Method for producing amide compound

Abstract

A method for producing a compound represented by formula (2) includes obtaining a compound represented by formula (1) by chemically reacting a compound represented by formula (4) with a compound represented by formula (3), and hydrolyzing the obtained compound represented by formula (1). (In formulae (1) to (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 tert-butoxycarbonyloxy group, a halogen group, or a 1H-imidazole-1-group).

Description

TECHNICAL FIELD

[0001] The present application relates to a production method of an amide compound. More specifically, it relates to a production method of an N-BOC amino acid amide compound.

[0002] This application claims priority based on Japanese Patent Application No. 2023-121036 filed on July 25, 2023, and the contents thereof are incorporated herein. BACKGROUND

[0003] The N-BOC amino acid amide compound and the amino acid amide compound are useful compounds as a manufacturing intermediate of a pharmaceutical or a pesticide, and the like. For example, Patent Literature 1 discloses that in a manufacturing example of a compound 1-1 having a miticidal activity, tert-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 condensation reaction of an 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 deprotection reaction.

[0004]

[0005] PRIOR ART DOCUMENTS

[0006] PATENT LITERATURE

[0007] Patent Literature 1: International Publication No. 2019 / 198592 SUMMARY

[0008] An object of the present application is to provide a novel production method of an N-BOC amino acid amide compound.

[0009] In order to achieve the object of the present application, research has been conducted, and as a result, the present application including the following mode has been completed.

[0010] (1) A production method of a compound represented by formula (2), comprising subjecting a compound represented by formula (1) to hydrolysis.

[0011]

[0012] In formula (1), R 1 and R 2 each independently is 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 2They can be combined to form substituted or unsubstituted C2-5 alkylene groups.

[0013] R 3 It can be a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted C2-6 alkenyl, a substituted or unsubstituted C2-6 alkynyl, a substituted or unsubstituted C3-6 cycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-6 heteroaryl.

[0014]

[0015] In equation (2), R 1 R 2 and R 3 R in equation (1) 1 R 2 and R 3 same.

[0016] [2] The manufacturing method according to [1] further includes chemically reacting the compound represented by formula (4) with the compound represented by formula (3) to obtain the compound represented by formula (1).

[0017]

[0018] In equation (3), R 1 R 2 and R 3 R in equation (1) 1 R 2 and R 3 same.

[0019]

[0020] In formula (4), Z is a tert-butoxycarbonyloxy group, a halogen group, or a 1H-imidazol-1-yl group.

[0021] [3] The manufacturing method according to [1] further includes: chemically reacting phosgene, diphosgene or triphosgene with the compound represented by formula (3) to obtain the compound represented by formula (5),

[0022] The compound represented by formula (1) is obtained by chemically reacting an alkali metal tert-butoxide with the compound represented by formula (5).

[0023]

[0024] In equation (5), R 1 R 2 and R 3 R in equation (1) 1 R 2 and R 3 same.

[0025] [4] The manufacturing method according to [2] or [3] further includes: chemically reacting the compound represented by formula (7) with the compound represented by formula (6) to obtain the compound represented by formula (3).

[0026]

[0027] In equation (6), R 1 and R 2 R in equation (1) 1 and R 2 same.

[0028]

[0029] In equation (7), R 3 R in equation (1) 3 Same. R a It can be methyl, trifluoromethyl, phenyl, or tolyl.

[0030] Typically, hydrolysis of hydantoin yields glycine. Similarly, hydrolysis of 5-substituted hydantoin yields various amino acids.

[0031]

[0032] In addition, the chemical reaction described below is carried out in compounds formed by the bonding of methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl with an amino group (the compound represented by formula (1a)).

[0033]

[0034] In equation (1a), R 4 It can be methyl, ethyl, n-propyl or isopropyl.

[0035] On the other hand, according to the manufacturing method of the present invention, due to the influence of the tert-butoxycarbonyl group (BOC group: a group known as a group protecting the amino group) in the compound represented by formula (1), positional hydrolysis can be carried out, and the compound represented by formula (2) can be obtained in high yield. If the compound represented by formula (2) is subjected to a deprotection reaction, the corresponding amino acid amide compound can be obtained. The amino acid amide compound obtained by the manufacturing method of the present invention is useful as an intermediate for the manufacture of active ingredients in pharmaceutical pesticides such as compound 1-1.

[0036] Detailed Implementation

[0037] One method of manufacturing the present invention includes 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)).

[0038] Another way of manufacturing the present invention includes converting the compound represented by formula (3) (hereinafter sometimes referred to as compound (3)) into compound (1) and converting compound (1) into compound (2).

[0039] Another way of manufacturing the present invention includes converting the 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).

[0040] In this invention, the term "unsubstituted" refers to a group that serves only as the parent nucleus. When the term "substituted" is not used and the name of the group that serves as the parent nucleus is used instead, it is considered "unsubstituted" unless otherwise specified.

[0041] On the other hand, the term "substitution" refers to the replacement of any hydrogen atom in the parent nucleus by a group (substituent) with a group having the same or different structure as the parent nucleus. Therefore, a "substituent" refers to another group bonded to the parent nucleus. There can be one or more substituents. Two or more substituents can be the same or different.

[0042] The terms "C1-6" indicate that the number of carbon atoms in the group forming the parent nucleus is 1 to 6. This number of carbon atoms does not include the number of carbon atoms present in the substituents. For example, butyl with an ethoxy substituent is classified as C2 alkoxy C4 alkyl.

[0043] There are no particular restrictions on the "substituents" as long as they are chemically permissible and have the effects of this invention.

[0044] The following are examples of groups that can be "substituents".

