WO2019160037A1

WO2019160037A1 - Methods for producing compounds using acid halide

Info

Publication number: WO2019160037A1
Application number: PCT/JP2019/005345
Authority: WO
Inventors: 智彦大和田; 陸人大塚; 和夫丸橋
Original assignee: 国立大学法人東京大学
Priority date: 2018-02-14
Filing date: 2019-02-14
Publication date: 2019-08-22
Also published as: JPWO2019160037A1; JP7364841B2

Abstract

The purpose of the present invention is to provide methods for producing a carboxamide compound, a sulfonamide compound, and an ester compound using an acid halide. The methods for producing a carboxamide compound, a sulfonamide compound, and an ester compound each include a step in which an acid halide is reacted with an amine, an amide compound, or an alcohol in the presence of an amide-based solvent and/or a urea-based solvent. The amine can be selected from among aliphatic amines, aromatic amines, and zwitterionic molecules and derivatives thereof. The acid halide can be selected from among carbonyl halides and sulfonyl halides.

Description

Method for producing compound with acid halide

Reference to related applications

This application enjoys the benefit of priority of Japanese Patent Application No. 2018-23935 (filing date: February 14, 2018), which is a prior Japanese application, the entire disclosure of which is incorporated herein by reference. To be part of

The present invention relates to a method for producing a compound using an acid halide, and particularly relates to a method for producing a carboxylic acid amide compound, a sulfonic acid amide compound and an ester compound using an acid halide.

The most common reaction for forming a normal amide bond is a condensation reaction between an acid halide and an amine. In this reaction process, hydrogen halide such as hydrogen chloride is generated, and the hydrogen halide and the raw material amine form a salt. For this reason, the reaction was saturated at about 50%, and the amide compound could not be obtained in high yield.

In order to solve this problem, a technology for neutralizing hydrogen halide by adding a base catalyst to the reaction system has been developed. However, when a base catalyst is added, it is necessary to treat the salt of the base by a post-treatment, which increases the synthesis process and is not practical. In addition, it has been considered that amines having almost no basicity (low nucleophilicity) do not react with acid halides, but development of an amide forming reaction applicable to all amines has been desired.

An object of the present invention is to provide a novel method for producing a carboxylic acid amide compound, a sulfonic acid amide compound and an ester compound using an acid halide.

According to the present invention, the following inventions are provided.
[1] A step of reacting an acid halide with an amine, an amide compound and / or an alcohol in the presence of one or more solvents selected from the group consisting of an amide solvent and a urea solvent. A process for producing a carboxylic acid amide compound, a sulfonic acid amide compound or an ester compound.
[2] The production method according to [1], wherein the amine is one or more selected from the group consisting of aliphatic amines, aromatic amines, zwitterionic molecules and derivatives thereof.
[3] The production method of the above-mentioned [2], wherein the zwitterionic molecule is an amino acid, anthranilic acid, 3-carboxyaniline or 4-carboxyaniline.
[4] The production method according to any one of [1] to [3], wherein the amine is an amine having a pK _{BH +} value of 2 or less.
[5] The production method according to the above [1], wherein the amide compound is a urea compound, carbamic acid, carbamate, thiourea compound, thiocarbamic acid and / or thiocarbamate.
[6] The production method according to the above [1], wherein the alcohol is an aliphatic alcohol or an aromatic alcohol.
[7] The production method according to any one of [1] to [6], wherein the acid halide is a carboxylic acid halide or a sulfonic acid halide.
[8] The production method according to any one of [1] to [6], wherein the acid halide is an amino acid halide or a peptide halide.
[9] The production method according to any one of the above [1] to [8], wherein the acid halide is an acid chloride.
[10] The production method according to any one of [1] to [9] above, wherein the solvent is an amide solvent.
[11] The amide solvent is N, N-dimethylacetamide (DMAC), N, N-diethylacetamide (DEA), N, N-dimethylformamide (DMF), N, N-diethylformamide (DEF), N Any one of the above [1] to [10], which is one or more solvents selected from the group consisting of -methyl-2-pyrrolidone (NMP) and N-ethyl-2-pyrrolidone (NEP) The manufacturing method as described.
[12] The production method according to any one of the above [1] to [9], wherein the solvent is a urea solvent.
[13] The urea solvent is selected from the group consisting of N, N′-dimethylpropyleneurea (DMPU), tetramethylurea (TMU) and 1,3-dimethyl-2-imidazolidinone (DMI) 1 The production method according to any one of [1] to [9] and [12] above, which is a seed or two or more solvents.
[14] The production method according to any one of [1] to [13], wherein the solvent is used as a reaction solvent.
[15] The production method according to any one of the above [1] to [14], further comprising a step of mixing the acid halide and the amine, amide compound and / or alcohol at −15 ° C. to 35 ° C.
[16] The production method of the above-mentioned [15], further comprising a step of stirring the mixture at −15 ° C. to 35 ° C. after the mixing step.
[17] The production method according to any one of the above [1] to [16], wherein the step is carried out in a reaction system substantially free of a base catalyst that captures hydrogen halide generated by the reaction.
[18] The production method according to any one of [1] to [17] above, wherein a carboxylic acid amide compound is produced by reacting a carboxylic acid halide with an amine as the acid halide.
[18-1] The production method according to the above [18], wherein the amine is an aliphatic amine.
[18-2] The production method of the above-mentioned [18], wherein the amine is an aromatic amine.
[18-3] The production method of the above-mentioned [18], wherein the amine is an amino acid.
[18-4] The production method of the above-mentioned [18], wherein the amine is anthranilic acid or an ester thereof.
[18-5] The production method of the above-mentioned [18], wherein the carboxylic acid halide is an amino acid halide or a peptide halide.
[19] The production method according to any one of [1] to [17] above, wherein a carboxylic acid amide compound is produced by reacting a carboxylic acid halide with an amide compound as the acid halide.
[19-1] The production method according to the above [19], wherein the amide compound is a urea compound.
[20] The production method according to any one of the above [1] to [17], wherein a sulfonic acid amide compound is produced by reacting a sulfonic acid halide with an amine as an acid halide.
[21] The production method according to any one of [1] to [17] above, wherein an ester compound is produced by reacting a carboxylic acid halide with an alcohol as the acid halide.
[22] The production method according to any one of the above [1] to [17], wherein an ester compound is produced by reacting a sulfonic acid halide with an alcohol as an acid halide.
[23] The above [1] to [17], wherein the acid halide is an amino acid halide or a peptide halide, the amine is an amino acid or a peptide, and the produced carboxylic acid amide compound is a peptide. The manufacturing method in any one of.
[24] The above, wherein the acid halide is a carboxylic acid halide, the amine is an optically active amino acid, and the produced carboxylic acid amide compound is an optically active carboxylic acid amide compound. [1] The production method according to any one of [18] to [18].
[25] Select one of two or more carboxylic acid amide compounds or sulfonic acid amide compounds by reacting an acid halide with two or more amines and / or amide compounds having different basicities The manufacturing method according to any one of [1] to [19] above, wherein
[26] reacting an acid halide with an amine or an amide compound having two or more amino groups having different basicities to selectively form an amide bond with respect to any one of the amino groups. The production method according to any one of [1] to [20] above, which is characterized in that

In a synthesis reaction using an acid halide, hydrogen halide such as hydrogen chloride is generated by a condensation reaction, which adversely affects the progress of the reaction and has problems such as safety and equipment limitations. Such a problem can be solved without the addition of a base catalyst for capturing hydrogen fluoride. The production method of the present invention is also advantageous in that the amide formation reaction proceeds efficiently even with amines and amide compounds that are weakly basic and have low reactivity.

FIG. 1 is a diagram showing an HPLC chromatogram of a mixture of the product obtained in Example F5 (1) and the product obtained in Example F5 (2) (LD mixed sample). FIG. 2 shows the HPLC chromatogram of the product mixture (L preparation) obtained in Example F5 (1). FIG. 3 shows the HPLC chromatogram of the product mixture (D preparation) obtained in Example F5 (2).

Detailed description of the invention

<Definition>
In the present invention, alkyl as all or part of the group is a linear, branched or cyclic hydrocarbon chain having 1 to 8 carbon atoms (preferably 1 to 6 or 1 to 4 carbon atoms). Which may contain a plurality of double bonds or triple bonds), for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, ethenyl, ethynyl, propenyl and butenyl.

In the present invention, examples of “halogen” and “halogen atom” include chlorine (Cl), bromine (Br), fluorine (F), and iodine (I), with chlorine (Cl) being preferred. For example, when the halogen portion of the acid halide is chlorine, the acid halide is an acid chloride (acid chloride).

In the present invention, “may be substituted” means that one or more hydrogen atoms on a group to be substituted or an atom are substituted with another group.

The “aliphatic hydrocarbon chain” and the groups R ¹ , R ² , R ⁵ , R ⁷ , R constituting “aliphatic amine”, “aliphatic alcohol”, “aliphatic carboxylic acid” and “aliphatic sulfonic acid” ^The number of carbon atoms of the “aliphatic hydrocarbon group” represented by ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹⁴ , R ¹⁵ , R ¹⁸ , R ¹⁹ and R ²⁰ can be 1 to 22, It is preferably 1 to 12, more preferably 1 to 8, still more preferably 1 to 6, 1 to 5, or 1 to 4. The aliphatic hydrocarbon group may be linear, branched or cyclic, and may contain one or more double bonds or triple bonds in the group.

Examples of linear and branched aliphatic hydrocarbon groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, ethynyl, propenyl and butenyl. However, it is not limited to these examples.

A cyclic aliphatic hydrocarbon group means that the group contains at least one cyclic structure, and may be composed of only a cyclic structure. The cyclic structure may be carbocyclic or heterocyclic. The carbocyclic ring structure is a 3- to 10-membered saturated or unsaturated carbocycle (aliphatic carbocycle), which may be monocyclic or bicyclic, for example, cyclopropane , Cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane. The heterocyclic ring structure includes 3 to 10-membered saturated or saturated ring members containing one or more (for example, 1 to 3) different atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. Unsaturated heterocycle (aliphatic heterocycle), which may be monocyclic or bicyclic, such as oxetane, pyrrolidine, piperidine, piperazine, morpholine, indoline, tetrahydrofuran and tetrahydrothiophene Can be mentioned.

