Amine hydrochloride with maleimide group and preparation method thereof

Abstract

The invention relates to amine hydrochloride containing maleimide group and a small amount of hydrogen chloride adduct and a preparation method thereof. An amine protection body having a maleimide group represented by formula (2) is deprotected with trifluoroacetic acid to obtain an amine trifluoroacetate salt having a maleimide group represented by formula (3) (step (a)). And mixing the amine trifluoroacetate salt with an organic solvent solution of hydrogen chloride to perform salt exchange to obtain an amine hydrochloride having a maleimide group represented by formula (1) (step (b)). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to an amine hydrochloride having a maleimide group and a preparation method thereof. Background Art

[0002] Generally, maleimide groups are known to have high reactivity and, in particular, to readily react with thiols or conjugated dienes. Therefore, maleimide compounds are used as coupling agents with these compounds and are widely used as raw materials for resins, agricultural chemicals, and pharmaceutical products.

[0003] For example, when a maleimide group is introduced into an electron-withdrawing group such as a carboxylic acid or sulfonic acid, a compound having a maleimide group and an amine can be used as a candidate coupling agent. Amines readily react with maleimide groups, leading to intramolecular or intermolecular reactions. Therefore, for example, the technique described in Non-Patent Document 1 is believed to be a technique for stabilizing a compound having a maleimide group and an amine by converting the amine into an amine salt using an acid.

[0004] In Non-Patent Document 1, a maleimide group is used as a peptide introduction site in the synthesis of cholesterol-polyethylene glycol-peptide. As a method for introducing a maleimide group, cholesterol-polyethylene glycol is reacted with amine trifluoroacetate having a maleimide group.

[0005] By reacting (tert-butoxycarbonyl)-ethylenediamine with 3-maleimidopropionic acid in the presence of EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) hydrochloride, and then deprotecting the tert-butoxycarbonyl group with trifluoroacetic acid, a maleimide-containing amine trifluoroacetate is obtained. After cholesterol-polyethylene glycol is converted to a carboxylic acid chloride, the carboxylic acid chloride is reacted with the maleimide-containing amine trifluoroacetate in the presence of a base to introduce a maleimide group into the cholesterol-polyethylene glycol.

[0006] As described above, amine trifluoroacetates having a maleimide group can be used to react with compounds having strong electron-withdrawing properties, such as carboxylic acid chlorides, at the terminal of the target compound. However, when reacting with a target compound having a carboxyl group at the terminal that has poorer electron-withdrawing properties than trifluoroacetic acid, trifluoroacetic acid also reacts with the amine to cause reaction inhibition, thereby forming trifluoroacetamide.

[0007] Examples of methods for preventing reaction inhibition include the method described in Patent Document 1. In Patent Document 1, a tert-butoxycarbonyl-protected form of an amino group having a maleimide group is deprotected using a 1,4-dioxane solution of hydrogen chloride to obtain an amine hydrochloride having a maleimide group.

[0008] Prior art documents

[0009] Patent Literature

[0010] Patent Document 1: US Pat. No. 8,034,558B

[0011] Non-patent literature

[0012] Non-patent document 1: ACS Omega 2020, 5, pp. 5508–5519 Summary of the Invention

[0013] Problems to be solved by the present invention

[0014] However, when synthesizing amine hydrochloride having a maleimide group by the method of Patent Document 1, a compound in which hydrogen chloride is added to the maleimide group (hereinafter referred to as "hydrogen chloride adduct") is by-produced, resulting in a decrease in the purity of the amine hydrochloride having a maleimide group.

[0015] Therefore, there is a demand for a high-purity amine hydrochloride having a maleimide group with a small amount of hydrogen chloride adduct and a method for producing the same.

[0016] The present invention has been made in view of the above-mentioned objects, and an object thereof is to provide an amine hydrochloride having a maleimide group having a small amount of hydrogen chloride adduct and a method for producing the same.

[0017] Solutions to the Problem

[0018] Thus, the present invention is as follows.