[0045] C1-6 alkyl groups including methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl;

[0046] Vinyl, 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, and other C2-6 alkenyl groups;

[0047] Acetylene, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, etc., C2-6 ynyl groups;

[0048] Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and other C3-6 cycloalkyl groups;

[0049] Phenyl;

[0050] 3- to 6-membered heterocyclic groups;

[0051] Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, and other C1-6 alkoxy groups;

[0052] Phenoxy, naphthoxy, and other C6-10 aryloxy groups;

[0053] Thiazoloxy, pyridinoxy, and other 5- to 6-membered heteroaryloxy groups;

[0054] Methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, and other C1-6 alkoxycarbonyl groups;

[0055] Halogen groups such as fluorine, chlorine, bromine, and iodine;

[0056] Chloromethyl, chloroethyl, trifluoromethyl, 1,2-dichloropropyl, 1-fluorobutyl, perfluoropentyl and other C1-6 haloalkyl groups;

[0057] Trifluoromethoxy, 2-chloropropoxy, 2,3-dichlorobutoxy, and other C1-6 haloalkoxy groups;

[0058] Formylamino;

[0059] Acetylamino, propionylamino, butyrylamino, isopropylcarbonylamino, and other C1-6 alkylcarbonylamino groups;

[0060] Methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, and other C1-6 alkoxycarbonylamino groups;

[0061] Aminocarbonyl, dimethylaminocarbonyl, phenylaminocarbonyl, N-phenyl-N-methylaminocarbonyl, and other unsubstituted or substituted aminocarbonyl groups;

[0062] C1-6 alkylthio groups, including methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, etc.

[0063] Trifluoromethylthio, 2,2,2-trifluoroethylthio, and other C1-6 haloalkylthio groups;

[0064] C1-6 alkylsulfonyl groups, such as methylsulfonyl, ethylsulfonyl, and tert-butylsulfonyl;

[0065] Trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl and other C1-6 haloalkylsulfonyl groups;

[0066] Cyano group; Nitro group.

[0067] Furthermore, for these "substituents," any hydrogen atom in the aforementioned substituents can be replaced by a group with a different structure. Examples of substituents in this case include C1-6 alkyl groups, C1-6 haloalkyl groups, C1-6 alkoxy groups, C1-6 haloalkoxy groups, halogen groups, cyano groups, nitro groups, etc.

[0068] Furthermore, the aforementioned "3- to 6-membered heterocyclic groups" contain 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms as constituent atoms of the ring. The heterocyclic group can be either a monocyclic or polycyclic group. For polycyclic heterocyclic groups, as long as at least one ring is a heterocyclic ring, the remaining rings can be any of a saturated alicyclic, unsaturated alicyclic, or aromatic rings. Examples of "3- to 6-membered heterocyclic groups" include 3- to 6-membered saturated heterocyclic groups, 5- to 6-membered heteroaryl groups, and 5- to 6-membered partially unsaturated heterocyclic groups.

[0069] Examples of 3- to 6-membered saturated heterocyclic groups include aziridinyl, epoxy, pyrrolyl, tetrahydrofuranyl, thiazolyl, piperidinyl, piperazine, morpholinyl, dioxolane, and dioxolane. Alkyl groups, etc.

[0070] Examples of 5-membered heteroaryl groups include pyrrole, furanyl, thiophene, imidazolyl, and pyrazolyl. azole group, iso Azolyl, thiazolyl, isothiazolyl, triazolyl Diazole, thiadiazole, tetrazolium, etc.

[0071] Examples of 6-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.

[0072] Examples of 5-membered partially unsaturated heterocyclic groups include pyrrolinyl, dihydrofuranyl, imidazolinyl, and pyrazolinyl. Azoline group, iso Azoline group, etc.

[0073] Examples of 6-membered partially unsaturated heterocyclic groups include dihydropyranyl groups.

[0074] [Transformation from compound (1) to compound (2) (Chemical Reaction III)]

[0075] Compound (2) obtained by one method of manufacturing according to the present invention is a compound represented by formula (2).

[0076]

[0077] In equation (2), R 1 R 2 and R 3 R in equation (1)1 R 2 and R 3 same.

[0078] The substrate used for chemical reaction III is compound (1).

[0079]

[0080] In equation (1), R 1 and R 2 Each of the following is 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 ynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 heteroaryl group, R 1 and R 2 They can be combined to form substituted or unsubstituted C2-5 alkylene groups.

[0081] In equation (1), R 3 It can be a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted C2-6 alkenyl, a substituted or unsubstituted C2-6 alkynyl, a substituted or unsubstituted C3-6 cycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-6 heteroaryl.

[0082] R 1 ~R 3 The "C1-6 alkyl" in this context can be either straight-chain or branched. As R 1 ~R 3 Examples of "C1-6 alkyl" in this context include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, 2-methylbutyl, and isohexyl.

[0083] As R 1 ~R 3 Examples of "C2-6 alkenyl" in this context include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

[0084] As R 1 ~R 3Examples of "C2-6 ynyl" in this context include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-methyl-3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-pentynyl, 1-hexynyl, and 1,1-dimethyl-2-butynyl.

[0085] As R 1 ~R 3 The substituents on the "C1-6 alkyl", "C2-6 alkenyl" or "C2-6 alkynyl" groups are preferably halogen groups such as fluorine, chloro, bromine, iodo; hydroxyl; C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy; C1-6 haloalkoxy groups such as 2-chloro-n-propoxy, 2,3-dichlorobutoxy, trifluoromethoxy; phenyl; phenyl groups such as 4-chlorophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl substituted with halogen groups, C1-6 haloalkyl or C1-6 haloalkoxy groups; or cyano.