The “aromatic ring” and the groups R ³ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ , R constituting the “aromatic amine”, “aromatic alcohol”, “aromatic carboxylic acid” and “aromatic sulfonic acid” ¹⁶ , “aromatic ring group” represented by R ²¹ and R ¹⁰² refers to a ring system compound having aromatic characteristics or a portion thereof, for example, a stable structure including a cyclic conjugated system having 4n + 2 π electrons. Have. The “aromatic ring group” may be an aromatic hydrocarbon group or an aromatic heterocyclic group. An “aromatic hydrocarbon group” is a 6-18 membered (preferably 6-14 membered) unsaturated carbocyclic ring, which may be monocyclic, 2, 3 or 4 cyclic (preferably 2 or 3 (Cyclic) aromatic condensed ring group, and examples thereof include benzene, naphthalene, anthracene, phenanthrene, naphthacene and pyrene. The “aromatic heterocyclic group” includes one or more (for example, 1 to 3 or 1 to 2) hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom as ring member atoms. A 14-membered heterocyclic ring, which may be monocyclic or bicyclic or tricyclic fused aromatic heterocyclic group, such as furan, thiophene, pyrrole, imidazole, pyridine, pyrimidine, quinoline , Isoquinoline, indole and 1,10-phenanthroline.

In the present invention, the hydroxyl group represents —OH, the carboxyl group represents —COOH, the sulfonic acid group represents (—S (═O) ₂ OH), and the carbonyl group represents —CO — (— C (═O) — And the thiocarbonyl group represents —CS — (— C (═S) —).

<Raw material: Amine>
Examples of amines that can be used as a raw material for the production method of the present invention include aliphatic amines, aromatic amines, and zwitterionic molecules.

Aliphatic amine Aliphatic amine means an amine having an aliphatic hydrocarbon chain. In the present invention, the aliphatic amine is represented by, for example, the formula 1: HN (—R ¹ ) (— R ² ) (wherein R ¹ and R ² may be the same or different and are each a hydrogen atom or an aliphatic hydrocarbon. R ¹ and R ² together may form a cyclic aliphatic hydrocarbon group, provided that R ¹ and R ² do not represent a hydrogen atom at the same time) be able to. One of R ¹ and R ² preferably represents a hydrogen atom, and the other represents an aliphatic hydrocarbon group. Examples of the cyclic aliphatic hydrocarbon group formed by R ¹ and R ² together include 1,2,3,4-tetrahydroisoquinoline and pyrrolidine.

The aliphatic hydrocarbon group constituting the aliphatic amine may be substituted with one or a plurality of substituents. Examples of the substituent include a halogen atom, a group —R ¹⁰¹ —R ¹⁰² (where R ¹⁰¹ represents A single bond, —O—, —O— (C═O) —, — (C═O) —O—, —NHCO— or —CONH—, wherein R ¹⁰² represents an aromatic ring group), a hydroxyl group , Alkoxy groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylcarbonyloxy groups, carboxyl groups, sulfonic acid groups, amino groups, nitro groups and cyano groups (hereinafter referred to as substituent A). Of the above substituent A, the amino group may be further substituted with one or more substituents, and examples of the substituent include an alkyl group. Among the above substituents A, the alkoxy group, alkylcarbonyl group, alkoxycarbonyl group, and alkylcarbonyloxy group may be further substituted with one or more substituents. Examples of the substituent include a halogen atom, a hydroxyl group , Alkoxy groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylcarbonyloxy groups, carboxyl groups, sulfonic acid groups, amino groups, nitro groups, and cyano groups. Of the above substituents A, the group —R ¹⁰¹ —R ¹⁰² may be further substituted with one or more substituents. Examples of the substituent include a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an alkyl group Examples include carbonyl group, alkoxycarbonyl group, alkylcarbonyloxy group, carboxyl group, sulfonic acid group, amino group, nitro group and cyano group. When the aliphatic amine is substituted with a plurality of substituents, the substituents may be the same or different.

Aromatic amine An aromatic amine means an amine having a structure in which at least one aromatic ring group is directly bonded to the amine. The aromatic amine may be, for example, formula 2: HN (—R ³ ) (— R ⁴ ) (wherein R ³ and R ⁴ may be the same or different and each represents a hydrogen atom or an aromatic ring group, Alternatively, R ³ represents an aromatic ring group, R ⁴ represents an aliphatic hydrocarbon group having 3 to 5 carbon atoms (which may have 1 or 2 double bonds in the group), and R ⁴ The aliphatic hydrocarbon group represented by R ³ together with the aromatic ring group represented by R ³ forms a bicyclic or tricyclic heterocyclic ring, provided that R ³ and R ⁴ do not represent a hydrogen atom at the same time) Can be represented. One of R ³ and R ⁴ preferably represents a hydrogen atom, and the other represents an aromatic ring group. Examples of the bicyclic or tricyclic heterocyclic compound formed by combining R ³ and R ⁴ include indoline, 1,2,3,4-tetrahydroquinoline and 2,3,4,5-tetrahydrobenzoazepine. Is mentioned.

The aromatic ring group constituting the aromatic amine may be substituted with one or a plurality of substituents. Examples of the substituent include a halogen atom, a group —R ²⁰¹ —R ²⁰² (where R ²⁰¹ represents a single group). A bond, —O—, —O— (C═O) —, — (C═O) —O—, —NHCO— or —CONH—, wherein R ²⁰² represents an aromatic ring group), a hydroxyl group, an alkyl Group, alkoxy group, alkylcarbonyl group, alkoxycarbonyl group, alkylcarbonyloxy group, carboxyl group, sulfonic acid group, amino group, nitro group and cyano group (hereinafter referred to as substituent B). Among the substituents B, the amino group may be further substituted with one or more substituents, and examples of the substituent include an alkyl group. Among the substituents B, the alkyl group, alkoxy group, alkylcarbonyl group, alkoxycarbonyl group, and alkylcarbonyloxy group may be further substituted with one or more substituents. Atoms, hydroxyl groups, alkoxy groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylcarbonyloxy groups, carboxyl groups, sulfonic acid groups, amino groups, nitro groups, and cyano groups can be mentioned. Of the substituents B, the group —R ²⁰¹ —R ²⁰² may be further substituted with one or more substituents. Examples of the substituent include a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an alkyl group Examples include carbonyl group, alkoxycarbonyl group, alkylcarbonyloxy group, carboxyl group, sulfonic acid group, amino group, nitro group and cyano group. The substituent of the aromatic ring group constituting the aromatic amine is preferably the substituent A which may be further substituted. When the aromatic amine is substituted with a plurality of substituents, the substituents may be the same or different.

Zwitterionic molecule Zwitterionic molecule means a molecule having an amino group (basic group) and a carboxyl group (acidic group) in the molecule and having both positive and negative charges, and is synonymous with zwitterionic molecule. The aliphatic amines and aromatic amines include those having an amino group in the molecule. When such a molecule further has a carboxyl group, It can be called a zwitterionic molecule.

In the present invention, a zwitterionic molecule in which a carboxyl group is esterified (that is, an ester of a zwitterionic molecule) or a zwitterionic molecule in which a carboxyl group or an amino group is amidated (that is, a zwitterion). Derivatives of zwitterionic molecules such as molecular amides can also be used as raw materials for the production method of the present invention.

That is, zwitterionic molecules and their esters in the present invention, the formula ^{1: HN (-R 1) (} - R 2) ( wherein, although ^{R 1} and ^{R 2} are as defined above, ^{R 1} and / Or the aliphatic hydrocarbon group represented by R ² is substituted by a substituent containing at least one carboxyl group or alkoxycarbonyl group, which substituent preferably contains at least one carboxyl group or alkoxycarbonyl group Further, the substituent A may be further substituted) and the above formula 2: HN (—R ³ ) (— R ⁴ ) (wherein R ³ and R ⁴ are as defined above, but R ³ And / or the aromatic ring group represented by R ⁴ is substituted with a substituent containing at least one carboxyl group or alkoxycarbonyl group. Preferably, it is the above-mentioned substituent A or substituent B which may further be substituted, including at least one carboxyl group or alkoxycarbonyl group.

A typical example of a zwitterionic molecule is an amino acid. Examples of amino acids in the present invention include α-amino acids (particularly, 20 types of amino acids constituting proteins), but are not limited thereto, and amino acids in which an amino group is bonded to a carbon atom other than the α carbon (for example, , Β-amino acid, γ-amino acid, δ-amino acid, ω-amino acid). In addition, some amino acids have at least one asymmetric carbon atom and have optical activity, and any optically active form (for example, D form and L form) is included in the amino acid. In addition, zwitterionic molecules include not only amino acids but also peptides formed by polymerizing a plurality of amino acids and compounds containing amino acids. Furthermore, amino acid and peptide derivatives (for example, carboxyl groups formed esters). Also included are ester forms and amide forms in which an amino group forms an amide).

Other examples of zwitterionic molecules include, but are not limited to, anthranilic acid, 3-carboxyaniline and 4-carboxyaniline.