[0019] [1] A method for preparing an amine hydrochloride having a maleimide group represented by formula (1), the method comprising:

[0020] Step (a), deprotecting the protected amine having a maleimide group represented by formula (2) with trifluoroacetic acid to obtain the amine trifluoroacetate having a maleimide group represented by formula (3); and

[0021] Step (b), mixing the amine trifluoroacetate obtained in step (a) with an organic solvent solution of hydrogen chloride to perform salt exchange, thereby obtaining an amine hydrochloride having a maleimide group represented by formula (1),

[0022] [Chemical Formula 1]

[0023]

[0024] (In formula (1), L represents a linking group connecting the maleimide group and the amino group)

[0025] [Chemical Formula 2]

[0026]

[0027] (In formula (2), L represents a linking group connecting the maleimide group and the protected amino group, and R represents a protecting group for the amino group)

[0028] [Chemical Formula 3]

[0029]

[0030] (In formula (3), L represents a linking group connecting the maleimide group and the amino group).

[0031] [2] The method for preparing an amine hydrochloride having a maleimide group according to [1], wherein

[0032] The protecting group R has a structure of formula (4), (5), (6), (7), (8) or (9),

[0033] [Chemical Formula 4]

[0034]

[0035] [Chemical Formula 5]

[0036]

[0037] [Chemical Formula 6]

[0038]

[0039] [Chemical Formula 7]

[0040]

[0041] [Chemical Formula 8]

[0042]

[0043] [Chemical Formula 9]

[0044]

[0045] [3] The method for preparing an amine hydrochloride having a maleimide group according to [2], wherein

[0046] The linking group L has a structure of formula (10),

[0047] [Chemical Formula 10]

[0048] -X1-Y-X2- …(10).

[0049] (In formula (10), X1 and X2 are each independently a divalent hydrocarbon group, and Y represents an amide

[0050] [4] The method for preparing an amine hydrochloride having a maleimide group according to [3], wherein X1 and X2 are hydrocarbon groups having 2 to 10 carbon atoms.

[0051] [5] The method for producing an amine hydrochloride having a maleimide group according to any one of [1] to [4], wherein

[0052] The organic solvent solution of hydrogen chloride used in the step (b) has an equivalent weight relative to the amino group of the amine-trifluoroacetate of 1.5 equivalents or more and 12 equivalents or less.

[0053] [6] An amine hydrochloride having a maleimide group represented by formula (1), comprising:

[0054] A hydrogen chloride adduct of an amine hydrochloride represented by formula (11), wherein

[0055] The content of the hydrogen chloride adduct is 0.001 mass % or more and 2.5 mass % or less,

[0056] [Chemical Formula 11]

[0057]

[0058] [Chemical Formula 12]

[0059]

[0060] (In formula (1) and formula (11), L represents a linking group connecting the maleimide group and the amino group).

[0061] Effects of the Invention

[0062] Since step (b) of salt exchange using an organic solvent solution of hydrogen chloride can be easily performed in the preparation method of the present invention, a high-purity maleimide-containing amine hydrochloride can be obtained without complicated treatments such as ion exchange chromatography or column chromatography. That is, according to the present invention, a high-purity maleimide-containing amine hydrochloride, which is difficult to obtain using conventional techniques, can be easily obtained using two steps including deprotection and salt exchange. DETAILED DESCRIPTION

[0063] The present invention is an amine hydrochloride having a maleimide group represented by formula (1), which comprises a hydrogen chloride adduct of an amine hydrochloride represented by formula (11), wherein the content of the hydrogen chloride adduct is 0.001 mass % or more and 2.5 mass % or less.

[0064] [Chemical Formula 13]

[0065]

[0066] [Chemical Formula 14]

[0067]

[0068] Here, in formula (1) and formula (11), L represents a linker connecting the maleimide group and the amino group. The structure of the linker L may be a linear structure, a branched structure, or a cyclic structure.

[0069] In a preferred embodiment, the linking group L may contain a hydrocarbon group or may have an amide bond. The hydrocarbon group may not have an unsaturated bond or may have an unsaturated bond, and the number of unsaturated bonds is preferably two or less, and more preferably one or less. The linking group L is preferably a substituent having a linear structure, branched structure or cyclic structure containing a hydrocarbon group and an amide bond. The number of carbon atoms of the hydrocarbon group is preferably 2 to 20, and more preferably 4 to 16.

