Examples of 6-membered partially unsaturated heterocyclyl groups include dihydropyranyl groups.

[0039] [Conversion of compound (1) to compound (2) (chemical reaction III)]

[0040] The compound (2) obtained by one embodiment of the production method of the present invention is a compound represented by formula (2).

[0041] In formula (2), R １ , R ２ , and R ３is the same as in equation (1).

[0042] The substrate used in chemical reaction III is compound (1).

[0043]

[0044] In formula (1), R １ and R ２ are each independently a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered heteroaryl group; R １ and R ２ may be joined together to form a substituted or unsubstituted C2-5 alkylene group.

[0045] In formula (1), R ３ is a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered heteroaryl group.

[0046] R １ ~R ３ The "C1-6 alkyl group" in the formula may be a straight chain or a branched chain. １ ~R ３ Examples of the "C1-6 alkyl group" in the above formula include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an i-propyl group, an i-butyl group, an s-butyl group, a t-butyl group, an i-pentyl group, a neopentyl group, a 2-methylbutyl group, an i-hexyl group, and the like.

[0047] R １ ~R ３Examples of the "C2-6 alkenyl group" in the above formula include vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, and 5-hexenyl group.

[0048] R １ ~R ３ Examples of the "C2-6 alkynyl group" in the above formula include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2-methyl-3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 2-methyl-3-pentynyl group, 1-hexynyl group, 1,1-dimethyl-2-butynyl group, and the like.

[0049] R １ ~R ３ Preferred substituents on the "C1-6 alkyl group," "C2-6 alkenyl group," or "C2-6 alkynyl group" in the above are halogeno groups such as fluoro, chloro, bromo, and iodo; hydroxyl group; C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, and t-butoxy; C1-6 haloalkoxy groups such as 2-chloro-n-propoxy, 2,3-dichlorobutoxy, and trifluoromethoxy; phenyl group; phenyl groups substituted with halogeno groups, C1-6 haloalkyl groups, or C1-6 haloalkoxy groups, such as 4-chlorophenyl, 4-trifluoromethylphenyl, and 4-trifluoromethoxyphenyl; or cyano group.

[0050] R １ ~R ３ Examples of the "C3-6 cycloalkyl group" in the above formula include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0051] R １ ~R ３ The "5- to 6-membered heteroaryl group" in the above formula (I) is a 5- or 6-membered ring containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring-constituting atoms. When there are two or more heteroatoms, they may be the same or different. Examples of 5-membered heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl groups. Examples of 6-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl groups.

[0052] R １ ~R ３ Substituents on the "C3-6 cycloalkyl group," "phenyl group," or "5- or 6-membered heteroaryl group" in the above formula (I) include halogeno groups such as fluoro, chloro, bromo, and iodo; C1-6 alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, and n-hexyl; C1-6 haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, 1,2-dichloro-n-propyl, and 1-fluoro-n-butyl; hydroxyl; C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, and t-butoxy; A C1-6 haloalkoxy group such as a 2-chloro-n-propoxy group, a 2,3-dichlorobutoxy group, or a trifluoromethoxy group; or a cyano group; is preferred.

[0053] R １ and R ２Examples of the C2-5 alkylene group formed by combining these groups include a dimethylene group, a trimethylene group, a tetramethylene group, and a pentamethylene group. Preferred substituents on the "C2-5 alkylene group" are halogeno groups such as a fluoro group, a chloro group, a bromo group, and an iodo group.

[0054] In this embodiment, R １ and R ２ is preferably a substituted or unsubstituted C1-6 alkyl group, for example, a methyl group. ３ is preferably a substituted or unsubstituted C1-6 alkyl group, for example, a 2,2,2-trifluoroethyl group.

[0055] In chemical reaction III, the N-C bond between positions 1 and 2 and the N-C bond between positions 2 and 3 in compound (1) are broken, converting compound (1) to compound (2). Carbon dioxide is produced during the conversion to compound (2).

[0056] Chemical reaction III can be carried out, for example, in the presence of an inorganic base in a solvent.

[0057] Examples of inorganic bases that can be used in chemical reaction III include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc. The amount of inorganic base used is, for example, 0.5 to 10 mol, preferably 1.0 to 7.0 mol, per 1 mol of compound (1).

[0058] In chemical reaction III, depending on the solvent, any of an aqueous phase consisting of water alone, a homogeneous phase consisting of water and an organic solvent, or a heterogeneous phase consisting of water and an organic solvent may be formed as the reaction site. There are no particular limitations on the organic solvent that can be used in chemical reaction III, as long as it is inert to chemical reaction III. Examples of organic solvents that can form a homogeneous phase include alcohols such as methanol, ethanol, n-propanol, i-propanol, and n-butanol; acetone, dimethyl sulfoxide (abbreviation: DMSO), and dimethylformamide (abbreviation: DMF). Examples of organic solvents for forming a heterogeneous phase include ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diglyme), tetrahydrofuran (abbreviation: THF), 4-methyltetrahydropyran (abbreviation: MTHP), and dioxane; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (abbreviation: DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; and aromatic hydrocarbons such as toluene and xylene. In either case, the organic solvent can be used alone or in combination of two or more. The amount of solvent used in Chemical Reaction III is not particularly limited, but is preferably 1 to 100 parts by mass per part by mass of Compound (1).