[0086] As R 1 ~R 3 Examples of "C3-6 cycloalkyl" in this context include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0087] R 1 ~R 3 The term "5-6 membered heteroaryl" refers to a 5- or 6-membered ring containing 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms as ring constituent atoms. When there are two or more heteroatoms, they can be the same or different.

[0088] Examples of 5-membered heteroaryl groups include pyrrole, furanyl, thiophene, imidazolyl, and pyrazolyl. azole group, iso Azolyl, thiazolyl, isothiazolyl, triazolyl Diazole, thiadiazole, tetrazolium, etc.

[0089] Examples of 6-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.

[0090] As R 1 ~R 3The substituents on the "C3-6 cycloalkyl", "phenyl", or "5-6 heteroaryl" groups are preferably halogen groups such as fluorine, chloro, bromine, and iodo; C1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-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 groups; C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, and tert-butoxy; C1-6 haloalkoxy groups such as 2-chloro-n-propoxy, 2,3-dichlorobutoxy, and trifluoromethoxy; or cyano groups.

[0091] As R 1 and R 2 Examples of C2-5 alkylene groups formed together include diallyl, trimethylene, tetramethylene, and pentamethylene. Halogen groups such as fluorine, chloro, bromine, and iodo groups are preferred as substituents on the "C2-5 alkylene group".

[0092] In this embodiment, R 1 and R 2 Preferred substituted or unsubstituted C1-6 alkyl groups, such as methyl.

[0093] In this embodiment, R 3 Preferred substituted or unsubstituted C1-6 alkyl groups, for example 2,2,2-trifluoroethyl.

[0094] Through chemical reaction III, the N-C bond between positions 1 and 2 and between positions 2 and 3 in compound (1) dissociates and is converted into compound (2). Carbon dioxide is generated during the conversion into compound (2).

[0095] Chemical reaction III can, for example, be carried out in a solvent in the presence of an inorganic base.

[0096] 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, and potassium hydride.

[0097] The amount of inorganic base used relative to 1 mole of compound (1) is, for example, 0.5 to 10 moles, preferably 1.0 to 7.0 moles.

[0098] In chemical reaction III, the reaction site can be any of the following: an aqueous phase consisting only of water, a homogeneous phase consisting of water and an organic solvent, or a heterogeneous phase consisting of water and an organic solvent.

[0099] There are no particular restrictions on the organic solvents that can be used in chemical reaction III, as long as they are inactive to chemical reaction III.

[0100] Examples of organic solvents used to form homogeneous phases include alcohols such as methanol, ethanol, n-propanol, isopropanol, and n-butanol; acetone, dimethyl sulfoxide (DMSO), and dimethylformamide (DMF).

[0101] Examples of organic solvents used to form heterogeneous phases include diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diethylene glycol dimethyl ether (diglyme)), tetrahydrofuran (abbreviated as THF), 4-methyltetrahydropyran (abbreviated as MTHP), and diethyl ether. Alkanes and other ethers; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (DCE); aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane, and octane; and aromatic hydrocarbons such as toluene and xylene.

[0102] In any case, organic solvents can be used alone or in combination of two or more.

[0103] The amount of solvent used in chemical reaction III is not particularly limited, but is preferably 1 to 100 parts by mass relative to 1 part by mass of compound (1).

[0104] One implementation of chemical reaction III involves dissolving an inorganic base in a solvent and adding compound (1) thereto to complete the hydrolysis.

[0105] The addition of compound (1) to the reaction site can be carried out all at once or slowly. Dropwise addition is suitable for slow addition. The addition of compound (1) to the reaction site is preferably carried out while stirring. The temperature at which compound (1) is added (dropwise) is preferably 0°C to 15°C. There is no particular limitation on the temperature at which the hydrolysis reaction is carried out after the addition is completed, but the temperature at which the addition (dropwise) is carried out is preferred, and more preferably 0°C to 15°C.

[0106] The pressure during the hydrolysis reaction is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, and more preferably 0.1 MPa. The time taken for the hydrolysis reaction is not particularly limited, for example, 0.5 hours to 24 hours. Chemical reaction III is preferably carried out under an inert gas atmosphere.

[0107] After chemical reaction III is completed, extraction can be performed using an organic solvent, and the resulting organic layer can be dried, concentrated, or otherwise processed. Furthermore, the product (compound (2)) in chemical reaction III can be purified as needed through recrystallization, chromatography, or other operations.

[0108] The compound (1) used as a substrate for chemical reaction III is not particularly limited in its manufacturing method, and can be obtained, for example, by a method that includes converting compound (3) into compound (1).

[0109] [Transformation from compound (3) to compound (1) (Chemical Reaction II-1)]

[0110] Compound (3), which is the substrate in chemical reaction II-1, is the compound represented by formula (3).

[0111]

[0112] In equation (3), R 1 R 2 and R 3 R in equation (1) 1 R 2 and R 3 same.

[0113] Compound (4) is used in chemical reaction II-1. Compound (4) is the compound represented by formula (4).

[0114]

[0115] In formula (4), Z is a tert-butoxycarbonyloxy group, a halogen group, or a 1H-imidazol-1-yl group.

[0116] In this embodiment, Z is preferably a tert-butoxycarbonyloxy group and a halogen group.

[0117] Examples of "halogen groups" in Z include fluorine, chlorine, bromine, and iodine groups. Among these, the chlorine group is preferred.

[0118] The compound (4) used in this embodiment can be a compound synthesized by a known method or a compound synthesized and commercially available by another person by any method.

[0119] [When compound (4) is di-tert-butyl dicarbonate (chemical reaction II-1A)]

[0120] In formula (4), Z is the tert-butoxycarbonyloxy group of the compound, which is di-tert-butyl dicarbonate (abbreviation: (Boc)2O).