Weakly basic amines and neutral amines As shown in the examples described later, in the production method of the present invention, the lower the basicity, the more efficiently the condensation reaction with the acid halide can proceed. The degree of basicity can be determined using the pK _{BH +} value as an index (for example, Tso, W.-W .; Snyder, CH; Powell, HBJ Org. Chem., 1970, 35,849-850, Benedetti, IE; Di Blasio, B .; Baine, PJ Chem. Soc. Perkin 2, 1980, 500-503 and Arnett, EM, Quantitative Comparisons of Weak Organic Bases, Progress in Physical Organic Chemistry, vol. 1, Eds, Cohen, SG; Streitwieser , A .; Taft, RW, p223-403, 1963, Interscience Publishers, New York). That is, examples of the amine having low basicity include amines having a small pK _{BH +} value, for example, amines having a pK _{BH +} value of 2 or less (preferably a pK _{BH +} value of 1 or less), and these include weakly basic amines and neutral amines. Classified as amine. The pK _{BH +} value can be obtained as an experimental value or a calculated value. The calculation of pKBH ₊ values is known, for example, using software such as COSMOtherm (manufactured by COSMOlogic) or Epik (Journal of Computer-Aided Molecular Design, 2007, Volume 21, Issue 12, pp 681-691). can do. Specific examples of amines with low basicity include aromatic amines in which an amino group is directly bonded to an aromatic ring, and aromatic rings are nitro, cyano, halogen atoms, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, sulfonamide, amide, Aromatic amines substituted with electron withdrawing groups such as sulfonyl are mentioned, the latter being less basic amines. Examples of raw materials having low basicity other than amines include amide compounds described later, and according to the production method of the present invention, a condensation reaction with an acid halide can also be efficiently advanced.

<Raw material: Amide compound>
The amide compound that can be used as a raw material for the production method of the present invention is used to include a compound having an amide structure (—NHCO—) and a compound having a thioamide structure (—NHCS—). The amide compound that can be used as a raw material for the production method of the present invention includes a compound having a urea structure (—NHCONH—) (hereinafter referred to as a urea compound), a compound having a thiourea structure (—NHCSNH—) (hereinafter referred to as thiourea). Compound), carbamic acid and carbamate, and thiocarbamic acid and thiocarbamate.

In the present invention, the amide compound is represented by, for example, formula 3: R ⁵ -R ^6- (C = Q) (-NR ⁷ R ⁸ ) (wherein R ⁵ is a hydrogen atom, an aliphatic hydrocarbon group or an aromatic ring group. R ⁶ represents a single bond, —O— or — (N (—R ⁹ )) — (wherein R ⁹ represents a hydrogen atom, an amino group, an aliphatic hydrocarbon group or an aromatic ring group) R ⁷ and R ⁸ may be the same or different and each represents a hydrogen atom or an aliphatic hydrocarbon group, Q represents an oxygen atom or a sulfur atom, provided that when R ⁶ represents a single bond, R ⁵ represents a group other than a hydrogen atom. One of R ⁷ and R ⁸ preferably represents a hydrogen atom, and the other represents a hydrogen atom or an aliphatic hydrocarbon group.

The aliphatic hydrocarbon group and / or the aromatic ring group constituting the amide compound may be substituted with one or a plurality of substituents, and as the substituent, the above-described substituent A and And the substituent of the aliphatic hydrocarbon group is preferably the above-described substituent A which may be further substituted, and the substituent of the aromatic ring group is preferably further substituted. The substituent A or the substituent B. When the amide compound is substituted with a plurality of substituents, the substituents may be the same or different.

In Formula 3, when R ⁶ represents — (N (—R ⁹ )) — and Q represents an oxygen atom, the compound of Formula 3 represents a urea compound, and R ⁵ , R ⁷ , R ^8, and R ⁹ further represent When it represents a hydrogen atom, the compound of formula 3 represents urea, when R ⁵ , R ⁷ and R ⁸ further represent a hydrogen atom, and when R ⁹ further represents an amino group, the compound of formula 3 represents a semicarbazide. In the above case, R ⁷ , R ⁸ and R ⁹ preferably represent a hydrogen atom.

In Formula 3, when R ⁶ represents — (N (—R ⁹ )) — and Q represents a sulfur atom, the compound of Formula 3 represents a thiourea compound, and R ⁵ , R ⁷ , R ^8, and R ⁹ further represent When it represents a hydrogen atom, the compound of formula 3 represents thiourea, R ⁵ , R ⁷ and R ⁸ further represent a hydrogen atom, and when R ⁹ further represents an amino group, the compound of formula 3 represents a thiosemicarbazide. . In the above case, R ⁷ , R ⁸ and R ⁹ preferably represent a hydrogen atom.

In Formula 3, when R ⁶ represents —O— and Q represents an oxygen atom, the compound of Formula 3 represents a carbamate (when R ⁵ is a hydrogen atom) and a carbamate compound (when R ⁵ is other than a hydrogen atom). Represent. In this case, R ⁷ and R ⁸ preferably represent a hydrogen atom.

In Formula 3, when R ⁶ represents —O— and Q represents a sulfur atom, the compound of Formula 3 is a thiocarbamic acid (when R ⁵ is a hydrogen atom) and a thiocarbamate compound (when R ⁵ is other than a hydrogen atom). ). In this case, R ⁷ and R ⁸ preferably represent a hydrogen atom.

When R ⁶ represents a single bond in Formula 3, the compound of Formula 3 represents an amide compound other than a urea compound, a thiourea compound, a carbamic acid, a carbamate compound, a thiocarbamic acid, and a thiocarbamate. In this case, R ⁷ and R ⁸ preferably represent a hydrogen atom.

<Raw material: Alcohol>
Examples of the alcohol that can be used as a raw material for the production method of the present invention include aliphatic alcohols and aromatic alcohols.

An aliphatic alcohol means an alcohol having an aliphatic hydrocarbon chain. In the present invention, the aliphatic alcohol can be represented, for example, by the formula 4: R ¹⁰ —OH (wherein R ¹⁰ represents an aliphatic hydrocarbon group).

The aliphatic hydrocarbon group constituting the aliphatic alcohol may be substituted with one or a plurality of substituents, and examples of the substituent include the substituent A which may be further substituted. When the aliphatic alcohol is substituted with a plurality of substituents, the substituents may be the same or different.

An aromatic alcohol means an alcohol having an aromatic ring. In the present invention, the aromatic alcohol can be represented by, for example, Formula 5: R ¹¹ —OH (wherein R ¹¹ represents an aromatic ring group).

The aromatic ring group constituting the aromatic alcohol may be substituted with one or a plurality of substituents, and examples of the substituent include the substituent A and the substituent B which may be further substituted. Preferably, the substituent B may be further substituted. When the aromatic alcohol is substituted with a plurality of substituents, the substituents may be the same or different.

<Raw material: Acid halide>
Examples of the acid halide that can be used as a raw material for the production method of the present invention include carboxylic acid halides and sulfonic acid halides.

Carboxylic acid halides Carboxylic acid halide carboxylic acids include aliphatic carboxylic acids and aromatic carboxylic acids.

In the present invention, the aliphatic carboxylic acid means a carboxylic acid having an aliphatic hydrocarbon chain as a basic skeleton. The aliphatic carboxylic acid may be, for example, the formula 6: R ¹² —R ¹³ —COOH (wherein R ¹² represents a hydrogen atom or an aliphatic hydrocarbon group, R ¹³ represents a single bond or —NR ¹⁴ —, R ¹⁴ represents a hydrogen atom or an aliphatic hydrocarbon group.

The α-carbon and aliphatic hydrocarbon group of the carboxylic acid may be substituted with one or more substituents, and examples of the substituent include the substituent A which may be further substituted. When the aliphatic carboxylic acid is substituted with a plurality of substituents, the substituents may be the same or different.

In the present invention, the aliphatic carboxylic acid halide includes, for example, formula 7: R ¹² -R ¹³ -COHal (wherein R ¹² represents a hydrogen atom or an aliphatic hydrocarbon group, Hal represents a halogen atom, R ¹³ represents a single bond or —NR ¹⁴ —, and R ¹⁴ represents a hydrogen atom or an aliphatic hydrocarbon group. As described above, the aliphatic carboxylic acid in Formula 7 may be substituted with a substituent.

In the present invention, the halide of an aliphatic carboxylic acid includes a halide of an ester of an aliphatic carboxylic acid. Such a halide can be represented by, for example, the formula 7a: R ¹² —COR ¹⁵ (wherein R ¹² represents a halogen atom or an aliphatic hydrocarbon group substituted by a halogen atom, and R ¹⁵ represents an aliphatic hydrocarbon group. It can be expressed by As described above, the aliphatic carboxylic acid in Formula 7a may be substituted with a substituent.

Aliphatic carboxylic acid halides can be prepared according to known methods, for example, by reacting an aliphatic carboxylic acid or an ester thereof with a halogenating agent such as thionyl chloride or sulfuryl chloride. By carrying out this reaction in the presence of one or more solvents selected from the group consisting of amide solvents and urea solvents, the produced aliphatic carboxylic acid or its ester halide can be isolated. Without delay, the next reaction can proceed as it is (one-pot reaction).

In the present invention, the above zwitterionic molecule halide can be used as the carboxylic acid halide. That is, the zwitterionic molecule has a carboxyl group in addition to an amino group in the molecule, and a molecule in which a hydrogen atom of the carboxyl group is substituted with a halogen atom is a halide of the zwitterionic molecule. Such a zwitterionic halide can be prepared in the same manner as the aliphatic carboxylic halide.

As mentioned above, typical examples of zwitterionic molecules include amino acids. That is, in the present invention, an amino acid halide obtained by halogenating an α-carboxyl group can be used as a carboxylic acid halide. As described above, the zwitterionic molecule includes a peptide obtained by polymerizing a plurality of amino acids. Therefore, in the present invention, a peptide halide obtained by halogenating the C-terminal α-carboxyl group can also be used as the carboxylic acid halide. As described later, a peptide can be synthesized by carrying out the production method of the present invention using an amino acid halide or peptide halide as a carboxylic acid halide and using another amino acid or peptide as an amine.

In the present invention, the aromatic carboxylic acid means a carboxylic acid having an aromatic ring as a basic skeleton. The aromatic carboxylic acid may be, for example, formula 8: R ¹⁶ —R ¹⁷ —COOH (wherein R ¹⁶ represents an aromatic ring group, R ¹⁷ represents a single bond or —NR ¹⁸ —, and R ¹⁸ represents a hydrogen atom or Represents an aliphatic hydrocarbon group).