[0059] One embodiment of Chemical Reaction III involves dissolving an inorganic base in a solvent and adding Compound (1) to the solution to complete the hydrolysis. Compound (1) can be added to the reaction site all at once or gradually. Gradual dropwise addition is preferred. Compound (1) is preferably added to the reaction site with stirring. The temperature during the dropwise addition of Compound (1) is preferably 0°C to 15°C. The temperature during the hydrolysis reaction after the addition is not particularly limited, but is preferably the temperature during the addition (dropwise addition), more preferably 0°C to 15°C. The pressure during the hydrolysis reaction is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, more preferably 0.1 MPa. The time required for the hydrolysis reaction is not particularly limited, but is, for example, 0.5 to 24 hours. Chemical Reaction III is preferably carried out under an inert gas atmosphere.

[0060] After completion of chemical reaction III, post-treatments such as extraction with an organic solvent and drying and concentrating the resulting organic layer can be performed. If necessary, the product of chemical reaction III (compound (2)) can be further purified by recrystallization, chromatography, or other procedures.

[0061] Compound (1), which is the substrate used in chemical reaction III, is not particularly limited by its production method, but can be obtained, for example, by a method including converting compound (3) to compound (1).

[0062] [Conversion of Compound (3) to Compound (1) (Chemical Reaction II-1)] Compound (3), which is the substrate in Chemical Reaction II-1, is a compound represented by formula (3).

[0063] In formula (3), R １ , R2, and R ３ is the same as in equation (1).

[0064] Compound (4) is used in chemical reaction II-1. Compound (4) is a compound represented by formula (4).

[0065] In formula (4), Z is a t-butoxycarbonyloxy group, a halogeno group, or a 1H-imidazol-1-yl group. In this embodiment, Z is preferably a t-butoxycarbonyloxy group or a halogeno group.

[0066] Examples of the "halogeno group" in Z include a fluoro group, a chloro group, a bromo group, an iodo group, etc. Among these, a chloro group is preferred.

[0067] The compound (4) used in this embodiment may be one synthesized by the inventors themselves using a known method, or may be one synthesized by another person using some method and commercially available.

[0068] [When compound (4) is di-t-butyl dicarbonate (chemical reaction II-1A)] The compound in which Z in formula (4) is a t-butoxycarbonyloxy group is di-t-butyl dicarbonate (English name: di-tert-butyl dicarbonate; abbreviation: (Boc) ２ O).

[0069] Compound (4) (Boc) ２ When O is used, chemical reaction II-1 can be carried out in an organic solvent in the presence of an organic base.

[0070] Examples of organic bases that can be used in Chemical Reaction II-1A include triethylamine, tetramethylethylenediamine, N,N-diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, 4-methylmorpholine, 1-azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (abbreviation: DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, 4-(dimethylamino)pyridine, and 2,6-dimethylpyridine.

[0071] (Boc) in Chemical Reaction II-1A ２The amount of O used is, for example, preferably 1.0 to 2.0 mol, more preferably 1.0 to 1.5 mol, relative to 1 mol of compound (3). The amount of the organic base used in chemical reaction II-1A is, for example, preferably 2.0 to 5.0 mol, more preferably 2.0 to 3.0 mol, relative to 1 mol of compound (3).

[0072] The organic solvent that can be used in Chemical Reaction II-1A is not particularly limited as long as it is inert to Chemical Reaction II-1A. Examples of organic solvents that can be used in Chemical Reaction II-1A include ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diglyme), tetrahydrofuran (abbreviation: THF), 4-methyltetrahydropyran (abbreviation: MTHP), and dioxane; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (abbreviation: DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as toluene and xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, dimethyl carbonate, and diethyl carbonate; ketones such as acetone, anone, and methyl isobutyl ketone (abbreviation: MIBK); and other solvents such as dimethyl sulfoxide (abbreviation: DMSO) and dimethylformamide (abbreviation: DMF). These organic solvents can be used alone or in combination of two or more. The amount of the organic solvent used is not particularly limited, but is preferably 1 to 100 parts by mass per part by mass of compound (3).