[0121]

[0122] When (Boc)2O is used as compound (4), chemical reaction II-1 can be carried out in an organic solvent in the presence of an organic base.

[0123] 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 (abbreviated as 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.

[0124] The amount of (Boc)2O used in chemical reaction II-1A is preferably 1.0 to 2.0 moles, more preferably 1.0 to 1.5 moles, relative to 1 mole of compound (3).

[0125] The amount of organic base used in chemical reaction II-1A is preferably 2.0 to 5.0 moles, more preferably 2.0 to 3.0 moles, relative to 1 mole of compound (3).

[0126] There are no particular restrictions on the organic solvents that can be used in chemical reaction II-1A, as long as they are inactive to chemical reaction II-1A. Examples of organic solvents that can be used in chemical reaction II-1A include diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diethylene glycol dimethyl ether), tetrahydrofuran (abbreviated as THF), 4-methyltetrahydropyran (abbreviated as MTHP), and diethyl ether. Alkane and other ethers; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (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, cyclohexanone, and methyl isobutyl ketone (MIBK); and other solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF). These organic solvents can be used alone or in combination of two or more. There is no particular limitation on the amount of organic solvent used, but it is preferably 1 to 100 parts by mass relative to 1 part by mass of compound (3).

[0127] One embodiment of chemical reaction II-1A involves dissolving compound (3) and an organic base in an organic solvent and adding (Boc)2O thereto to complete the chemical reaction.

[0128] In order to suppress the sharp temperature rise caused by the reaction heat, the addition of (Boc)₂O is preferably carried out slowly. The temperature inside the reactor can be monitored to adjust the addition rate of (Boc)₂O. The temperature during the addition of (Boc)₂O is not particularly limited, and for example, it can be room temperature. The temperature for carrying out Chemical Reaction II-1A is not particularly limited, and it can be the temperature during the addition or a temperature higher than that. For example, it is room temperature to 80 °C. The pressure during the carrying out of 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 taken for Chemical Reaction II-1A is not particularly limited, and for example, it is 0.5 hours to 24 hours. Chemical Reaction II-1A is preferably carried out in an inert gas atmosphere.

[0129] After the completion of Chemical Reaction II-1A, extraction can be carried out using an organic solvent, and post-treatments such as drying and concentration can be performed on the obtained organic layer. Furthermore, the product in Chemical Reaction II-1A can be purified by operations such as recrystallization and chromatography as needed.

[0130] [When Compound (4) is tert-butyl haloformate (Chemical Reaction II-1B)]

[0131] The compound in which Z in Formula (4) is a halogen group is tert-butyl haloformate (English name: tert-butylhaloformate, Japanese name: t-butyl haloformate).

[0132]

[0133] X is a halogen group.

[0134] When using tert-butyl haloformate as Compound (4), Chemical Reaction II-1B can be carried out in an organic solvent in the presence of an inorganic base.

[0135] Examples of the inorganic base that can be used in Chemical Reaction II-1B include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc.

[0136] Relative to 1 mole of Compound (3), the usage amount of tert-butyl haloformate in Chemical Reaction II-1B is, for example, preferably 1.0 to 3.0 moles, and more preferably 1.5 to 2.0 moles. Relative to 1 mole of Compound (3), the usage amount of the inorganic base in Chemical Reaction II-1B is, for example, preferably 2.0 to 5.0 moles, and more preferably 3.0 to 4.0 moles.

[0137] There are no particular restrictions on the organic solvents that can be used in chemical reaction II-1B, as long as they are inactive to chemical reaction II-1B. Examples of organic solvents that can be used in chemical reaction II-1B include diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diethylene glycol dimethyl ether), tetrahydrofuran (abbreviated as THF), 4-methyltetrahydropyran (abbreviated as MTHP), and diethyl ether. Alkane and other ethers; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (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, cyclohexanone, and methyl isobutyl ketone (MIBK); and other solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF). These organic solvents can be used alone or in combination of two or more. There is no particular limitation on the amount of organic solvent used, but it is preferably 1 to 100 parts by mass relative to 1 part by mass of compound (3).

[0138] One embodiment of chemical reaction II-1B involves dissolving compound (3) in an organic solvent and adding an inorganic base and tert-butyl halocarbamate thereto to complete the chemical reaction.

[0139] To suppress a rapid temperature rise caused by the heat of reaction, the addition of tert-butyl halocarbamate is preferably carried out slowly. The addition rate of tert-butyl halocarbamate can be adjusted by monitoring the temperature inside the reactor. The temperature at which tert-butyl halocarbamate is added is preferably -10°C to 5°C. There is no particular limitation on the temperature at which chemical reaction II-1B is carried out; it can be the temperature at which it is added, for example, -10°C to 10°C. The pressure at which chemical reaction II-1B is carried out is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, more preferably 0.1 MPa. There is no particular limitation on the time taken for chemical reaction II-1B, for example, 0.5 hours to 24 hours. Chemical reaction II-1B is preferably carried out under an inert gas atmosphere.

[0140] After chemical reaction II-1B is completed, the reaction solution is added to an acidic aqueous solution to neutralize the residual inorganic base. Then, extraction can be performed using an organic solvent, followed by drying, concentration, and other post-processing of the resulting organic layer. Furthermore, the product from chemical reaction II-1B can be purified as needed through recrystallization, chromatography, or other operations.

[0141] [When compound (4) is 1H-imidazolium-1-carboxylic acid tert-butyl ester (chemical reaction II-1C)]

[0142] The compound in formula (4) with Z being 1H-imidazol-1- group is tert-butyl 1H-imidazol-1-carboxylate.