The aromatic ring group constituting the aromatic carboxylic acid may be substituted with one or more substituents, and examples of the substituent include the substituent A and the substituent B which may be further substituted. The substituent B may be further substituted. When the aromatic carboxylic acid is substituted with a plurality of substituents, the substituents may be the same or different.

In the present invention, the aromatic carboxylic acid halide is represented by, for example, formula 9: R ¹⁶ -R ¹⁷ -COHal (wherein R ¹⁶ represents an aromatic ring group, Hal represents a halogen atom, and R ¹⁷ represents a single bond or —NR ¹⁸ —, wherein R ¹⁸ represents a hydrogen atom or an aliphatic hydrocarbon group. As described above, the aromatic carboxylic acid in Formula 9 may be substituted with a substituent.

In the present invention, the aromatic carboxylic acid halide includes an aromatic carboxylic acid ester halide. Such a halide is, for example, the formula 9a: R ¹⁶ -COR ¹⁹ (wherein R ¹⁶ represents a halogen atom or an aromatic ring group substituted by a halogen atom, and R ¹⁹ represents an aliphatic hydrocarbon group) Can be expressed as As described above, the aromatic carboxylic acid in Formula 9a may be substituted with a substituent.

The halide of aromatic carboxylic acid can be prepared according to a known method. For example, it can be prepared by reacting aromatic carboxylic acid or its ester with a halogenating agent such as thionyl chloride or sulfuryl chloride. By carrying out this reaction in the presence of one or more solvents selected from the group consisting of amide solvents and urea solvents, the produced aromatic carboxylic acid or its ester halide can be isolated. Without delay, the next reaction can proceed as it is (one-pot reaction).

Sulfonic acid halides Examples of sulfonic acid halides include aliphatic sulfonic acids and aromatic sulfonic acids.

In the present invention, the aliphatic sulfonic acid means a sulfonic acid having an aliphatic hydrocarbon chain. The aliphatic sulfonic acid can be represented, for example, by the formula 10: R ²⁰ —S (═O) ₂ OH (wherein R ²⁰ represents an aliphatic hydrocarbon group).

The aliphatic hydrocarbon group constituting the aliphatic sulfonic acid may be substituted with one or a plurality of substituents, and examples of the substituent include the substituent A which may be further substituted. When the aliphatic sulfonic acid is substituted with a plurality of substituents, the substituents may be the same or different.

In the present invention, the halide of the aliphatic sulfonic acid is, for example, the formula 11: R ²⁰ —S (═O) ₂ Hal (wherein R ²⁰ represents an aliphatic hydrocarbon group and Hal represents a halogen atom). Can be represented. As described above, the aliphatic hydrocarbon group in Formula 11 may be substituted with a substituent.

The halide of aliphatic sulfonic acid can be prepared according to a known method, for example, by reacting aliphatic sulfonic acid or a metal salt thereof with a halogenating agent such as thionyl chloride or sulfuryl chloride. By carrying out this reaction in the presence of one or two or more solvents selected from the group consisting of amide solvents and urea solvents, the produced aliphatic sulfonic acid halide is not isolated and is used as it is. The reaction can proceed.

In the present invention, the aromatic sulfonic acid means a sulfonic acid having an aromatic ring. The aromatic sulfonic acid can be represented by, for example, Formula 12: R ²¹ —S (═O) ₂ OH (wherein R ²¹ represents an aromatic ring group).

The aromatic ring group constituting the aromatic sulfonic acid may be substituted with one or a plurality of substituents, and examples of the substituent include the substituent A and the substituent B which may be further substituted. The substituent B may be further substituted. When the aromatic sulfonic acid is substituted with a plurality of substituents, the substituents may be the same or different.

In the present invention, the aromatic sulfonic acid halide is, for example, represented by the formula 13: R ²¹ —S (═O) ₂ Hal (wherein R ²¹ represents an aromatic ring group and Hal represents a halogen atom). Can do. As described above, the aromatic ring group in formula 13 may be substituted with a substituent.

The halide of aromatic sulfonic acid can be prepared according to a known method. For example, it can be prepared by reacting aromatic sulfonic acid or a metal salt thereof with a halogenating agent such as thionyl chloride or sulfuryl chloride. By carrying out this reaction in the presence of one or two or more solvents selected from the group consisting of amide solvents and urea solvents, the produced aromatic sulfonic acid halide is not isolated and is used as follows. The reaction can proceed.

<Manufacturing method>
Solvent In the production method of the present invention, an amide solvent and a urea solvent can be used as the reaction solvent. As shown in Examples below, in the production method of the present invention, an amide solvent and a urea solvent serve as a potential Bronsted base (proton acceptor), and a synthetic reaction using an acid halide. Can solve the problems caused by the hydrogen halide generated.

In the production method of the present invention, the amide solvent and the urea solvent may be used alone or in combination. In the production method of the present invention, a solvent other than an amide solvent or a urea solvent (for example, an aprotic polar solvent such as acetone or ethyl acetate or a nonpolar solvent such as dichloromethane) is used as a reaction solvent. An amide solvent and / or a urea solvent may be added. In this case, the amide solvent and the urea solvent can be added so as to be 1 to 6 equivalents (preferably 1 to 2 equivalents) with respect to the amine, the amide compound, and the alcohol that are raw materials. From the viewpoint of the yield of the final product and the ease of recovery of the reaction product, it is preferable to use the amide solvent and the urea solvent alone or in combination as the reaction solvent.

Examples of amide solvents that can be used in the present invention include organic solvents having an amide structure (—NHCO—) (particularly a dialkylamide structure (> N—CO—)), such as N, N-dimethylacetamide (DMAC). ), N, N-diethylacetamide (DEA), N, N-dimethylformamide (DMF), N, N-diethylformamide (DEF), N-methyl-2-pyrrolidone (NMP) and N-ethyl-2-pyrrolidone (NEP).

Examples of urea solvents that can be used in the present invention include organic solvents having a urea structure (—NHCONH—), such as N, N′-dimethylpropyleneurea (DMPU), tetramethylurea (TMU) and 1,3. -Dimethyl-2-imidazolidinone (DMI).

As shown in the examples described later, when a urea solvent is used as a reaction solvent in an amide formation reaction and an ester formation reaction using an acid halide, adverse effects on the reaction progress due to hydrogen halide such as hydrogen chloride are suppressed. Furthermore, the formation of salts (precipitates) of raw materials such as amines and hydrogen halides and the formation of precipitates of reaction products are suppressed. For this reason, the use of a urea-based solvent as a reaction solvent in the production method of the present invention is advantageous in that an amide compound and an ester compound can be produced in a high yield on an industrial scale without hindering stirring.

Reaction Conditions and Procedures In the production method of the present invention, the amount of reaction components is not particularly limited as long as the amide formation reaction and the ester formation reaction using an acid halide proceed. For example, a stoichiometric amount is used. Alternatively, either one of the raw materials may be excessive. In the production method of the present invention, the ratio of the acid halide and the amine, amide compound or alcohol in the reaction system can be 1: 0.5 to 1: 2, preferably 1: 0. .95 to 1: 1.05.

In the production method of the present invention, the reaction temperature and time of the amide formation reaction and the ester formation reaction can be appropriately determined according to the reactivity between the raw material components. (Ie, addition to one of the other) can be carried out in the range of −15 ° C. to 100 ° C., and preferably −15 ° C. from the viewpoint of suppressing heat generation during mixing and increasing the yield The mixing can be performed at ˜35 ° C., more preferably at 0 ° C.-20 ° C. This mixing step is preferably carried out with stirring from the viewpoint of preventing the salt of hydrogen halide and amine or the like, or the salt of hydrogen halide and solvent to form a precipitate as it is.

In the production method of the present invention, the mixing step is performed at −15 ° C. from the viewpoint of suppressing the generation of hydrogen halide gas (for example, hydrogen chloride gas) due to the reaction with an acid halide and improving the yield of the final product. It is preferably carried out in the temperature range of ˜35 ° C.

After the mixing of the acid halide with the amine, amide compound or alcohol is completed, the reaction of the acid halide with the amine, amide compound or alcohol can be continued by subsequently stirring the mixed solution. In this case, the reaction temperature can be −15 ° C. to 35 ° C. (preferably 0 ° C. to 20 ° C.).

In the production method of the present invention, an amide formation reaction and an ester formation reaction using an acid halide can proceed without substantially generating hydrogen halide from the reaction system. This effect can be exhibited more effectively by adjusting the temperature of the mixing step of the acid halide and the amine, amide compound or alcohol as described above. Therefore, the production method of the present invention is advantageous in that it can be carried out in a reaction system that substantially does not contain a base catalyst that captures hydrogen halide produced by the reaction.

In the production method of the present invention, after an amide formation reaction and an ester formation reaction using an acid halide, after-treatment is performed as necessary, the reaction product is subjected to silica gel chromatography, column chromatography, filtration, crystallization. It can be separated and purified by known methods such as

Here, the post-treatment after the amide formation reaction and the ester formation reaction includes the following treatments. That is, when an amide solvent or urea solvent is used as a reaction solvent, the reaction product is precipitated and precipitated by adding a poor solvent (eg, 1 to 5 times the amount of the reaction solution) to the reaction solution. This can be easily collected by a method such as filtration (precipitation method). Examples of the poor solvent include solvents that do not dissolve reaction products such as water, methanol, ethanol, acetone, toluene, and benzene, and water and toluene can be preferably used. Alternatively, the reaction product can be extracted into an organic layer by treating the reaction solution with an organic solvent such as ethyl acetate, chloroform, or methyl ethyl ketone (extraction method). Although it is preferable to use a precipitation method from the viewpoint of easy recovery and yield of the reaction product, an extraction method can be used when it is difficult to recover the reaction product by the precipitation method.