[0073] In one embodiment of chemical reaction II-1A, compound (3) and an organic base are dissolved in an organic solvent, and then (Boc) ２ O is added to complete the chemical reaction. (Boc) ２ It is preferable to add O gradually to prevent a sudden temperature rise due to the heat of reaction. ２ The rate of addition of O may be adjusted. ２The temperature during the addition of O is not particularly limited and may be, for example, room temperature. The temperature during chemical reaction II-1A is not particularly limited and may be the temperature during the addition or a higher temperature. For example, it is room temperature to 80°C. The pressure during chemical reaction II-1A is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, and more preferably 0.1 MPa. The time required for chemical reaction II-1A is not particularly limited and may be, for example, 0.5 to 24 hours. Chemical reaction II-1A is preferably carried out under an inert gas atmosphere.

[0074] After completion of chemical reaction II-1A, post-treatments such as extraction with an organic solvent and drying and concentrating the resulting organic layer can be performed. If necessary, the product of chemical reaction II-1A can be further purified by recrystallization, chromatography, or other procedures.

[0075] [When compound (4) is t-butyl haloformate (chemical reaction II-1B)] The compound in which Z in formula (4) is a halogeno group is t-butyl haloformate (English name: tert-butyl haloformate, Japanese name: t-butyl haloformate). X is a halogeno group.

[0076] When t-butyl haloformate is used as compound (4), chemical reaction II-1B can be carried out in an organic solvent in the presence of an inorganic base.

[0077] Examples of inorganic bases that can be used in Chemical Reaction II-1B include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride.

[0078] The amount of t-butyl haloformate used in Chemical Reaction II-1B is, for example, preferably 1.0 to 3.0 mol, more preferably 1.5 to 2.0 mol, relative to 1 mol of Compound (3). The amount of inorganic base used in Chemical Reaction II-1B is, for example, preferably 2.0 to 5.0 mol, more preferably 3.0 to 4.0 mol, relative to 1 mol of Compound (3).

[0079] The organic solvent that can be used in Chemical Reaction II-1B is not particularly limited as long as it is inert to Chemical Reaction II-1B. Examples of organic solvents that can be used in Chemical Reaction II-1B include ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diglyme), tetrahydrofuran (abbreviation: THF), 4-methyltetrahydropyran (abbreviation: MTHP), and dioxane; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (abbreviation: DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as toluene and xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, dimethyl carbonate, and diethyl carbonate; ketones such as acetone, anone, and methyl isobutyl ketone (abbreviation: MIBK); and other solvents such as dimethyl sulfoxide (abbreviation: DMSO) and dimethylformamide (abbreviation: DMF). These organic solvents can be used alone or in combination of two or more. The amount of the organic solvent used is not particularly limited, but is preferably 1 to 100 parts by mass per part by mass of compound (3).

[0080] One embodiment of chemical reaction II-1B involves dissolving compound (3) in an organic solvent, adding an inorganic base and t-butyl haloformate to the solution, and completing the chemical reaction. The addition of t-butyl haloformate is preferably carried out gradually to prevent a sudden temperature rise due to the heat of reaction. The temperature inside the reactor may be monitored to adjust the rate of addition of t-butyl haloformate. The temperature during the addition of t-butyl haloformate is preferably -10°C to 5°C. The temperature during chemical reaction II-1B is not particularly limited and may be the temperature during addition, for example, -10°C to 10°C. The pressure during chemical reaction II-1B is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, and more preferably 0.1 MPa. The time required for chemical reaction II-1B is not particularly limited and may be, for example, 0.5 to 24 hours. Chemical reaction II-1B is preferably carried out under an inert gas atmosphere.

[0081] After completion of chemical reaction II-1B, the reaction solution is added to an acidic aqueous solution to neutralize the remaining inorganic base. The reaction mixture is then extracted with an organic solvent, and the resulting organic layer can be subjected to post-treatments such as drying and concentration. If necessary, the product of chemical reaction II-1B can be further purified by recrystallization, chromatography, or other procedures.

[0082] [When compound (4) is t-butyl 1H-imidazole-1-carboxylate (chemical reaction II-1C)] The compound in which Z in formula (4) is a 1H-imidazol-1-yl group is t-butyl 1H-imidazol-1-carboxylate.

[0083] When t-butyl 1H-imidazole-1-carboxylate is used as compound (4), chemical reaction II-1 can be carried out in an organic solvent.

[0084] The amount of t-butyl 1H-imidazole-1-carboxylate used in Chemical Reaction II-1C is, for example, preferably 1.0 to 2.0 moles, more preferably 1.0 to 1.5 moles, per mole of Compound (3).

[0085] The organic solvent that can be used in Chemical Reaction II-1C is not particularly limited as long as it is inert to Chemical Reaction II-1C. Examples of organic solvents that can be used in Chemical Reaction II-1C include ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diglyme), tetrahydrofuran (abbreviation: THF), 4-methyltetrahydropyran (abbreviation: MTHP), and dioxane; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (abbreviation: DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as toluene and xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, dimethyl carbonate, and diethyl carbonate; ketones such as acetone, anone, and methyl isobutyl ketone (abbreviation: MIBK); and other solvents such as dimethyl sulfoxide (abbreviation: DMSO) and dimethylformamide (abbreviation: DMF). These organic solvents can be used alone or in combination of two or more. The amount of the organic solvent used is not particularly limited, but is preferably 1 to 100 parts by mass per part by mass of compound (3).