[0143]

[0144] When 1H-imidazolium-1-carboxylic acid tert-butyl ester is used as compound (4), chemical reaction II-1 can be carried out in an organic solvent.

[0145] The amount of 1H-imidazolium-1-carboxylic acid tert-butyl ester used in chemical reaction II-1C is preferably 1.0 to 2.0 moles, more preferably 1.0 to 1.5 moles, relative to 1 mole of compound (3).

[0146] There are no particular restrictions on the use of organic solvents in chemical reaction II-1C, provided they are inert to chemical reaction II-1C. Examples of organic solvents that can be used in chemical reaction II-1C include diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diethylene glycol dimethyl ether), tetrahydrofuran (abbreviated as THF), 4-methyltetrahydropyran (abbreviated as MTHP), and diethyl ether. Alkane and other ethers; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (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, cyclohexanone, and methyl isobutyl ketone (MIBK); and other solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF). These organic solvents can be used alone or in combination of two or more. There is no particular limitation on the amount of organic solvent used, but it is preferably 1 to 100 parts by mass relative to 1 part by mass of compound (3).

[0147] One embodiment of chemical reaction II-1C involves dissolving compound (3) in an organic solvent and adding 1H-imidazolium-1-carboxylic acid tert-butyl ester thereto to complete the chemical reaction.

[0148] To suppress a rapid temperature rise caused by the heat of reaction, the addition of 1H-imidazolium-1-carboxylic acid tert-butyl ester is preferably carried out slowly. The addition rate of 1H-imidazolium-1-carboxylic acid tert-butyl ester can be adjusted by monitoring the temperature inside the reactor. There are no particular limitations on the temperature at which 1H-imidazolium-1-carboxylic acid tert-butyl ester is added; it can be at room temperature. There are no particular limitations on the temperature at which chemical reaction II-1C is carried out; it can be the temperature at which it is added or a higher temperature, for example, room temperature to 80°C. The pressure at which chemical reaction II-1C is carried out is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, more preferably 0.1 MPa. The time taken for chemical reaction II-1C is not particularly limited; for example, it can be 0.5 hours to 24 hours. Chemical reaction II-1C is preferably carried out in an inert gas atmosphere.

[0149] After chemical reaction II-1C is completed, extraction can be performed using an organic solvent, followed by drying, concentration, and other post-processing of the resulting organic layer. Furthermore, the products from chemical reaction II-1C can be purified as needed through recrystallization, chromatography, or other operations.

[0150] [Transformation from compound (3) to compound (1) (Chemical reaction II-2)]

[0151] Chemical reaction II-2 is a two-stage reaction.

[0152] First, phosgene, diphosgene, or triphosgene is chemically reacted with compound (3) (chemical reaction II-2a). From this, the compound represented by formula (5) is obtained (hereinafter sometimes referred to as compound (5)).

[0153]

[0154] In equation (5), R 1 R 2 and R 3 R in equation (1) 1 R 2 and R 3 same.

[0155] Next, the alkali metal tert-butoxide is reacted with compound (5) in a chemical reaction (chemical reaction II-2b). As a result, compound (1) is obtained.

[0156] Chemical reaction II-2a can be carried out in an organic solvent in the presence of an organic base.

[0157] 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 (abbreviated as 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.

[0158] The amount of phosgene used in chemical reaction II-2a is preferably 1.0 to 2.0 moles, more preferably 1.2 to 1.5 moles, relative to 1 mole of compound (3).

[0159] The amount of phosgene used in chemical reaction II-2a is preferably 0.5 to 1.0 moles, more preferably 0.6 to 0.8 moles, relative to 1 mole of compound (3).

[0160] The amount of triphosgene used in chemical reaction II-2a is preferably 0.35 to 0.7 moles, more preferably 0.5 to 0.6 moles, relative to 1 mole of compound (3).

[0161] Phosgene, diphosgene, or triphosgene can be used alone or in combination of any two or more. One mole of diphosgene decomposes into two moles of phosgene. One mole of triphosgene decomposes into three moles of phosgene. When any two or more of phosgene, diphosgene, or triphosgene are used in combination, considering the phosgene that may be obtained through decomposition, the amount of phosgene can be set to, for example, preferably 0.5 to 1.0 moles, more preferably 0.6 to 0.8 moles, relative to one mole of compound (3). The amount of organic base used in chemical reaction II-2a relative to one mole of compound (3) is preferably 2.0 to 5.0 moles, more preferably 2.0 to 3.0 moles.

[0162] There are no particular restrictions on the organic solvents that can be used in chemical reaction II-2a, provided they are inert to chemical reaction II-2a. Examples of organic solvents that can be used in chemical reaction II-2a include diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diethylene glycol dimethyl ether), tetrahydrofuran (abbreviated as THF), 4-methyltetrahydropyran (abbreviated as MTHP), and diethyl ether. Alkane and other ethers; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (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, cyclohexanone, and methyl isobutyl ketone (MIBK). These organic solvents can be used alone or in combination of two or more. There is no particular limitation on the amount of organic solvent used, but it is preferably 1 to 100 parts by mass relative to 1 part by mass of compound (3).

[0163] One embodiment of chemical reaction II-2a involves dissolving compound (3) and phosgene, diphosgene or triphosgene in an organic solvent and adding an organic base thereto to complete the chemical reaction.

[0164] To suppress a rapid temperature rise caused by the heat of reaction, the addition of the organic base is preferably carried out slowly. The rate of addition of the organic base can be adjusted by monitoring the temperature inside the reactor. The temperature at which the organic base is added is preferably -10°C to 10°C. There is no particular limitation on the temperature at which chemical reaction II-2a is carried out, and it can be the temperature at which the organic base is added, for example, -10°C to 10°C. The pressure at which chemical reaction II-2a is carried out is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, and more preferably 0.1 MPa. There is no particular limitation on the time taken for chemical reaction II-2a, for example, 0.5 hours to 24 hours. Chemical reaction II-2a is preferably carried out in an inert gas atmosphere.