[0070] In a particularly preferred embodiment, the linking group L has the structure of formula (10).

[0071] [Chemical Formula 15]

[0072] -X1-Y-X2- …(10)

[0073] Here, in formula (10), X1 and X2 are each independently a divalent hydrocarbon group, and Y represents an amide bond.

[0074] Each hydrocarbon group constituting X1 and X2 may have a linear structure, a branched structure, or a cyclic structure. Each hydrocarbon group may or may not have an unsaturated bond, and the number of unsaturated bonds is preferably two or less, and more preferably one or less. The number of carbon atoms in each hydrocarbon group is preferably 2 to 10.

[0075] The hydrogen chloride adduct of formula (11) is an impurity produced in the step of salt-exchanging the amine hydrochloride having a maleimide group represented by formula (1). The content of the hydrogen chloride adduct in the amine hydrochloride having a maleimide group of the present invention is 0.001 mass % or more and 2.5 mass % or less. The content of the hydrogen chloride adduct in the amine hydrochloride having a maleimide group is preferably 1.0 mass % or less, and more preferably 0.5 mass % or less. In addition, since the hydrogen chloride adduct is produced as a by-product as long as a hydrogen chloride source is present during the salt-exchange process, from the perspective of actual production, the content is 0.001 mass % or more, but is often 0.01 mass % or more.

[0076] (Protected amine having a maleimide group represented by formula (2))

[0077] The protected amine having a maleimide group used as a raw material in the present invention has a structure represented by formula (2).

[0078] [Chemical Formula 16]

[0079]

[0080] Here, L represents a linking group linking the maleimide group and the protected amino group, and R represents a protecting group for the amino group.

[0081] R shown in formula (2) is an amino protecting group that can be deprotected with trifluoroacetic acid, and is preferably a protecting group of formula (4) to formula (9). Among these protecting groups, the protecting group of formula (4) produces only volatile isobutylene and carbon dioxide as by-products during deprotection, and post-processing is also simple, and therefore the protecting group of formula (4) is most preferred.

[0082] [Chemical Formula 17]

[0083]

[0084] [Chemical Formula 18]

[0085]

[0086] [Chemical Formula 19]

[0087]

[0088] [Chemical Formula 20]

[0089]

[0090] [Chemical Formula 21]

[0091]

[0092] [Chemical Formula 22]

[0093]

[0094] As the amine protected body having a maleimide group represented by formula (2), for example, an amine protected body having a structure represented by formula (12), formula (13) or formula (14) is particularly preferred. The amine protected body represented by formula (12) can be prepared by reacting N-(tert-butoxycarbonyl)-1,2-diaminoethane with N-succinimidylmaleimide propionate. The amine protected body represented by formula (13) can be prepared by reacting N-(tert-butoxycarbonyl)-5-methyl-1,5-diaminoethane with N-succinimidylmaleimide butyrate. The amine protected body represented by formula (14) can be prepared by reacting N-(tert-butoxycarbonyl)-1,2-diaminoethane with N-succinimidyl-4-(N-maleimidomethyl)cyclohexanecarboxylate.

[0095] [Chemical Formula 23]

[0096]

[0097] [Chemical Formula 24]

[0098]

[0099] [Chemical Formula 25]

[0100]

[0101] [Method for preparing amine hydrochloride having a maleimide group represented by formula (1)]

[0102] (Step (a))

[0103] In step (a), the protected amine having a maleimide group represented by formula (2) is deprotected with trifluoroacetic acid to obtain trifluoroacetic acid salt of the amine having a maleimide group represented by formula (3).

[0104] As a deprotection method, a system using trifluoroacetic acid as an organic acid or a system using hydrochloric acid as an inorganic acid is known. Here, since hydrogen chloride contained in hydrochloric acid has a high nucleophilicity of chloride ions and easily undergoes an addition reaction with a maleimide group, the content of the hydrogen chloride adduct represented by formula (11) increases. Therefore, hydrogen chloride is not a preferred acid for deprotecting amine protected bodies having a maleimide group.