According to the production method the present invention the carboxylic acid amide compound, a carboxylic acid halide (e.g., Formula 7 or a compound of formula 9) and an amine (e.g., a compound of Formula 1 or Formula 2) and the amide solvent and / or Provided is a method for producing a carboxylic acid amide compound comprising a step of reacting in the presence of a urea-based solvent. In carrying out this production method, raw materials, solvents, reaction conditions and procedures can be determined according to the description in this specification.

Here, the carboxylic acid amide compound of the reaction product includes a urea compound and a carbamate compound, and the urea compound and the carbamate compound can be produced by appropriately selecting the carboxylic acid halide and amine to be reacted. For example, a urea compound can be produced by using a compound in which R ¹³ represents —NR ¹⁴ — in formula 7 or a compound in which R ¹⁷ represents —NR ¹⁸ — in formula 9 as a carboxylic acid halide and reacting with an amine. Can do. Further, a carbamate compound can be produced by using a halide of a carboxylic acid ester of formula 7a or 9a as a carboxylic acid halide and reacting with an amine.

According to the present invention, a carboxylic acid halide (for example, a compound of formula 7 or 9) and an amide compound (for example, a compound of formula 3) are reacted in the presence of an amide solvent and / or a urea solvent. There is provided a method for producing a carboxylic acid amide compound comprising the step of: In carrying out this production method, raw materials, solvents, reaction conditions and procedures can be determined according to the description in this specification.

Here, the carboxylic acid amide compound of the reaction product contains a urea compound, and the urea compound can be produced by appropriately selecting the carboxylic acid halide and amine to be reacted. For example, a urea compound in which R ⁶ in formula 3 represents — (N (—R ⁹ )) — and Q represents an oxygen atom is used as an amide compound, and reacted with a carboxylic acid halide to react with acetyl urea (ureido). Urea compounds such as can be produced.

According to the production method the present invention of the sulfonic acid amide, sulfonic acid halides (e.g., a compound of Formula 11 or Formula 13) with an amine (e.g., a compound of Formula 1 or Formula 2) and the amide solvent and / or urea Provided is a method for producing a sulfonic acid amide compound comprising a step of reacting in the presence of a system solvent. In carrying out this production method, raw materials, solvents, reaction conditions and procedures can be determined according to the description in this specification.

Process for Producing Ester Compound According to the present invention, a carboxylic acid halide (for example, a compound of formula 7 or 9) and an alcohol (for example, a compound of formula 4 or 5) are converted into an amide solvent and / or a urea solvent. There is provided a method for producing a carboxylic acid ester compound comprising a step of reacting in the presence of In carrying out this production method, raw materials, solvents, reaction conditions and procedures can be determined according to the description in this specification.

According to the present invention, a sulfonic acid halide (for example, a compound of formula 11 or formula 13) and an alcohol (for example, a compound of formula 4 or formula 5) are combined in the presence of an amide solvent and / or a urea solvent. There is provided a method for producing a sulfonate compound comprising a step of reacting. In carrying out this production method, raw materials, solvents, reaction conditions and procedures can be determined according to the description in this specification.

According to the peptides of the manufacturing method of the present invention, the amino acid halide or peptide halide, an amino acid or peptide comprising the step of reacting in the presence of an amide-based solvent and / or urea-based solvent, the production method of peptide Provided. In carrying out this production method, unless otherwise specified, raw materials, solvents, reaction conditions and procedures can be determined according to the description of the present specification. Further, in the present invention, “peptide” is not limited by the chain length of amino acid residues, but is meant to include oligopeptides, polypeptides, and proteins.

In the method for producing a peptide of the present invention, an amino acid halide having an α-carboxyl group halogenated can be used as the amino acid halide, and the amino group of the amino acid is a protecting group (for example, a fluorenylmethoxycarbonyl group (Fmoc). ), Benzyloxycarbonyl group and tert-butoxycarbonyl group). As the peptide halide, a peptide in which the C-terminal α-carboxyl group is halogenated can be used, and the amino group at the N-terminal of the peptide is a protecting group (for example, a fluorenylmethoxycarbonyl group (Fmoc), Benzyloxycarbonyl group and tert-butoxycarbonyl group).

In the method for producing a peptide of the present invention, an amino acid to be reacted with an acid halide can be an amino acid in which an amino group forming an amide bond is not protected, and the carboxyl group of the amino acid is a protective group (for example, methyl It may be protected by a carboxylic acid ester group such as ester, ethyl ester or benzyl ester). As the peptide to be reacted with the acid halide, a peptide in which the N-terminal α-amino group forming an amide bond is not protected can be used, and the C-terminal carboxyl group of the peptide is a protecting group (for example, methyl It may be protected by a carboxylic acid ester group such as ester, ethyl ester or benzyl ester).

In the method for producing a peptide of the present invention, an amino acid halide or peptide halide and an amino acid or peptide are reacted in the presence of an amide solvent and / or a urea solvent to advance the amide formation reaction, It can be performed according to a known peptide synthesis method. For example, a functional group that does not participate in the amide formation reaction can be protected in advance, and deprotected with an appropriate deprotecting agent after completion of the reaction.

The method for producing a peptide of the present invention has a higher efficiency of amide formation reaction than the conventional method, and can produce the target peptide with high yield. In particular, the target peptide can be produced in a high yield without protecting the C-terminal amino acid or the carboxyl group of the peptide. For this reason, the peptide synthesis method of the present invention is advantageous in that the amide formation reaction can proceed continuously. The peptide production method of the present invention can also be scaled up because it can be carried out in a liquid phase, and can be used for large-scale synthesis of peptides. The peptide production method of the present invention is also advantageous in that the target peptide can be easily purified and recovered by the precipitation method using the poor solvent as described above.

<Method for producing carboxylic acid amide compound having optical activity>
According to one aspect of the production method of the present invention, an optically active carboxylic acid comprising a step of reacting a carboxylic acid halide with an optically active amino acid in the presence of an amide solvent and / or a urea solvent. A method for producing an acid amide compound is provided. That is, when the production method of the present invention is carried out using an optically active amino acid (for example, L-form amino acid, D-form amino acid) as a raw material, an optical isomer carboxylic acid amide compound is produced without racemization. be able to. The amino acid that can be used as a raw material for producing the optically active carboxylic acid amide compound is not particularly limited as long as it is an amino acid having optical activity. For example, L-alanine, D-alanine, L-phenylalanine, D-phenylalanine, Examples include L-valine and D-valine. The above production method is advantageous in that the amide formation reaction using an acid halide proceeds efficiently even though the amino group of the amino acid used as a raw material shows almost no basicity. In carrying out this production method, unless otherwise specified, raw materials, solvents, reaction conditions and procedures can be determined according to the description of the present specification.

<Selective production method of carboxylic acid amide compound and sulfonic acid amide compound>
According to another aspect of the production method of the present invention, a step of reacting an acid halide with two or more amines and / or amide compounds having different basicities in the presence of an amide solvent and / or a urea solvent. There is provided a method for selectively producing any one of two or more carboxylic acid amide compounds or sulfonic acid amide compounds comprising: According to the above production method, a carboxylic acid amide or a sulfonic acid amide of an amine or amide compound having the smallest basicity among the two or more kinds of amine and / or amide compounds can be selectively produced. Here, “selectively producing” means an amount exceeding the total amount of other reaction products (preferably 2 times or more, 3 times or more, 5 times or more, 10 times or more of the total amount of other reaction products, Means to manufacture in a quantity of 15 times or more, 20 times or more).

The amine and amide compound that are the raw materials for the selective production method between different molecules of the present invention are different from one or more different amines even if they are two or more different amines or two or more different amide compounds. It may be a combination of two or more amide compounds.

According to the above production method, the ratio of two or more carboxylic acid amide compounds or sulfonic acid amide compounds can be adjusted by adding an acid or a base to the reaction system. Specifically, an acid (pKa5 or less; for example, 1.5 to 5 equivalents with respect to the total of two or more amines and amide compounds having different basicities that are reacted with an acid halide) is added to the reaction system. Thus, the ratio of the carboxylic acid amide compound or the sulfonic acid amide compound of the amine having the smallest basicity can be increased. Examples of the additive as an acid include acetic acid, trifluoroacetic acid, citric acid, oxalic acid, formic acid, trichloroacetic acid, and sulfuric acid. On the other hand, by adding a base (pK _{BH +} 10 or more; for example, 1.5 to 5 equivalents with respect to the total of two or more amines and amide compounds having different basicities to be reacted with an acid halide) to the reaction system The ratio of the carboxylic acid amide compound or the sulfonic acid amide compound of the amine having the smallest basicity can be reduced. Examples of the additive as a base include triethylamine.

In the above production method, the reaction can be carried out in the presence of one or more solvents selected from the group consisting of an amide solvent and a urea solvent, but is carried out in the presence of an amide solvent. The amide solvents are preferably DMAC and DMF, and particularly preferably DMAC.

In carrying out the above production method, unless otherwise specified, raw materials, solvents, reaction conditions and procedures can be determined according to the description in this specification.

According to still another aspect of the production method of the present invention, an acid halide and an amine or amide compound having two or more amino groups having different basicities are combined in the presence of an amide solvent and / or a urea solvent. A method for producing a carboxylic acid amide compound or a sulfonic acid amide compound in which an amide bond is selectively formed with respect to any one of the amino groups is provided. According to the said manufacturing method, an amide bond can be selectively formed in the amino group with the smallest basicity among the said 2 or more types of amino groups. Here, “selectively formed” means an amount exceeding the total of amide bonds formed in other amino groups (preferably 2 times or more and 3 times the total of amide bonds formed in other amino groups). This means that an amide bond is formed (at least 5 times, 10 times, 15 times, 20 times or more). In addition, the basicity degree (namely, pKBH ₊ value) for every amino group can be calculated on the assumption that the amino group exists independently and the other amino group does not exist. The pKBH ₊ value can be determined as an experimental value or a calculated value according to the above description.