[0165] Next, chemical reaction II-2b can be carried out directly using the reaction solution containing compound (5) obtained in chemical reaction II-2a.

[0166] Examples of alkali metal tert-butoxide salts that can be used in chemical reaction II-2b include lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0167] The amount of alkali metal tert-butoxide used in chemical reaction II-2b is preferably 1.0 to 2.5 moles, more preferably 1.0 to 1.5 moles, relative to 1 mole of compound (3).

[0168] To suppress the rapid temperature rise caused by the heat of reaction, the addition of the alkali metal tert-butoxide is preferably carried out slowly. The addition rate of the alkali metal tert-butoxide can be adjusted by monitoring the temperature inside the reactor. The temperature at which the alkali metal tert-butoxide is added is preferably -10°C to 10°C. The temperature at which chemical reaction II-2b is carried out is not particularly limited and can be the same as the temperature at which the alkali metal tert-butoxide is added, or a higher temperature, for example, -10°C to 50°C. The pressure at which chemical reaction II-2b is carried out is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, more preferably 0.1 MPa. The time taken for chemical reaction II-2b is not particularly limited, for example, 0.5 hours to 24 hours. Chemical reaction II-2b is preferably carried out in an inert gas atmosphere.

[0169] After chemical reaction II-2b is completed, extraction can be performed using an organic solvent, followed by drying, concentration, and other post-processing of the resulting organic layer. Furthermore, the products from chemical reaction II-2b can be purified as needed through recrystallization, chromatography, or other operations.

[0170] [Transformation from compound (6) to compound (3) (Chemical reaction I)]

[0171] The compound (3) used as a substrate for chemical reaction II-1 or II-2 is not particularly limited in its manufacturing method, and can be obtained, for example, by a method involving the conversion of compound (6) into compound (3).

[0172] Compound (6), which is the substrate in chemical reaction I, is the compound represented by formula (6).

[0173]

[0174] In equation (6), R 1 and R 2 R in equation (1) 1 and R 2 same.

[0175] The compound (6) used in this embodiment can be a compound synthesized by a known method or a compound synthesized and commercially available by another person by any method.

[0176] Chemical reaction I uses compound (7). Compound (7) is the compound represented by formula (7).

[0177]

[0178] In equation (7), R 3 R in equation (1) 3 Same. R a It can be methyl, trifluoromethyl, phenyl, or tolyl.

[0179] In this embodiment, R a Phenyl is preferred.

[0180] The compound (7) used in this embodiment can be a compound synthesized by a known method or a compound synthesized and commercially available by another person by any method.

[0181] Inorganic bases 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.

[0182] The amount of compound (6) in chemical reaction I relative to 1 mole of compound (7) is not particularly limited, for example, it is 0.6 to 2.5 moles, preferably 1.0 to 2.0 moles, and more preferably 1.0 to 1.5 moles.

[0183] The amount of inorganic base used in chemical reaction I is preferably 1.0 to 2.0 moles, more preferably 1.0 to 1.5 moles, relative to 1 mole of compound (7).

[0184] Organic solvents can be used in chemical reaction I. There are no particular restrictions on the use of organic solvents in chemical reaction I, provided they are inactive to chemical reaction I. Examples of organic solvents that can be used in chemical reaction I include diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diethylene glycol dimethyl ether), tetrahydrofuran (abbreviated as THF), 4-methyltetrahydropyran (abbreviated as MTHP), and diethyl ether. Alkane and other ethers; halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane (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, cyclohexanone, and methyl isobutyl ketone (MIBK); and other solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF). These organic solvents can be used alone or in combination of two or more. The amount of organic solvent used is not particularly limited, but is preferably 1 to 100 parts by mass relative to 1 part by mass of compound (7).

[0185] One embodiment of chemical reaction I involves mixing compound (6), compound (7), an inorganic base, and an organic solvent to complete the chemical reaction.

[0186] There are no particular restrictions on the mixing temperature, and it can be at room temperature. The temperature for carrying out chemical reaction I is, for example, 60°C to 120°C. The pressure for carrying out chemical reaction I is, for example, 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa, more preferably 0.1 MPa. There are no particular restrictions on the time taken for chemical reaction I, for example, 0.5 hours to 24 hours. Chemical reaction I is preferably carried out in an inert gas atmosphere.

[0187] After chemical reaction I is completed, the reaction solution is added to an acidic aqueous solution to neutralize the residual inorganic base. Then, extraction can be performed using an organic solvent, followed by drying, concentration, and other post-processing of the resulting organic layer. Furthermore, the product from chemical reaction I can be purified as needed through recrystallization, chromatography, or other operations.

[0188] Example

[0189] The present invention will be described in more detail below with reference to embodiments. The present invention is not limited to the embodiments described below.

[0190] [Example 1]

[0191] Synthesis of 5,5-dimethyl-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione (compound 3)

[0192]

[0193] Compound 7 (2,2,2-trifluoroethylbenzenesulfonate, 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) were added to the reactor and stirred at 105–115 °C for 5.5 hours. Then, water (500 mL), toluene (500 mL), and 35 wt% hydrochloric acid (52.1 g) were added and mixed. The mixture was separated, and the aqueous layer was extracted twice with toluene (500 mL), and the toluene layer was obtained. NaCl (10.0 g) and toluene (500 mL) were added to the aqueous layer obtained by separation, and the temperature was set to 50 °C. Separation was then performed to obtain the toluene layer. The resulting toluene layers were combined and then distilled off the toluene under reduced pressure to obtain a dimethyl sulfoxide solution of compound 3 in 74% yield. The aqueous layer contained compound 3 in 17% yield.