[0105] Therefore, in the present invention, trifluoroacetic acid is used for the deprotection of amine protected bodies having a maleimide group. This is because the nucleophilicity of the trifluoroacetic acid anion is lower than that of the chloride ion, and therefore it is difficult to undergo an addition reaction with the maleimide group, and thus the purity of the target product is increased.

[0106] After the deprotection step (a), there is a concern that an amine may be added to the maleimide group, so it is necessary to form an amine salt under acidic conditions. That is, after the deprotection step (a), purification by a step of removing the amine counter ion, such as column chromatography, is not preferred.

[0107] In the deprotection reaction of step (a), the ratio of trifluoroacetic acid to the amine protected body having a maleimide group is preferably 2 to 5 times by weight, and more preferably 2.2 to 3 times by weight.

[0108] The reaction temperature of the deprotection reaction in step (a) is preferably 15°C to 40°C, and more preferably 20°C to 35°C.

[0109] The solvent used for the deprotection reaction in step (a) is preferably a halogen-based solvent such as dichloromethane or chloroform, or an ether-based solvent such as cyclopentyl methyl ether.

[0110] In the deprotection of step (a), the trifluoroacetate salt of the amine having a maleimido group can be crystallized.

[0111] (Step (b))

[0112] In step (b), the amine trifluoroacetate obtained in step (a) is mixed with an organic solvent solution of hydrogen chloride to perform salt exchange, thereby obtaining an amine hydrochloride having a maleimide group represented by formula (1). The organic solvent solution of hydrogen chloride used in step (b) uses a carboxylic acid ester, alcohol or alkyl ether, in which hydrogen chloride gas is soluble and which is liquid under the temperature conditions of step (b). Examples of carboxylic acid esters, alcohols and alkyl ethers include the following organic solvents.

[0113] Carboxylates:

[0114] The number of carbon atoms of the alkyl group of the carboxylic acid-derived structure is preferably 1 to 2. The number of carbon atoms of the alkyl group of the alcohol-derived structure is preferably 1 to 4, and more preferably 2 to 3.

[0115] alcohol:

[0116] The alcohol is a primary alcohol or a secondary alcohol, and the number of carbon atoms of the alkyl group is preferably 1 to 3, and more preferably 2 to 3.

[0117] Alkyl ether:

[0118] Preferred are alkyl ethers, alkyl and cycloalkyl ethers, or cyclic ethers. The alkyl group preferably has 1 to 4 carbon atoms. The cycloalkyl group preferably has 5 to 6 carbon atoms. The cyclic ether preferably has 1 to 2 ether bonds and 4 to 5 carbon atoms.

[0119] The organic solvent of the organic solvent solution of hydrogen chloride used in step (b) is preferably ethyl acetate, ethanol, isopropanol, 1,4-dioxane or cyclopentyl methyl ether, and most preferably ethyl acetate or 1,4-dioxane.

[0120] When an aqueous hydrochloric acid solution is used as a hydrogen chloride source in the salt exchange in step (b), it is difficult to separate the maleimide-containing amine hydrochloride as crystals from the aqueous solution due to its high water solubility. Even if separation is possible, the amount of impurities such as by-products such as hydrogen chloride adducts increases due to the large number of steps and the long exposure time to the hydrogen chloride source.

[0121] Because hydrogen chloride can be added to maleimide group, so the addition of the organic solvent solution of hydrogen chloride in the salt exchange in step (b) is preferably reduced as much as possible.On the other hand, when the addition of the organic solvent solution of hydrogen chloride is too small, it is difficult to fully carry out the salt exchange from trifluoroacetic acid to hydrogen chloride.From such a viewpoint, relative to the amino group of target compound (amine-trifluoroacetate with maleimide group), the addition of the organic solvent solution of hydrogen chloride is preferably more than 1.5 equivalents and less than 12 equivalents, more preferably more than 1.5 equivalents and less than 8.2 equivalents, and particularly preferably more than 2.0 equivalents and less than 4.0 equivalents. The mass molar concentration of hydrogen chloride in the reaction solution is preferably more than 0.011mol / kg and less than 3.2mol / kg, more preferably more than 0.011mol / kg and less than 2.19mol / kg, and particularly preferably more than 0.14mol / kg and less than 1.1mol / kg.