The two or more amino groups having different basicities of the amine and amide compound that are the raw materials for the intramolecular selective production method of the present invention are amino groups bonded to an aliphatic hydrocarbon chain as shown in Formula 1. In addition to the amino group bonded to the aromatic ring as shown in Formula 2, amino groups constituting an amide structure, thioamide structure, urea structure, thiourea structure, semicarbazide structure, thiosemicarbazide structure, and the like are included.

According to the said manufacturing method, the ratio of the amide bond originating in 2 or more types of amino groups can be adjusted by adding an acid or a base to a reaction system. Specifically, an acid (pKa 5 or less; for example, 1.5 to 5 equivalents with respect to the total amino groups) is added to the reaction system to increase the ratio of the amide bond of the amino group having the smallest basicity. be able to. The additive as an acid can use the same thing as the above. On the other hand, by adding a base (pK _{BH +} 10 or more; for example, 1.5 to 5 equivalents relative to the total of amino groups) to the reaction system, the ratio of the amide bond of the amino group having the smallest basicity can be reduced. Can do. As the additive as the base, the same ones as described above can be used.

The amine and amide compounds that are raw materials for the intramolecular selective production method of the present invention include, for example,
Formula 1: HN (—R ¹ ) (— R ² ) (wherein R ¹ and R ² have the same meanings as described above, but the aliphatic hydrocarbon group represented by R ¹ and / or R ² is at least Substituted with a substituent containing one amino group, which substituent is preferably said substituent A which contains at least one amino group and may be further substituted)
Formula 2: HN (—R ³ ) (— R ⁴ ) (wherein R ³ and R ⁴ are as defined above, but at least one aromatic ring group represented by R ³ and / or R ⁴ is present) Substituted with a substituent containing an amino group, which is preferably said substituent A or substituent B which contains at least one amino group and which may be further substituted, and said formula 3 : R ⁵ -R ^6- (C = Q) (-NR ⁷ R ⁸ ) (wherein R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined above, R ⁵ , R ⁶ The aliphatic hydrocarbon group and aromatic ring group represented by R ⁷ and R ⁸ are substituted with a substituent containing at least one amino group, and the substituent preferably contains at least one amino group. Further, the substituent A or the optionally substituted group A or A substituent B, more preferably, the substituent of the aliphatic hydrocarbon group is the substituent A which includes at least one amino group and may be further substituted, and is a substituent of the aromatic ring group Is the above-mentioned substituent A or substituent B which contains at least one amino group and may be further substituted)
It can be expressed as

Examples of amine and amide compounds that are raw materials for the intramolecular selective production method of the present invention include 4-aminobenzylamine, 3-aminobenzylamine, semicarbazide (H ₂ N— (C═O) —NH—NH ₂ ), thiosemicarbazide (H ₂ N— (C═S) —NH—NH ₂ ), but is not limited thereto. When these are used as reaction substrates, an amide bond can be selectively formed at one terminal amino group due to the difference in basicity between the amino groups at both ends of the molecule.

The present invention will be described more specifically based on the following examples, but the present invention is not limited to these examples.

In this example, commercially available products were used as the raw material compound and the solvent. In this example, the equipment used for measuring the compounds is as follows.
¹ H-NMR measurement: Bruker Avance 400, thin layer chromatography manufactured by Bruke, TLC glass plate, silica gel 60 F ₂₅₄ , manufactured by Merck

Example A: Synthesis of carboxylic acid amide compound (1)
In Example A, a carboxylic acid amide compound was synthesized by reacting an aliphatic amine and an acid chloride in various organic solvents.

Example A1: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (1)
<Adding amine to acid chloride>

4-Methoxybenzylamine (1.4370 g, 10.475 mmol) was dissolved in 5 mL of DMAC to make an amine solution. Chloroacetyl chloride (1.1315 g, 10.19 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. After adding the amine solution to the pre-cooled acid chloride solution at 0 ° C. (on ice water bath) over 3 minutes, the mixture was stirred at 0 ° C. for 10 minutes. A white precipitate was formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. Completion of the reaction was confirmed by thin layer chromatography. 30 mL of water was added to the reaction vessel to form a white precipitate. The mixture was stirred at 23 ° C. for 5 hours. The resulting precipitate was collected by suction filtration and the solid was washed with 70 mL of water. Then, it was dried in vacuum to obtain 1.6713 g of the title compound 4a (white solid) (yield: 78%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. In order to examine the remaining amount of the title compound 4a in the filtrate, the filtrate was extracted four times with 20 mL of dichloromethane, and the combined organic fractions were washed three times with 50 mL of water and dried using magnesium sulfate. The organic solvent was evaporated to obtain a colorless liquid (1.0910 g) which is a mixture of the title compound 4a and DMAC. Based on the integration of the ¹ H-NMR signal, the calculated amount of the title compound 4a in the extract was 0.1420 g (6.6%), and the total yield of the title compound 4a (the product extracted from the precipitate and the filtrate) ) Was 85%.

4a: Melting point: 102 ° C (colorless plate).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.220 (2H, d, J = 8.8 Hz), 6.880 (2H, d, J = 8.8 Hz), 6.832 (1H, br), 4.418 (2H, d, J = 5.6 Hz), 4.075 (2H , s), 3.800 (3H, s) 13 C-NMR (100 MHz, CDCl 3):. 165.79, 159.35, 129.45, 129.32, 114.30, 55.41, 43.46, 42.71.
Analytical results: C ₁₀ H ₁₂ ClNO ₂ , calculated values: C, 56.22; H, 5.66; N, 6.56, measured values: C, 55.98; H, 5.63; N, 6.61, HRMS (ESI-TOF, [N + Na ] ⁺ ): Analysis result: C ₁₀ H ₁₂ ClNO ₂ Na, calculated value: 236.0449. Measured value: 236.0451.

4-Methoxybenzylamine (1.4423 g, 10.51 mmol) was dissolved in 5 mL of DMAC to make an amine solution. Chloroacetyl chloride (1.1357 g, 10.06 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. The acid chloride solution was added to the previously cooled (0 ° C., ice water bath) amine solution over 5 minutes. A white precipitate was formed. The whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the mixture was stirred at 23 ° C. for 2 hours. Completion of the reaction was confirmed by thin layer chromatography. 40 mL of water was added to the reaction vessel to form a white precipitate. The mixture was stirred at 23 ° C. overnight. The resulting precipitate was collected by suction filtration and the solid was washed with water and dried in vacuo to give 1.7549 g of the title compound 4a (white solid) (yield: 82%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: Analysis result: C ₁₀ H ₁₂ ClNO _2, calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 55.99; H, 5.65; N, 6.60.

Example A2: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (2)

4-Methoxybenzylamine (1.4012 g, 10.214 mmol) was dissolved in 5 mL of DMAC at room temperature to obtain an amine solution. Chloroacetyl chloride (1.1045 g, 9.780 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 4 minutes. A white precipitate was formed. The mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 17 hours. 30 mL of water was added to the mixture. The mixture was stirred at 23 ° C. for 23 hours. The resulting precipitate was collected by suction filtration and the solid was washed with 100 mL of water. Then, it was dried in vacuum to obtain 1.6547 g of the title compound 4a (white solid) (yield: 79%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.227 (2H, d, J = 8.8 Hz), 6.886 (2H, d, J = 8.7 Hz), 6.784 (1H, br, s), 4.429 (2H , d, J = 5.7 Hz), 4.093 (2H, s), 3.808 (3H, s).
Analytical result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 56.08; H, 5.69; N, 6.63.

Example A3: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (3)

4-Methoxybenzylamine (1.2448 g, 9.074 mmol) was dissolved in 5 mL of dichloromethane at room temperature to form an amine solution. Chloroacetyl chloride (1.3261 g, 11.742 mmol) was dissolved in 5 mL of dichloromethane at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 3 minutes. A white precipitate was formed. The mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 17 hours. 30 mL of water was added to the mixture. The mixture was extracted 3 times with 20 mL dichloromethane and the combined organic fractions were washed 3 times with water (total volume 150 mL) and dried over magnesium sulfate. The organic solvent was evaporated to give a white solid and dried in vacuo to give 0.8788 g of the title compound 4a (white solid) (yield: 45%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

Sodium hydroxide (solid) 0.96 g was added to basify the water fraction. The water fraction was extracted 4 times with 20 mL of dichloromethane, and the organic layer was dried over magnesium sulfate. The solvent was evaporated to give 4-methoxybenzylamine recovered as a colorless oil (0.5663 g) (yield: 45% recovery)

4a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.223 (2H, d, d, d, J = 8.8, 2.9, 2.2 Hz), 6.883 (2H, d, d, d, J = 8.7, 3.0, 2.2 Hz), 6.816 (1H, br), 4.423 (2H, d, J = 5.7 Hz), 4.084 (2H, s), 3.804 (3H, s). ¹³ C-NMR (100 MHz, CDCl ₃ ): 165.82. , 159.38, 129.45, 129.34, 114.34, 55.44, 43.50, 42.74. Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 55.97; ; N, 6.40. HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₀ H ₁₂ ClNO ₂ Na, 236.0449.
Measurement value: 236.0446.
Recovered amine 2a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.232 (2H, d, d, d, J = 8.2, 2.8, 2.1 Hz), 6.870 (2H, d, d, d, J = 8.7, 2.9, 2.1 Hz), 4.084 (2H, s), 3.804 (3H, s).
¹³ C-NMR (100 MHz, CDCl ₃ ): 158.63, 135.71, 128.40, 114.05, 55.43, 46.05.

Example A4: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (4)

Dichloromethane was added to N, N-dimethylaniline (2.4331 g, 20.788 mmol) to prepare 5 mL of a solution (N, N-dimethylaniline-dichloromethane solvent). 4-Methoxybenzylamine (1.4435 g, 10.523 mmol) was dissolved in 5 mL of N, N-dimethylaniline-dichloromethane solvent to give an amine solution. Chloroacetyl chloride (1.1316 g, 10.020 mmol) was dissolved in 5 mL of dichloromethane at room temperature to make an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 3 minutes, and then the mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. 30 mL of water was added to the mixture. The mixture was extracted 4 times with 20 mL of dichloromethane and the combined organic fractions were washed 3 times with 50 mL of 0.01M hydrochloric acid solution and dried over magnesium sulfate. The organic solvent was evaporated to give a white solid which was washed with 50 mL water and 50 mL n-hexane and dried in vacuo to give 1.8619 g of the title compound 4a (white solid) (yield: 87%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.226 (2H, d, J = 8.8 Hz), 6.885 (2H, d, J = 8.8 Hz), 4.428 (2H, d, J = 5.7 Hz), 4.091 (2H, s), 3.807 (3H, s). Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 56.11; H, 5.61; N, 6.63.