[0194] Compound 3 was purified from a dimethyl sulfoxide solution by silica gel column chromatography to obtain compound 3. The obtained compound 3... 1 H-NMR data and 13 The C-NMR data are shown below.

[0195] 1 H-NMR (CDCl3 / TMS, δ (ppm)) 6.33 (brs, 1H), 4.16-4.10 (q, 2H), 1.49 (s, 6H)

[0196] 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

[0197] [Example 2]

[0198] Synthesis of tert-butyl 5,5-dimethyl-2,4-dioxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxylate (compound 1)

[0199]

[0200] A dimethyl sulfoxide solution (2.87 g, 74.5 wt% purity, 10.2 mmol), toluene (2.0 mL, 0.2 L / mol), and dimethyl sulfoxide (3.4 mL, 0.3 L / mol) of compound 3 obtained in Example 1 were added to a reactor. 85% KOH granules (2.64 g, 3.9 eq.) were added while stirring at 25 °C, followed by stirring at 25–30 °C for 40 minutes. The reactor was then cooled to -2 °C, and a separately prepared tert-butylcarbonochloridate / toluene solution (14.06 g, 19.4 wt% purity, 2.0 eq.) was added dropwise over 15 minutes at -2–0 °C. The mixture was then stirred at -5–2 °C for 2 hours to obtain the reaction solution. Then, 5 wt% hydrochloric acid (10 mL) was added to a flask, and the mixture was cooled. The reaction solution was added dropwise over 10 minutes at -2–1 °C. After the addition was complete, the mixture was stirred at 0–20 °C for 1 hour. The mixture was separated to obtain a toluene layer. A toluene solution of compound 1 was obtained in 87% yield. This toluene solution also contained compound 2 in 9% yield.

[0201] Toluene was distilled off from a toluene solution of compound 1 to give a yellow oily compound 1 (3.28 g, purity 80.61 wt%, 8.53 mmol). This oil was purified by silica gel column chromatography to obtain compound 1.

[0202] The obtained compound 1 1 H-NMR data and 13 The C-NMR data are shown below.

[0203] 1 H-NMR (CDCl3 / TMS, δ (ppm)) 4.21-4.14 (q, 2H), 1.67 (s, 6H), 1.58 (s, 9H)

[0204] 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

[0205] [Example 3]

[0206] Synthesis of tert-butyl (2-methyl-1-oxo-1-((2,2,2-trifluoroethyl)amino)propan-2-yl)carbamate (compound 2)

[0207]

[0208] Toluene was distilled off from the toluene solution of compound 1 obtained in Example 2 to give a yellow oily compound 1 (3.28 g, purity 80.61 wt%, 8.53 mmol). This was added to a reactor. n-Butanol (18.8 mL, 2.2 L / mol) was added and dissolved. The mixture was cooled to 7°C, and 10 wt% NaOH (15.02 g, 4.4 eq.) was added. The mixture was stirred at 5–10°C for 24 hours, followed by the addition of 10 wt% NaOH (7.51 g, 2.2 eq.), and further stirring at 5–10°C for 23 hours. Then, water (9.6 mL) was added, and the mixture was neutralized to pH 5.7 using 35 wt% hydrochloric acid (5.78 g, 6.5 eq.). Next, water (9.6 mL) and n-Butanol (24.0 mL) were added, and the mixture was stirred at 30–40°C for 30 minutes. The mixture was then separated to obtain the n-Butanol layer. A n-butanol solution of compound 2 was obtained in 84% yield. A portion of the n-butanol was removed from this solution by vacuum distillation to obtain a slurry of compound 2. This slurry was then filtered to obtain compound 2 as white crystals.

[0209] The obtained compound 2 1 H-NMR data and 13 The C-NMR data are shown below.

[0210] 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)

[0211] 13 C-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

[0212] [Example 4]

[0213] Synthesis of tert-butyl 5,5-dimethyl-2,4-dioxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxylic acid (compound 1)

[0214]

[0215] 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 added dropwise to the reactor while stirring at 25 °C. (Boc)₂O (di-tert-butyl dicarbonate, 0.69 g, 1.1 eq.) dissolved in tetrahydrofuran (0.5 mL) was added dropwise. After the addition was complete, the mixture was stirred at 25–50 °C for 1.5 h, followed by stirring at 70 °C for 13 h. Triethylamine (0.30 g, 1.0 eq.) and (Boc)₂O (di-tert-butyl dicarbonate, 0.16 g, 0.2 eq.) were then added during the stirring process. Next, water (6.0 mL), toluene (6.0 mL), and 35 wt% hydrochloric acid (0.72 g) were added and mixed, followed by separation. The organic layer was washed twice with 5 wt% hydrochloric acid (5.0 mL), once with water (5.0 mL), dehydrated with magnesium sulfate, filtered, and the organic solvent was removed by vacuum distillation to obtain compound 1 in 95% yield.

[0216] [Example 5]

[0217] Synthesis of tert-butyl 5,5-dimethyl-2,4-dioxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxylic acid (compound 1)

[0218]

[0219] Compound 3 (1.09 g, 96.3 wt%, 50 mmol), tetrahydrofuran (5.0 mL, 1.0 L / mol), and triphosgene (0.74 g, 0.5 eq.) were added to a reactor 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 h. Then, the mixture was 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 h, then at 25–50 °C for 1.5 h. Next, t-BuONa (0.24 g, 0.5 eq.) was added, and the mixture was stirred at 50 °C for 1 h. 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.