[0122] From the viewpoint of reducing the amount of by-produced hydrogen chloride adduct, the temperature of the salt exchange in step (b) is preferably -100°C or higher and 40°C or lower, more preferably -10°C or higher and 20°C or lower, and most preferably 0°C or higher and 10°C or lower.

[0123] After step (b), the maleimide-containing amine hydrochloride is recovered from the solution by a step including any one of concentration, crystallization, drying, etc. Since the solubility of the maleimide-containing amine hydrochloride in an organic solvent is always low, when crystals precipitate during the salt exchange process, the crystals can be recovered by filtration, etc. In this way, a high-purity maleimide-containing amine hydrochloride can be obtained without the need for complicated treatments such as ion exchange chromatography or column chromatography.

[0124] Example

[0125] [Step of preparing a protected amine having a maleimide group (compound (A))]

[0126] N-(tert-Butoxycarbonyl)-1,2-diaminoethane (manufactured by Tokyo Chemical Industry Co., Ltd.) and N-succinimidyl-3-maleimidopropionate (manufactured by Tokyo Chemical Industry Co., Ltd.) were reacted in acetonitrile for 2 hours. The crystals obtained by subjecting the obtained reaction solution to desolvation were washed with a solvent or purified by column chromatography to obtain an amine-protected body having a maleimide group (Compound (A)).

[0127] <Example 1>

[0128] (Step (a))

[0129] Trifluoroacetic acid (manufactured by Kanto Chemical Co., Inc., 2.0 g) was added to a dichloromethane (manufactured by Kanto Chemical Co., Inc., 5.0 g) solution of an amine protected body having a maleimide group (compound (A), 1.0 g, purity: 100% by mass), and the mixture was stirred at 25° C. for 3 hours under nitrogen. After stirring, the residual amount of the amine protected body having a maleimide group was confirmed to be 5% by mass or less by thin layer chromatography (hereinafter referred to as “TLC”). The obtained reaction solution was added dropwise to dichloromethane (300 g) cooled to 5° C. for crystallization, and the amine trifluoroacetate crystals (compound (B)) were recovered by filtration.

[0130] (Step (b))

[0131] Ethyl acetate (manufactured by Kanto Chemical Co., Inc., 451 mg) was added to the obtained crystals (50 mg) of compound (B), and a 4M ethyl acetate solution of hydrogen chloride (manufactured by FUJIFILM Wako Pure Chemical Corporation, 341 mg) was added at 25° C., and the mixture was stirred for 30 minutes. Here, the equivalent of the ethyl acetate solution of hydrogen chloride was set to 8.2 equivalents relative to the amino group of the amine protected body having a maleimide group. The precipitated crystals were separated by filtration and washed with ethyl acetate (manufactured by Kanto Chemical Co., Inc.) to obtain white crystals of amine hydrochloride having a maleimide group (compound (C)).

[0132] The purity of the amine hydrochloride having a maleimide group (compound (C)) obtained as described above was 98.5% by mass, and the content of the hydrogen chloride adduct (compound (D)) was 1.3% by mass.

[0133] [Method for analyzing amine hydrochloride and hydrogen chloride adduct having a maleimide group]

[0134] The purity of the maleimide-containing amine hydrochloride and the content of the hydrogen chloride adduct were evaluated by high performance liquid chromatography with a charged aerosol detector (HPLC-CAD). The content of the hydrogen chloride adduct can also be confirmed by nuclear magnetic resonance spectroscopy (NMR).

[0135] <Example 2>

[0136] (Step (a))

[0137] Trifluoroacetic acid (200 mg) was added to a protected amine having a maleimide group (compound (A), 100 mg, purity: 88.7% by mass) in dichloromethane (200 mg), and the mixture was stirred at 25° C. for 3 hours under nitrogen. The amine trifluoroacetate (compound (B)) thus obtained was confirmed by TLC to contain 5% by mass or less of the protected amine having a maleimide group.