[0086] One embodiment of chemical reaction II-1C involves dissolving compound (3) in an organic solvent, adding t-butyl 1H-imidazole-1-carboxylate to the solution, and completing the chemical reaction. The addition of t-butyl 1H-imidazole-1-carboxylate is preferably carried out gradually to prevent a rapid temperature rise due to the heat of reaction. The addition rate of t-butyl 1H-imidazole-1-carboxylate may be adjusted by monitoring the temperature inside the reactor. The temperature during the addition of t-butyl 1H-imidazole-1-carboxylate is not particularly limited and may be room temperature. The temperature during chemical reaction II-1C is not particularly limited and may be the temperature at the time of addition or a higher temperature. For example, it may be room temperature to 80°C. The pressure during chemical reaction II-1C is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, and more preferably 0.1 MPa. The time required for chemical reaction II-1C is not particularly limited and is, for example, 0.5 to 24 hours. Chemical reaction II-1C is preferably carried out in an inert gas atmosphere.

[0087] After completion of chemical reaction II-1C, post-treatments such as extraction with an organic solvent and drying and concentrating the resulting organic layer can be performed. If necessary, the product of chemical reaction II-1C can be further purified by recrystallization, chromatography, or other procedures.

[0088] [Conversion of Compound (3) to Compound (1) (Chemical Reaction II-2)] Chemical Reaction II-2 is a two-step reaction. First, Compound (3) is chemically reacted with phosgene, diphosgene, or triphosgene (Chemical Reaction II-2a). This produces a compound represented by Formula (5) (hereinafter sometimes referred to as Compound (5)).

[0089] In formula (5), R １ , R ２ , and R ３ is the same as in equation (1).

[0090] Next, compound (5) is subjected to a chemical reaction with an alkali metal t-butoxide (chemical reaction II-2b), thereby obtaining compound (1).

[0091] Chemical reaction II-2a can be carried out in an organic solvent in the presence of an organic base.

[0092] Examples of organic bases that can be used in Chemical Reaction II-2a include triethylamine, tetramethylethylenediamine, N,N-diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, 4-methylmorpholine, 1-azabicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (abbreviation: DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, 4-(dimethylamino)pyridine, 2,6-dimethylpyridine, etc. The amount of phosgene used in Chemical Reaction II-2a is, for example, preferably 1.0 to 2.0 moles, more preferably 1.2 to 1.5 moles, per mole of Compound (3). The amount of diphosgene used in chemical reaction II-2a is, for example, preferably 0.5 to 1.0 mol, more preferably 0.6 to 0.8 mol, per mol of compound (3). The amount of triphosgene used in chemical reaction II-2a is, for example, preferably 0.35 to 0.7 mol, more preferably 0.5 to 0.6 mol, per mol of compound (3). Phosgene, diphosgene, or triphosgene may be used alone or in combination of two or more. One mole of diphosgene decomposes to give two moles of phosgene. One mole of triphosgene decomposes to give three moles of phosgene. When two or more of phosgene, diphosgene, or triphosgene are used in combination, the amount of phosgene can be set to, for example, preferably 0.5 to 1.0 mol, more preferably 0.6 to 0.8 mol, per mol of compound (3), taking into account the phosgene that will be obtained by decomposition. The amount of the organic base used in Chemical Reaction II-2a is, for example, preferably 2.0 to 5.0 moles, more preferably 2.0 to 3.0 moles, per mole of Compound (3).

[0093] The organic solvent that can be used in Chemical Reaction II-2a is not particularly limited, as long as it is inert to Chemical Reaction II-2a. Examples of organic solvents that can be used in Chemical Reaction II-2a include ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diglyme), tetrahydrofuran (abbreviation: THF), 4-methyltetrahydropyran (abbreviation: MTHP), and dioxane; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (abbreviation: DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as toluene and xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, dimethyl carbonate, and diethyl carbonate; and ketones such as acetone, anone, and methyl isobutyl ketone (abbreviation: MIBK). These organic solvents can be used alone or in combination of two or more. The amount of the organic solvent used is not particularly limited, but is preferably 1 to 100 parts by mass per part by mass of compound (3).

[0094] One embodiment of chemical reaction II-2a involves dissolving compound (3) and phosgene, diphosgene, or triphosgene in an organic solvent, adding an organic base to the solution, and completing the chemical reaction. The organic base is preferably added gradually to prevent a rapid temperature rise due to the heat of reaction. The temperature inside the reactor may be monitored to adjust the rate of addition of the organic base. The temperature during addition of the organic base is preferably -10°C to 10°C. The temperature during chemical reaction II-2a is not particularly limited and may be the temperature during addition of the organic base, for example, -10°C to 10°C. The pressure during chemical reaction II-2a is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, and more preferably 0.1 MPa. The time required for chemical reaction II-2a is not particularly limited and may be, for example, 0.5 to 24 hours. Chemical reaction II-2a is preferably performed under an inert gas atmosphere.