[0220] [Comparative Example 1]

[0221] Hydrolysis of compound 3

[0222]

[0223] Compound 3 (0.22 g, 96.3 wt%, 1.0 mmol) and n-butanol (1.0 mL, 1.0 L / mol) were added to a flask, and 28 wt% NaOH (0.29 g, 2.0 eq.) was added while stirring. The mixture was stirred at 20–25 °C for 5 hours. Then, water (2.0 mL) and n-butanol (1.0 mL) were added and mixed, and the mixture was separated. A n-butanol solution of compound 9 with a yield of 39% and an aqueous solution of compound 9 with a yield of 60% were obtained. The n-butanol was removed from the n-butanol solution of compound 9 by vacuum distillation to obtain compound 9.

[0224] The obtained compound 9 1 The H-NMR data are shown below.

[0225] 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)

[0226] [Comparative Example 2]

[0227] Hydrolysis of compound 1'

[0228]

[0229] 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 with stirring. Isopropyl chloroformate (0.40 g, 1.1 eq.) was added dropwise. After the addition was complete, the mixture was stirred at 20–40 °C for 4.5 hours. Then, triethylamine (0.33 g, 1.1 eq.) and isopropyl chloroformate (0.40 g, 1.1 eq.) were added, and the mixture was stirred at 40 °C for 20 hours. Chloroform (5.0 mL), water (5.0 mL), and 35 wt% hydrochloric acid (0.39 g) were added and mixed. The mixture was then 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' for dehydration, followed by filtration, removal of the organic solvent by vacuum distillation, and purification by silica gel column chromatography to obtain compound 1'. The obtained compound 1' was then... 1 The H-NMR data are shown below.

[0230] 1H-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)

[0231]

[0232] Compound 1' (0.10 g, 81 wt% purity, 0.27 mmol) and 1,4-dioxanone were added to the flask. Alkane (0.32 mL, 1.2 L / mol) was added with 28 wt% NaOH (0.04 g, 1.0 eq.) while stirring. The mixture was stirred at 20–50 °C for 7 hours, and then at 80 °C for 6 hours. Then, 28 wt% NaOH (0.24 g, 6.0 eq.) was added during the same stirring process. Water (4.0 mL) and chloroform (4.0 mL) were added and mixed, and the mixture was separated. An aqueous solution of compound 9 was obtained in 80% yield. Compound 2' was not detectable in either the chloroform or aqueous layer.

[0233] [Example 6]

[0234] Synthesis of the hydrochloride of 2-amino-2-methyl-N-(2,2,2-trifluoroethyl)propanamide (compound 8)

[0235]

[0236] 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.) were added to a flask and stirred at 40–50 °C for 4.5 hours. Then, toluene (30.1 mL) and water (13.1 mL) were added and mixed, followed by separation. An aqueous solution of the hydrochloride salt of compound 8 was obtained in 97% yield.

[0237] [Example 7]

[0238] Synthesis of 2-amino-2-methyl-N-(2,2,2-trifluoroethyl)propionamide (compound 8)

[0239] To an aqueous solution (7.37 g, 5.90 wt%, 2.36 mmol) of the hydrochloride salt of compound 8 obtained in Example 6, chloroform (5.0 mL) was added and the mixture was stirred. 28 wt% NaOH (1.75 g, 5.2 eq.) was added to neutralize to pH 11.3, and the mixture was separated. The aqueous layer was extracted twice with chloroform (3.0 mL), and the extraction was repeated. The organic layers were combined to obtain a chloroform solution of compound 8 with a partition rate of 98%. The chloroform was removed by vacuum distillation to obtain compound 8.

[0240] The obtained compound 8 1 H-NMR data and 13 The C-NMR data are shown below.

[0241] 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)

[0242] 13 C-NMR (CDCl3 / TMS, δ (ppm)) 178.04, 128.39-120.08 (q), 54.99, 41.18-40.15 (q), 29.08

[0243] Industrial availability

[0244] A new method for manufacturing N-BOC amino acid amide compounds can be provided.

Claims

1. A method for manufacturing a compound represented by formula (2), comprising hydrolyzing the compound represented by formula (1), ， In equation (1), R 1 and R 2 Each of the following is 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 ynyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-6 heteroaryl group, R 1 and R 2 They can form substituted or unsubstituted C2-5 alkylene groups together. R 3 The substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 ynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 heteroaryl, ， In equation (2), R 1 R 2 and R 3 R in equation (1) 1 R 2 and R 3 same.

2. The manufacturing method according to claim 1, wherein, Further, it includes chemically reacting the compound represented by formula (4) with the compound represented by formula (3) to obtain the compound represented by formula (1). ， In equation (3), R 1 R 2 and R 3 R in equation (1) 1 R 2 and R 3 same, ， In formula (4), Z is a tert-butoxycarbonyloxy group, a halogen group, or a 1H-imidazol-1-yl group.

3. The manufacturing method according to claim 1, wherein, Further, it includes: reacting phosgene, diphosgene, or triphosgene with a compound represented by formula (3) to obtain a compound represented by formula (5). The compound represented by formula (5) is obtained by chemically reacting an alkali metal tert-butoxide with it. ， In equation (3), R 1 R 2 and R 3 R in equation (1) 1 R 2 and R 3 same, ， In equation (5), R 1 R 2 and R 3 R in equation (1) 1 R 2 and R 3 same.

4. The manufacturing method according to claim 2 or 3, wherein, Further, it includes chemically reacting the compound represented by formula (7) with the compound represented by formula (6) to obtain the compound represented by formula (3). ， In equation (6), R 1 and R 2 R in equation (1) 1 and R 2 same, ， In equation (7), R 3 R in equation (1) 3 Same, R a It can be methyl, trifluoromethyl, phenyl, or tolyl.

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