[0138] (Step (b))

[0139] Ethyl acetate (75.0g) is added to the reaction solution obtained in step (a) and cooled to 10 ° C, 4M hydrogen chloride in 1,4-dioxane solution (manufactured by Tokyo Chemical Industry Co., Ltd., 229mg) is added, and the mixture is stirred for 30 minutes. Here, the equivalent of 1,4-dioxane solution of hydrogen chloride is set to 3.0 equivalents relative to the amino group of the amine protective body with maleimide group. The precipitated crystals are separated by filtration and washed with ethyl acetate (4.8g) to obtain white crystals (compound (C)) of amine hydrochloride with maleimide group.

[0140] The purity of the amine hydrochloride having a maleimide group (compound (C)) obtained as described above was 94.8% by mass, and the content of the hydrogen chloride adduct (compound (D)) was 2.5% by mass.

[0141] <Example 3>

[0142] Trifluoroacetic acid (4.0 g) was added to a maleimide-protected amine compound (Compound (A), 2.0 g, purity: 100% by mass) in dichloromethane (10 g), and the mixture was stirred at 25° C. for 3 hours under nitrogen. The amine trifluoroacetate (Compound (B)) thus obtained was confirmed by TLC to contain 5% or less of the maleimide-protected amine compound. The resulting reaction solution was added dropwise to dichloromethane (600 g) cooled to 5° C. to crystallize the amine trifluoroacetate (Compound (B)), and Compound (B) was recovered by filtration.

[0143] (Step (b))

[0144] Ethyl acetate (59 g) was added to the obtained compound (B) (1.3 g) and cooled to 10° C., and a 4M hydrogen chloride ethyl acetate solution (8.2 g) was added, and the mixture was stirred for 30 minutes. Here, the equivalent of the hydrogen chloride ethyl acetate solution was set to 8.2 equivalents relative to the amino group of the amine protected body having a maleimide group. The precipitated crystals were recovered by filtration and subsequently washed with ethyl acetate (58 g) to obtain white crystals of amine hydrochloride having a maleimide group (compound (C)).

[0145] The purity of the amine hydrochloride having a maleimide group (compound (C)) obtained as described above was 99.8%, and the content of the hydrogen chloride adduct (compound (D)) was 0.2% by mass.

[0146] <Example 4>

[0147] (Step (a))

[0148] Trifluoroacetic acid (1.2 g) was added to a protected amine having a maleimide group (Compound (A), 600 mg, purity: 99.9% by mass) in dichloromethane (1.2 g), and the mixture was stirred at 25° C. for 3 hours under nitrogen. The amine trifluoroacetate (Compound (B)) thus obtained was confirmed by TLC to contain 5% by mass or less of the protected amine having a maleimide group.

[0149] (Step (b))

[0150] Ethyl acetate (9.0 g) was added to the reaction solution obtained in step (a) and cooled to 10 ° C., 4 M hydrogen chloride in ethyl acetate (371 mg) was added, and the mixture was stirred for 30 minutes. Here, the equivalent of hydrogen chloride in ethyl acetate was set to 2.5 equivalents relative to the amino group of the amine protective body (compound (A)) with maleimide group. The precipitated crystals were recovered by filtration and then washed three times with ethyl acetate (2.2 g) to obtain white crystals (compound (C)) of amine hydrochloride with maleimide group.

[0151] The purity of the amine hydrochloride having a maleimide group (compound (C)) obtained as described above was 97.4% by mass, and the content of the hydrogen chloride adduct (compound (D)) was 0.001% by mass.

[0152] The structures of compounds (A), (B), (C) and (D) are as follows.