[0095] Subsequently, the reaction solution containing the compound (5) obtained in the chemical reaction II-2a can be used as it is to carry out the chemical reaction II-2b.

[0096] Examples of alkali metal t-butoxides that can be used in Chemical Reaction II-2b include lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, etc. The amount of alkali metal t-butoxide used in Chemical Reaction II-2b is, for example, preferably 1.0 to 2.5 mol, more preferably 1.0 to 1.5 mol, per 1 mol of compound (3).

[0097] The alkali metal t-butoxide is preferably added gradually to prevent a sudden temperature rise due to the heat of reaction. The rate of addition of the alkali metal t-butoxide may be adjusted by monitoring the temperature inside the reactor. The temperature during addition of the alkali metal t-butoxide is preferably -10°C to 10°C. The temperature during chemical reaction II-2b is not particularly limited and may be the temperature during addition of the alkali metal t-butoxide or a higher temperature, for example, -10°C to 50°C. The pressure during chemical reaction II-2b is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, and more preferably 0.1 MPa. The time required for chemical reaction II-2b is not particularly limited and may be, for example, 0.5 to 24 hours. Chemical reaction II-2b is preferably performed under an inert gas atmosphere.

[0098] After completion of chemical reaction II-2b, post-treatments such as extraction with an organic solvent and drying and concentrating the resulting organic layer can be performed. If necessary, the product of chemical reaction II-2b can be further purified by recrystallization, chromatography, or other procedures.

[0099] [Conversion of Compound (6) to Compound (3) (Chemical Reaction I)] Compound (3), which is the substrate used in Chemical Reaction II-1 or II-2, is not particularly limited by its production method, and can be obtained, for example, by a method comprising converting Compound (6) to Compound (3).

[0100] Compound (6), which is the substrate in chemical reaction I, is a compound represented by formula (6).

[0101] In formula (6), R １ and R ２ is the same as in equation (1).

[0102] The compound (6) used in this embodiment may be one synthesized by the inventors themselves using a known method, or may be one synthesized by another person using some method and commercially available.

[0103] Compound (7) is used in Chemical Reaction I. Compound (7) is a compound represented by formula (7).

[0104] In formula (7), R ３ is the same as in formula (1). ａ is a methyl group, a trifluoromethyl group, a phenyl group, or a tolyl group. ａ is preferably a phenyl group.

[0105] The compound (7) used in this embodiment may be one synthesized by the inventors themselves using a known method, or may be one synthesized by another person using some method and commercially available.

[0106] An inorganic base can be used in Chemical Reaction I. Examples of inorganic bases include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride. The amount of compound (6) relative to 1 mole of compound (7) in Chemical Reaction I is not particularly limited, but is, for example, 0.6 to 2.5 moles, preferably 1.0 to 2.0 moles, and more preferably 1.0 to 1.5 moles. The amount of inorganic base used in Chemical Reaction I relative to 1 mole of compound (7) is, for example, preferably 1.0 to 2.0 moles, and more preferably 1.0 to 1.5 moles.

[0107] An organic solvent can be used in Chemical Reaction I. There are no particular limitations on the organic solvent that can be used in Chemical Reaction I, as long as it is inert to Chemical Reaction I. Examples of organic solvents that can be used in Chemical Reaction I include ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diglyme), tetrahydrofuran (abbreviation: THF), 4-methyltetrahydropyran (abbreviation: MTHP), and dioxane; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (abbreviation: DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; aromatic hydrocarbons such as toluene and xylene; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, dimethyl carbonate, and diethyl carbonate; ketones such as acetone, anone, and methyl isobutyl ketone (abbreviation: MIBK); and other solvents such as dimethyl sulfoxide (abbreviation: DMSO) and dimethylformamide (abbreviation: DMF). These organic solvents can be used alone or in combination of two or more. The amount of the organic solvent used is not particularly limited, but is preferably 1 to 100 parts by mass per part by mass of compound (7).

[0108] One embodiment of chemical reaction I involves mixing compound (6), compound (7), an inorganic base, and an organic solvent and completing the chemical reaction. The temperature during mixing is not particularly limited and may be room temperature. The temperature during chemical reaction I is, for example, 60°C to 120°C. The pressure during chemical reaction I is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, and more preferably 0.1 MPa. The time required for chemical reaction I is not particularly limited and is, for example, 0.5 to 24 hours. Chemical reaction I is preferably carried out under an inert gas atmosphere.