Example A5: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (5)

Dichloromethane was added to triethylamine (2.0332 g, 20.093 mmol) to prepare 10 mL of a solution (triethylamine-dichloromethane solvent). 4-Methoxybenzylamine (1.4373 g, 10.477 mmol) was dissolved in 5 mL of triethylamine-dichloromethane solvent to prepare an amine solution. Chloroacetyl chloride (1.1313 g, 10.17 mmol) was dissolved in 5 mL of triethylamine-dichloromethane solvent at room temperature to obtain an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution over 5 minutes with stirring at 0 ° C., and then the mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. 30 mL of water was added to the mixture, followed by 8 mL of 2M hydrochloric acid solution. The mixture was extracted 4 times with 20 mL of dichloromethane and the combined organic fractions were washed 3 times with 50 mL of water and dried using magnesium sulfate. The organic solvent was evaporated to give a black solid and dried in vacuo to give 1.5088 g (black solid). The product was purified by open column chromatography (ethyl acetate: hexane = 1: 1) to obtain 1.329 g of the title compound 4a (white solid) (yield: 53%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.228 (2H, d, J = 8.8 Hz), 6.887 (2H, d, J = 8.7 Hz), 6.783 (1H, br, s), 4.430 (2H , d, J = 5.7 Hz), 4.095 (2H, s), 3.809 (3H, s). Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value : C, 56.16; H, 5.71; N, 6.57 (after column chromatography).

Example A6: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (6)

Dichloromethane was added to DMAC (0.4341 g, 4.983 mmol) to prepare 10 mL of a solution (DMAC-dichloromethane solvent). 4-Methoxybenzylamine (1.4469 g, 10.547 mmol) was dissolved in 5 mL of DMAC-dichloromethane solvent to give an amine solution. Chloroacetyl chloride (1.1383 g, 10.079 mmol) was dissolved in 5 mL of DMAC-dichloromethane solvent at room temperature to give an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. After adding the amine solution to the acid chloride solution over 4 minutes, the mixture was stirred at 0 ° C. for 12 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 17 hours. 30 mL of water was added to the mixture. The mixture was extracted 4 times with 20 mL of dichloromethane and the combined organic fractions were washed 3 times with 50 mL of water and dried using magnesium sulfate. The organic solvent was evaporated to give a white solid and dried in vacuo to give 1.1791 g of the title compound 4a (white solid) (yield: 55%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: ¹ H-NMR (400 MHz, CDCl ₃ ) 7.272-7.210 (2H, m), 6.901-6.869 (2H, m), 6.803 (1H, br, s), 4.434 (2H, s), 4.092 (2H , s), 3.809 (3H, s). Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 55.98; H, 5.66; N, 6.58 .

Example A7: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (7)

Dichloromethane was added to DMAC (0.8725 g, 10.15 mmol) to prepare 10 mL of a solution (DMAC-dichloromethane solvent). 4-Methoxybenzylamine (1.4385 g, 10.486 mmol) was dissolved in 5 mL of DMAC-dichloromethane solvent to give an amine solution. Chloroacetyl chloride (1.1329 g, 10.031 mmol) was dissolved in 5 mL of DMAC-dichloromethane solvent at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. After the amine solution was added to the acid chloride solution over 4 minutes, the mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 17 hours. 30 mL of water was added to the mixture. The mixture was extracted 4 times with 20 mL of dichloromethane and the combined organic fractions were washed 3 times with 50 mL of water and dried using magnesium sulfate. The organic solvent was evaporated to give a white solid and dried in vacuo to give 1.5062 g of the title compound 4a (white solid) (yield: 70%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.227 (2H, d, J = 8.8 Hz), 6.886 (2H, d, J = 8.7 Hz), 4.429 (2H, d, J = 5.7 Hz), 4.093 (2H, s), 3.806 (3H, s). Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 56.09; H, 5.62; N, 6.60.

Example A8: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (8)

Dichloromethane was added to DMAC (1.7638 g, 20.297 mmol (2 equivalents)) to prepare 10 mL of the solution (DMAC-dichloromethane solvent). 4-Methoxybenzylamine (1.4384 g, 10.485 mmol) was dissolved in 5 mL of DMAC-dichloromethane solvent to give an amine solution. Chloroacetyl chloride (1.1303 g, 10.008 mmol) was dissolved in 5 mL of DMAC-dichloromethane solvent at room temperature to obtain an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 3 minutes, and then the mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 17 hours. 30 mL of water was added to the mixture. The mixture was extracted 4 times with 20 mL of dichloromethane and the combined organic fractions were washed 3 times with 50 mL of water and dried using magnesium sulfate. The organic solvent was evaporated to give a white solid and dried in vacuo to give 1.7519 g of the title compound 4a (white solid) (yield: 82%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.220 (2H, d, J = 9.0 Hz), 6.886 (2H, d, J = 8.8 Hz), 4.428 (2H, d, J = 5.7 Hz), 4.092 (2H, s), 3.807 (3H, s). Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 56.05; H, 5.54; N, 6.44.

Example A9: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (9)

Dichloromethane was added to DMAC (1.7376 g, 19.994 mmol (2 eq)) to prepare 10 mL of the solution (DMAC-dichloromethane solvent). 4-Methoxybenzylamine (1.4426 g, 10.516 mmol) was dissolved in 5 mL of DMAC-dichloromethane solvent to give an amine solution. Chloroacetyl chloride (1.1336 g, 10.037 mmol) was dissolved in 5 mL of DMAC-dichloromethane solvent at room temperature to give an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 3 minutes, and then the mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. 30 mL of water was added to the mixture. The mixture was extracted 4 times with 20 mL of dichloromethane and the combined organic fractions were washed 3 times with 50 mL of water and dried using magnesium sulfate. The organic solvent was evaporated to give a white solid and dried in vacuo to give 1.2890 g of the title compound 4a (white solid) (yield: 60%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.225 (2H, d, J = 8.8 Hz), 6.885 (2H, d, J = 8.8 Hz), 4.426 (2H, d, J = 5.7 Hz), 4.089 (2H, s), 3.806 (3H, s). Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 56.10; H, 5.67; N, 6.60.

Example A10: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (10)

4-Methoxybenzylamine (1.4388 g, 10.488 mmol) was dissolved in 5 mL of acetone to make an amine solution. Chloroacetyl chloride (1.1301 g, 10.006 mmol) was dissolved in 5 mL of acetone at room temperature to obtain an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 3 minutes, and then the mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 17 hours. 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 4 hours. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 0.8124 g of the title compound 4a (white solid) (yield: 38%). The absence of product in the filtrate was confirmed by thin layer chromatography. The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.227 (2H, d, J = 8.8 Hz), 6.887 (2H, d, J = 8.7 Hz), 4.430 (2H, d, J = 5.7 Hz), 4.094 (2H, s), 3.808 (3H, s). Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 56.20; H, 5.82; N, 6.56.

Example A11: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (11)

4-Methoxybenzylamine (1.4433 g, 10.521 mmol) was dissolved in 5 mL of ethyl acetate to obtain an amine solution. Chloroacetyl chloride (1.1336 g, 10.037 mmol) was dissolved in 5 mL of ethyl acetate at room temperature to obtain an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring and cooling at 0 ° C. over 4 minutes, and then the mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 17 hours. 30 mL of water was added to the mixture. The mixture was stirred at 23 ° C. for 15 hours. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 0.8124 g of the title compound 4a (white solid) (yield: 38%). The filtrate was extracted 4 times with 20 mL of dichloromethane and the combined organic fractions were washed 3 times with 50 mL of water and dried over magnesium sulfate. The organic solvent was evaporated to give a white solid and dried in vacuo to give 0.2302 g of the title compound 4a (white solid). In total, 1.0426 g was obtained (combined yield: 49%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

Precipitated compound (4a): ¹ H-NMR (400 MHz, CDCl ₃ ): 7.227 (2H, d, J = 8.4 Hz), 6.887 (2H, d, J = 8.4 Hz), 6.790 (1H, br, s ), 4.429 (2H, d, J = 5.5 Hz), 4.093 (2H, s), 3.808 (3H, s). Analysis results: C ₁₀ H ₁₂ ClNO ₂ , calculated values: C, 56.22; H, 5.66; N , 6.56, measurements: C, 56.28; H, 5.94; N, 6.58.
Compound from the filtrate (4a): ¹ H-NMR (400 MHz, CDCl ₃ ): 7.225 (2H, d, J = 8.8 Hz), 6.887 (2H, d, J = 8.7 Hz), 6.782 (1H, br, s), 4.430 (2H, d, J = 5.7 Hz), 4.094 (2H, s), 3.808 (3H, s). Analysis results: C ₁₀ H ₁₂ ClNO ₂ , calculated values: C, 56.22; H, 5.66; N, 6.56, measured value: C, 55.92; H, 5.65; N, 6.55.

Example A12: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (12)

Acetone was added to DMAC (1.7431 g, 20.008 mmol (2 equivalents)) to prepare 10 mL of a solution (DMAC-acetone solvent). 4-Methoxybenzylamine (1.4497 g, 10.568 mmol) was dissolved in 5 mL of DMAC-acetone solvent to obtain an amine solution. Chloroacetyl chloride (1.1360 g, 10.59 mmol) was dissolved in 5 mL of DMAC-acetone solvent at room temperature to obtain an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 3 minutes, and then the mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 17 hours. 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 22 hours. The solid was filtered off with suction and washed with 70 mL of water. Then, it was dried in vacuum to obtain 1.5788 g of the title compound 4a (white solid) (yield: 73%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.227 (2H, d, J = 8.8 Hz), 6.887 (2H, d, J = 8.7 Hz), 6.783 (1H, br, s), 4.430 (2H , d, J = 5.7 Hz), 4.094 (2H, s), 3.809 (3H, s). Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value : C, 56.01; H, 5.60; N, 6.55.