[0153] [Chemical Formula 26]

[0154]

[0155] <Comparative Example 1>

[0156] A 6N aqueous hydrochloric acid solution (manufactured by Kanto Chemical Co., Inc., 585 mg, 5.9 times by weight (10 equivalents) per compound (A)) was added to a maleimide-protected amine compound (compound (A), 100 mg, purity: 88.7% by mass) in dichloromethane (200 mg), and the mixture was stirred at 25°C under nitrogen for 3 hours. TLC confirmed that the residual amount of the maleimide-protected amine compound was 5% by mass or less. After distilling off water, ethyl acetate (4.8 g) was added, and the precipitated sticky solid was separated by filtration to obtain an amine hydrochloride (compound (C)) having a maleimide group.

[0157] The purity of the amine hydrochloride having a maleimide group (compound (C)) obtained as described above was 91.9% by mass, and the content of the hydrogen chloride adduct (compound (D)) was 3.1% by mass.

[0158] <Comparative Example 2>

[0159] A 4M hydrogen chloride 1,4-dioxane solution (manufactured by Tokyo Chemical Industry Co., Ltd., 313 mg) was added to an amine-protected body having a maleimide group (compound (A), 50 mg, purity: 100% by mass) in isopropyl alcohol (manufactured by Kanto Chemical Co., Inc., 1.0 g), and the mixture was stirred at 25° C. for 3 hours under nitrogen. Here, the equivalent of the hydrogen chloride 1,4-dioxane solution was set to 8.2 equivalents relative to the amino group of the amine-protected body having a maleimide group (compound (A)). The residual amount of the amine-protected body having a maleimide group was confirmed to be 40% by mass by TLC.

[0160] <Comparative Example 3>

[0161] 4M hydrogen chloride in 1,4-dioxane solution (manufactured by Tokyo Chemical Industry Co., Ltd., 7.7g) was added to an amine protected body with a maleimide group (compound (A), 500mg, purity: 88.7% by mass) in isopropanol (5.0g), and the mixture was stirred at 25 ° C for 3 hours under nitrogen. The equivalent of the 1,4-dioxane solution of hydrogen chloride was set to 20 equivalents relative to the amino group of the amine protected body (compound (A)) with a maleimide group. It was confirmed by TLC that the residual amount of the amine protected body with a maleimide group was less than 5% by mass. The mixture was diluted with isopropanol (25.0g), hexane (25.5g) was added, and the precipitated crystals were separated by filtration to obtain an amine hydrochloride (compound (C)) with a maleimide group.

[0162] The purity of the amine hydrochloride having a maleimide group (compound (C)) obtained as described above was 83.3% by mass, and the content of the hydrogen chloride adduct (compound (D)) was 16.7% by mass.

[0163] <Comparative Example 4>

[0164] Trifluoroacetic acid (200 mg) was added to a protected amine having a maleimide group (Compound (A), 100 mg, purity: 88.7% by mass) in dichloromethane (200 mg), and the mixture was stirred at 25° C. for 3 hours under nitrogen. TLC confirmed that the residual amount of the protected amine having a maleimide group was 5% by mass or less.

[0165] Dichloromethane (1.5 g) was added, and further 6N aqueous hydrochloric acid solution (535 mg, 10 equivalents per compound (A)) was added, and the mixture was stirred for 30 minutes. The solution was concentrated, ethyl acetate was added, and the precipitated sticky solid was separated by filtration to obtain an amine hydrochloride having a maleimide group (compound (C)).

[0166] The purity of the amine hydrochloride having a maleimide group (compound (C)) obtained as described above was 91.7% by mass, and the content of the hydrogen chloride adduct (compound (D)) was 3.0% by mass.

[0167] The results of Examples 1 to 4 and Comparative Examples 1 to 4 are shown in Tables 1 and 2.

[0168] [Table 1]

[0169]

[0170] [Table 2]

[0171]

[0172] * Since deprotection did not proceed sufficiently and 40% by mass of the amine-protected form having a maleimide group (compound (A)) remained, measurement was not performed.

[0173] As shown in Table 1, in Examples 1 and 2, after deprotection with trifluoroacetic acid, salt exchange was performed using an organic solvent solution of hydrogen chloride. As a result, the amount of hydrogen chloride adduct was reduced to 2.5% by mass or less.