[0109] After completion of Chemical Reaction I, the reaction solution is added to an acidic aqueous solution to neutralize the remaining inorganic base. The reaction mixture is then extracted with an organic solvent, and the resulting organic layer can be subjected to post-treatments such as drying and concentration. If necessary, the product of Chemical Reaction I can be further purified by recrystallization, chromatography, or other procedures.

[0110] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples.

[0111] Example 1: Synthesis of 5,5-dimethyl-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione (Compound 3)

[0112]

[0113] A reactor was charged with compound 7 (2,2,2-trifluoroethyl benzenesulfonate, 118.9 g, 0.50 mol), compound 6 (5,5-dimethylimidazolidine-2,4-dione, 96.1 g, 1.5 eq.), potassium carbonate (71.0 g, 1.0 eq.), and dimethyl sulfoxide (500 mL, 1.0 L / mol) and stirred at 105-115 °C for 5.5 hours. Water (500 mL), toluene (500 mL), and 35 wt% hydrochloric acid (52.1 g) were then added and mixed. The mixture was separated, and the aqueous layer was extracted twice with toluene (500 mL). The toluene layer was then separated. NaCl (10.0 g) and toluene (500 mL) were added to the aqueous layer, the temperature was raised to 50 °C, and the mixture was then separated to obtain the toluene layer. The resulting toluene layers were combined and then the toluene was distilled off under reduced pressure to obtain a dimethyl sulfoxide solution of compound 3 in a yield of 74%. The aqueous layer contained compound 3 in a yield of 17%.

[0114] The dimethyl sulfoxide solution of compound 3 was purified by silica gel column chromatography to obtain compound 3. 1 H-NMR data and 13 The C-NMR data is shown below. 1H-NMR(CDCl3 / TMS,δ(ppm)) 6.33(brs, 1H), 4.16-4.10(q, 2H), 1.49(s, 6H) 13 C-NMR(CDCl3 / TMS,δ(ppm))176.45, 154.98, 127.28-118.94(q), 59.29, 40.07-38.98(q), 24.73

[0115] Example 2: Synthesis of tert-butyl 5,5-dimethyl-2,4-dioxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxylate (Compound 1)

[0116]

[0117] A reactor was charged with a dimethyl sulfoxide solution of compound 3 obtained in Example 1 (2.87 g, purity 74.5 wt%, 10.2 mmol), toluene (2.0 mL, 0.2 L / mol), and dimethyl sulfoxide (3.4 mL, 0.3 L / mol). While stirring at 25°C, 85% KOH pellets (2.64 g, 3.9 eq.) were added, followed by stirring at 25-30°C for 40 minutes. The mixture was cooled to -2°C, and a separately prepared tert-butyl carbonochloridate / toluene solution (14.06 g, purity 19.4 wt%, 2.0 eq.) was added dropwise at -2 to 0°C over 15 minutes. The mixture was then stirred at -5 to 2°C for 2 hours to obtain a reaction solution. Subsequently, 5 wt% hydrochloric acid (10 mL) was charged into the flask, cooled, and the reaction solution was added dropwise to the cooled mixture at -2 to 1°C over 10 minutes. After the dropwise addition was completed, the mixture was stirred at 0 to 20°C for 1 hour. The layers were separated to obtain a toluene layer. A toluene solution of Compound 1 was obtained in an 87% yield. This toluene solution also contained Compound 2 in a 9% yield.

[0118] Toluene was distilled off from the toluene solution of Compound 1 to obtain Compound 1 (3.28 g, purity 80.61 wt%, 8.53 mmol) as a yellow oil. This was purified by silica gel column chromatography to obtain Compound 1. 1 H-NMR data and 13 The C-NMR data is shown below. 1H-NMR(CDCl3 / TMS,δ(ppm)) 4.21-4.14(q, 2H), 1.67(s, 6H), 1.58(s, 9H) 13 C-NMR(CDCl3 / TMS,δ(ppm))173.91, 150.48, 148.14, 127.03-118.69(q), 84.76, 63.51, 40.36-39.26(q), 28.04, 23.06

[0119] Example 3: Synthesis of tert-butyl (2-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)carbamate (Compound 2)

[0120]