[0174] Compared with Example 1, in Example 3, the reaction temperature of the salt exchange was lowered, but the amount of the by-produced hydrogen chloride adduct was further significantly reduced.

[0175] Compared with Example 1, in Example 4, the reaction temperature of the salt exchange was lowered, and the equivalent of the organic solvent solution of hydrochloric acid was also reduced, but the amount of the by-produced hydrogen chloride adduct was further significantly reduced.

[0176] On the other hand, in Comparative Examples 1 and 3, the amount of by-produced hydrogen chloride adduct increased, and the purity of the amine hydrochloride having a maleimide group decreased, compared to Examples 1 to 4. In Comparative Example 2, deprotection did not progress sufficiently. Therefore, it was found that the use of trifluoroacetic acid as a deprotecting agent is superior to the use of an organic solvent solution of hydrogen chloride or hydrochloric acid.

[0177] Furthermore, in Comparative Example 4, the amount of by-produced hydrogen chloride adduct increased, and the purity of the maleimide-containing amine hydrochloride decreased, compared to Examples 1 to 4. Furthermore, the obtained solid was viscous. Therefore, it was found that using an organic solvent solution of hydrogen chloride is superior to using hydrochloric acid in order to reduce the amount of by-produced hydrogen chloride adduct while performing salt exchange.

[0178] Industrial Applicability

[0179] The preparation method of the present invention can be used as a method for preparing amine hydrochloride having a maleimide group, which requires a high-purity product. The amine hydrochloride having a maleimide group prepared by the preparation method of the present invention can be used as a raw material for resins, agricultural chemicals, pharmaceuticals, etc.

[0180] While the present invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes or modifications can be made to the present invention without departing from the spirit and scope of the invention.

[0181] This application is based on the Japanese patent application (Japanese Patent Application No. 2023-016157) filed on February 6, 2023, the contents of which are incorporated herein by reference.

Claims

1. A method for preparing an amine hydrochloride having a maleimide group represented by formula (1), the method comprising: Step (a), deprotecting the amine protected form having a maleimide group represented by formula (2) with trifluoroacetic acid to obtain the amine trifluoroacetate having a maleimide group represented by formula (3); as well as Step (b), mixing the amine trifluoroacetate obtained in step (a) with an organic solvent solution of hydrogen chloride to perform salt exchange, thereby obtaining the amine hydrochloride having a maleimide group represented by formula (1), [Chemical Formula 1] In formula (1), L represents a linking group connecting the maleimide group and the amino group, [Chemical Formula 2] In formula (2), L represents a linking group connecting the maleimide group and the protected amino group, and R represents a protecting group for the amino group, [Chemical Formula 3] In formula (3), L represents a linking group that links the maleimide group and the amino group.

2. The method for preparing an amine hydrochloride having a maleimide group according to claim 1, wherein The protecting group R in formula (2) has a structure of formula (4), (5), (6), (7), (8) or (9), [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] [Chemical Formula 7] [Chemical Formula 8] [Chemical Formula 9] 3. The method for preparing an amine hydrochloride having a maleimide group according to claim 2, wherein The linking group L has a structure of formula (10), [Chemical Formula 10] -X1-Y-X2-…(10) In formula (10), X1 and X2 are each independently a divalent hydrocarbon group, and Y represents an amide bond.

4. The method for preparing an amine hydrochloride having a maleimide group according to claim 3, wherein X1 and X2 are hydrocarbon groups having 2 to 10 carbon atoms.

5. The method for preparing an amine hydrochloride having a maleimide group according to any one of claims 1 to 4, wherein The organic solvent solution of hydrogen chloride used in the step (b) has an equivalent weight relative to the amino group of the amine-trifluoroacetate of 1.5 equivalents or more and 12 equivalents or less.

6. An amine hydrochloride having a maleimide group represented by formula (1), comprising: A hydrogen chloride adduct of an amine hydrochloride represented by formula (11), wherein The content of the hydrogen chloride adduct is 0.001 mass % or more and 2.5 mass % or less, [Chemical Formula 11] [Chemical Formula 12] In formula (1) and formula (11), L represents a linking group that links the maleimide group and the amino group.

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