[0121] Toluene was distilled off from the toluene solution of Compound 1 obtained in Example 2 to obtain Compound 1 (3.28 g, purity 80.61 wt%, 8.53 mmol) as a yellow oil. This was charged into a reactor. n-Butanol (18.8 mL, 2.2 L / mol) was added to dissolve the compound, and the mixture was cooled to 7°C. 10 wt% NaOH (15.02 g, 4.4 eq.) was added and stirred at 5-10°C for 24 hours. 10 wt% NaOH (7.51 g, 2.2 eq.) was then added and stirred at 5-10°C for an additional 23 hours. Water (9.6 mL) was then added, and the mixture was neutralized to pH 5.7 with 35 wt% hydrochloric acid (5.78 g, 6.5 eq.). Water (9.6 mL) and n-butanol (24.0 mL) were then added, and the mixture was stirred at 30-40°C for 30 minutes. The mixture was then separated to obtain an n-butanol layer. An n-butanol solution of Compound 2 was obtained in a yield of 84%. Part of the n-butanol was distilled off from this solution under reduced pressure to obtain a slurry of Compound 2. This was then filtered to obtain Compound 2 as white crystals. 1 H-NMR data and 13 The C-NMR data is shown below. 1 H-NMR(CDCl3 / TMS,δ(ppm)) 7.22(brs, 1H), 4.82(brs, 1H), 3.96-3.87(dq, 2H), 1.50(s, 6H), 1.44(s, 9H) 13C-NMR(CDCl3 / TMS,δ(ppm))175.04, 155.05, 128.31-120.03(q), 80.88, 56.99, 41.35-40.32, 28.18, 25.62

[0122] Example 4 Synthesis of tert-butyl 5,5-dimethyl-2,4-dioxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxylate (Compound 1)

[0123]

[0124] Compound 3 (0.63 g, 3.0 mmol), tetrahydrofuran (2.5 mL, 0.8 L / mol), and triethylamine (0.61 g, 2.0 eq.) were charged into a reactor and dissolved in tetrahydrofuran (0.5 mL) with stirring at 25°C (Boc). ２ Di-tert-butyl dicarbonate (0.69 g, 1.1 eq.) was added dropwise. After the addition was completed, the mixture was stirred at 25-50°C for 1.5 hours, and then at 70°C for 13 hours. During the stirring, triethylamine (0.30 g, 1.0 eq.) and (Boc) ２ Di-tert-butyl dicarbonate (0.16 g, 0.2 eq.) was added to the mixture. Water (6.0 mL), toluene (6.0 mL), and 35 wt% hydrochloric acid (0.72 g) were then added, mixed, and the mixture was separated. The organic layer was washed twice with 5 wt% hydrochloric acid (5.0 mL), once with water (5.0 mL), dried over magnesium sulfate, filtered, and the organic solvent was removed under reduced pressure to obtain compound 1 in a 95% yield.

[0125] Example 5: Synthesis of tert-butyl 5,5-dimethyl-2,4-dioxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxylate (Compound 1)

[0126]

[0127] A reactor was charged with compound 3 (1.09 g, purity 96.3 wt%, 50 mmol), tetrahydrofuran (5.0 mL, 1.0 L / mol), and triphosgene (0.74 g, 0.5 eq.) and stirred at 5°C. Pyridine (0.59 g, 1.5 eq.) was added dropwise. After the addition was complete, the mixture was stirred at 0-5°C for 0.5 hours. The mixture was then cooled to -1°C, and t-BuONa (0.48 g, 1.0 eq.) was added. The mixture was stirred at -3-10°C for 3.5 hours, then at 25-50°C for 1.5 hours. t-BuONa (0.24 g, 0.5 eq.) was added, and the mixture was stirred at 50°C for 1 hour. Water (10 mL), toluene (5.0 mL), and 28 wt% NaOH (0.85 g) were added, and the mixture was separated to obtain a toluene solution of compound 1 in 15% yield.

[0128] Comparative Example 1 Hydrolysis of Compound 3

[0129]

[0130] Compound 3 (0.22 g, purity 96.3 wt%, 1.0 mmol) and n-butanol (1.0 mL, 1.0 L / mol) were charged into a flask, and 28 wt% NaOH (0.29 g, 2.0 eq.) was added with stirring. The mixture was stirred at 20-25°C for 5 hours. Water (2.0 mL) and n-butanol (1.0 mL) were then added, mixed, and separated. An n-butanol solution of compound 9 (yield 39%) and an aqueous solution of compound 9 (yield 60%) were obtained. n-butanol was distilled off under reduced pressure from the n-butanol solution of compound 9 to obtain compound 9. 1 The H-NMR data is shown below. 1 H-NMR(DMSO-d6 / TMS,δ(ppm)) 7.26-7.23(brt, 1H), 6.83(s, 1H), 3.77-3.68(dq, 2H),1.36(s, 6H)

[0131] Comparative Example 2 Hydrolysis of Compound 1'

[0132]

[0133] Compound 3 (0.63 g, 3.0 mmol), dichloromethane (3.0 mL, 1.0 L / mol), and triethylamine (0.33 g, 1.1 eq.) were added to a flask, and isopropyl carbonochloridate (0.40 g, 1.1 eq.) was added dropwise with stirring. After the addition was complete, the mixture was stirred at 20-40°C for 4.5 hours. Triethylamine (0.33 g, 1.1 eq.) and isopropyl carbonochloridate (0.40 g, 1.1 eq.) were then added and stirred at 40°C for 20 hours. To this mixture, chloroform (5.0 mL), water (5.0 mL), and 35 wt% hydrochloric acid (0.39 g) were added, mixed, and the mixture was separated. The organic layer was washed with water (5.0 mL) and separated to obtain a chloroform solution of compound 1' in 59% yield. Magnesium sulfate was added to a chloroform solution of compound 1' to dehydrate it, filtered, the organic solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 1'. 1 The H-NMR data is shown below. 1 H-NMR(CDCl3 / TMS,δ(ppm)) 5.19-5.10(sep, 1H), 4.21-4.15(q, 2H), 1.68(s, 6H), 1.40-1.38(d, 6H)

[0134]

[0135] A flask was charged with compound 1' (0.10 g, purity 81 wt%, 0.27 mmol) and 1,4-dioxane (0.32 mL, 1.2 L / mol). 28 wt% NaOH (0.04 g, 1.0 eq.) was added with stirring, and the mixture was stirred at 20-50°C for 7 hours and then at 80°C for 6 hours. During the stirring process, 28 wt% NaOH (0.24 g, 6.0 eq.) was added. Water (4.0 mL) and chloroform (4.0 mL) were added, mixed, and the mixture was separated. An aqueous solution of compound 9 was obtained in 80% yield. Compound 2' was not detected in either the chloroform or aqueous layers.

[0136] Example 6: Synthesis of hydrochloride of 2-amino-2-methyl-N-(2,2,2-trifluoroethyl)propanamide (Compound 8)

[0137]

[0138] A slurry of compound 2 (1.92 g, 6.76 mmol) in n-butanol (18.3 mL, 2.7 L / mol) and 35 wt % hydrochloric acid (3.81 g, 5.4 eq.) was placed in a flask and stirred at 40-50°C for 4.5 hours. Toluene (30.1 mL) and water (13.1 mL) were then added, mixed, and the mixture was separated. An aqueous solution of the hydrochloride salt of compound 8 was obtained in 97% yield.

[0139] Example 7 Synthesis of 2-amino-2-methyl-N-(2,2,2-trifluoroethyl)propanamide (Compound 8) Chloroform (5.0 mL) was added to an aqueous solution of the hydrochloride salt of Compound 8 obtained in Example 6 (7.37 g, purity 5.90 wt%, 2.36 mmol), and the mixture was stirred. 28 wt% NaOH (1.75 g, 5.2 eq.) was added to the mixture to neutralize to pH 11.3, and the layers were separated. The aqueous layer was extracted twice with chloroform (3.0 mL), and the layers were separated. The organic layers were combined to obtain a chloroform solution of Compound 8 with a distribution rate of 98%. The chloroform was evaporated under reduced pressure to obtain Compound 8. The obtained Compound 8 1 H-NMR data and 13 The C-NMR data is shown below. 1 H-NMR(CDCl3 / TMS,δ(ppm)) 8.15(brs, 1H), 3.92-3.83(dq, 2H), 1.46(brs, 2H), 1.38(s, 6H) 13 C-NMR(CDCl3 / TMS,δ(ppm))178.04, 128.39-120.08(q), 54.99, 41.18-40.15(q), 29.08

[0140] A novel method for producing N-BOC amino acid amide compounds can be provided.

Claims

1. A method for producing a compound represented by formula (2), which comprises hydrolyzing a compound represented by formula (1). (In formula (1), R １ and R ２ are each independently a hydrogen atom, a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- to 6-membered heteroaryl group; R １ and R ２ may be taken together to form a substituted or unsubstituted C2-5 alkylene group. ３ is a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C2-6 alkenyl group, a substituted or unsubstituted C2-6 alkynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- to 6-membered heteroaryl group. (In formula (2), R １ , R ２ , and R ３ is the same as in formula (1).

2. The method according to claim 1, further comprising chemically reacting a compound represented by formula (3) with a compound represented by formula (4) to obtain a compound represented by formula (1). (In formula (3), R １ , R ２ , and R ３ is the same as in formula (1).) (In formula (4), Z is a t-butoxycarbonyloxy group, a halogeno group, or a 1H-imidazol-1-yl group.) 3. The method according to claim 1, further comprising: chemically reacting the compound represented by formula (3) with phosgene, diphosgene, or triphosgene to obtain a compound represented by formula (5); and chemically reacting the compound represented by formula (5) with an alkali metal t-butoxide to obtain a compound represented by formula (1). (In formula (3), R １ , R ２ , and R ３ is the same as in formula (1).) (In formula (5), R １ , R ２ , and R ３ is the same as in formula (1).) 4. The method according to claim 2 or 3, further comprising chemically reacting a compound represented by formula (6) with a compound represented by formula (7) to obtain a compound represented by formula (3). (In formula (6), R １ and R ２ is the same as in formula (1).) (In formula (7), R ３ is the same as in formula (1). ａ is a methyl group, a trifluoromethyl group, a phenyl group, or a tolyl group.

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