Example A13: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (13)

Ethyl acetate was added to DMAC (1.7483 g, 20.0.067 mmol (2 equivalents)) to prepare 10 mL of a solution (DMAC-ethyl acetate solvent). 4-Methoxybenzylamine (1.4362 g, 10.469 mmol) was dissolved in 5 mL of DMAC-ethyl acetate solvent to obtain an amine solution. Chloroacetyl chloride (1.1232 g, 9.945 mmol) was dissolved in 5 mL of DMAC-ethyl acetate solvent at room temperature to obtain an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 3 minutes, and then the mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 17 hours. Completion of the reaction was confirmed by thin layer chromatography. 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 2 hours. The solid was filtered off with suction and washed with 60 mL of water. Then, it was dried in vacuum to obtain 1.5788 g of the title compound 4a (white solid) (yield: 74%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.225 (2H, d, J = 8.7 Hz), 6.885 (2H, d, J = 8.7 Hz), 6.801 (1H, br, s), 4.427 (2H , d, J = 5.7 Hz), 4.089 (2H, s), 3.806 (3H, s). Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value : C, 56.41; H, 5.77; N, 6.53.

The procedures and yields of Examples A1 to A13 are summarized in Table 1.

Example B: Synthesis of Carboxamide Compound (2)
In Example B, a carboxylic acid amide compound was synthesized by reacting an aliphatic amine with an acid chloride in various organic solvents. As the organic solvent, DMAC, amide solvents other than DMAC, and urea solvents were used.

Example B1: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (1)
Synthesized as described in Example A1 above.

Example B2: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (2)

4-Methoxybenzylamine (1.4460 g, 10.541 mmol) was dissolved in 5 mL of dimethylformamide (DMF) to obtain an amine solution. Chloroacetyl chloride (1.1353 g, 10.53 mmol) was dissolved in 5 mL of DMF at room temperature to obtain an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 3 minutes, and then the mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 25 ° C. for 2 hours. Completion of the reaction was confirmed by thin layer chromatography. 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 21 hours. The solid was filtered off with suction and washed with 80 mL of water. Then, it was dried in vacuum to obtain 1.5134 g of the title compound 4a (white solid) (yield: 70%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.226 (2H, d, J = 8.8 Hz), 6.885 (2H, d, J = 8.7 Hz), 6.796 (1H, br, s), 4.427 (2H , d, J = 5.7 Hz), 4.090 (2H, s), 3.807 (3H, s). Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value : C, 55.93; H, 5.58; N, 6.54.

Example B3: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (3)

4-Methoxybenzylamine (1.4619 g, 10.66 mmol) was dissolved in 5 mL of 1-methyl-2-pyrrolidinone (NMP) to obtain an amine solution. Chloroacetyl chloride (1.1283 g, 9.99 mmol) was dissolved in 5 mL of NMP to obtain an acid chloride solution. After adding the amine solution to the pre-cooled acid chloride solution over 2 minutes, the mixture was stirred at 0 ° C. for 5 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. 30 mL of water was added to the reaction vessel to form a white precipitate. The resulting precipitate was collected by suction filtration and washed with water. Then, it was dried in vacuum to obtain 1.6086 g of the title compound 4a (white solid) (yield: 75%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.223 (2H, d, J = 8.4 Hz), 6.882 (2H, d, J = 8.8 Hz), 4.425 (2H, d, J = 6.0 Hz), 4.088 (2H, s), 3.804 (3H, s). Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 56.25; H, 5.75; N, 6.37.

Example B4: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (4)

(1) Precipitation method 4-Methoxybenzylamine (1.4351 g, 10.461 mmol) was dissolved in 5 mL of N, N′-dimethylpropyleneurea (DMPU) to prepare an amine solution. Chloroacetyl chloride (1.1294 g, 10.000 mmol) was dissolved in 5 mL of DMPU at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 3 minutes, and the whole was stirred at 0 ° C. for 10 minutes. A precipitate was not formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. A precipitate was not formed. Completion of the reaction was confirmed by thin layer chromatography. 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 17 hours. The solid was filtered off with suction and washed with 70 mL of water. Then, it was dried in vacuum to obtain 1.3800 g of the title compound 4a (white solid) (yield: 65%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.227 (2H, d, J = 8.8 Hz), 6.887 (2H, d, J = 8.7 Hz), 6.781 (1H, br, s), 4.430 (2H , d, J = 5.7 Hz), 4.094 (2H, s), 3.809 (3H, s). Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value : C, 56.03; H, 5.66; N, 6.59.

(2) Extraction Method 4-Methoxybenzylamine (1.3758 g, 10.03 mmol) was dissolved in 5 mL of DMPU to prepare an amine solution. DMPU (5 mL) was added to chloroacetyl chloride (1.1324 g, 10.03 mmol) at 0 ° C. (ice water bath) over 4 minutes to obtain an acid chloride solution. After the amine solution was added to the acid chloride solution over 5 minutes with stirring at 0 ° C., the mixture was stirred at 0 ° C. for 5 minutes. A precipitate was not formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. A precipitate was not formed. A pale yellow viscous solution was obtained. Completion of the reaction was confirmed by thin layer chromatography. 80 mL of water was added to the mixture. A white precipitate was formed. The organic layer was washed repeatedly with 280 mL of water, and the filter residue was dried using magnesium sulfate. The organic solvent was evaporated to give 1.3736 g of the title compound 4a (white solid) (yield: 64%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: Analysis result: C ₁₀ H ₁₂ ClNO ₂ + 0.1H ₂ O, calculated value: C, 55.75; H, 5.71; N, 6.50, measured value: C, 55.76; H, 5.63; N, 6.53.

Example B5: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (5)

(1) Precipitation method 4-Methoxybenzylamine (1.4426 g, 10.52 mmol) was dissolved in 5 mL of tetramethylurea (TMU) to prepare an amine solution. Chloroacetyl chloride (1.1417 g, 10.11 mmol) was dissolved in 5 mL of TMU to make an acid chloride solution. The amine solution was added to the pre-cooled acid chloride solution (0 ° C. in an ice water bath) over 4 minutes, and the whole was stirred at 0 ° C. for 30 minutes. A precipitate was not formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. A precipitate was not formed. 60 mL of water was added to the reaction vessel to form a white precipitate. The resulting precipitate was collected by suction filtration and the solid was washed with water. Then, it was dried in vacuum to obtain 386.0 mg of the title compound 4a (white solid) (yield: 18%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: Analytical result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 56.06; H, 5.50; N, 6.53.

(2) Extraction method A TMU solution of 4-methoxybenzylamine (1.3778 g, 10.04 mmol) in a TMU solution (0 ° C., in an ice-water bath) of chilled chloroacetyl chloride (1.1305 g, 10.01 mmol) in advance. 5 mL was added at 0 ° C. over 2 minutes. The mixture was stirred at 0 ° C. for 5 minutes. A precipitate was not formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. A precipitate was not formed. 40 mL of water was added to the reaction vessel to form a white precipitate. The whole was extracted with 180 mL of ethyl acetate, and the combined organic layers were washed with 200 mL of water and dried using magnesium sulfate. The organic solvent was evaporated to give 1.2852 g of the title compound 4a (white solid) (yield: 60%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 55.82; H, 5.64; N, 6.56.

Example B6: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) (6)

(1) Precipitation method 4-Methoxybenzylamine (1.4574 g, 10.47 mmol) was dissolved in 5 mL of 1,3-dimethyl-2-imidazolidinone (DMI) to prepare an amine solution. Chloroacetyl chloride (1.1263 g, 9.97 mmol) was dissolved in 5 mL of DMI to make an acid chloride solution. The amine solution was added to the pre-cooled acid chloride solution (0 ° C. in an ice-water bath) over 2 minutes, and the whole was stirred at 0 ° C. for 20 minutes. A precipitate was not formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. A precipitate was not formed. 20 mL of water was added to the reaction vessel to form a white precipitate. The resulting precipitate was collected by suction filtration and the solid was washed with water. Then, it was dried in vacuum to obtain 1.0840 g of the title compound 4a (white solid) (yield: 51%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: Analysis result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 56.04; H, 5.63; N, 6.46.

(2) Extraction method DMI solution of 4-methoxybenzylamine (1.3795 g, 10.06 mmol) in a DMI solution (0 ° C. in an ice-water bath) of chloroacetyl chloride (1.1275 g, 9.98 mmol) cooled in advance 5 mL was added at 0 ° C. over 3 minutes. The mixture was stirred at 0 ° C. for 5 minutes. A precipitate was not formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. A precipitate was not formed. 50 mL of water was added to the reaction vessel to form a white precipitate. The whole was extracted with 80 mL of ethyl acetate, and the combined organic layers were washed repeatedly with 200 mL of water and dried using magnesium sulfate. The organic solvent was evaporated to give 1.1778 g of the title compound 4a (white solid) (yield: 55%). The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4a: colorless plate, recrystallized from dichloromethane / n-hexane: analytical result: C ₁₀ H ₁₂ ClNO ₂ , calculated value: C, 56.22; H, 5.66; N, 6.56, measured value: C, 56.22; H, 5.66 ; N, 6.56.

The procedures and yields of Examples B1 to B6 (a: yield by precipitation method, b: yield by extraction method) are summarized in Table 2.

Example C: Synthesis of carboxylic acid amide compound (3)
In Example C, a carboxylic acid amide compound was synthesized by reacting an aromatic amine and an acid chloride in various organic solvents. As the organic solvent, an amide solvent and a urea solvent were used.

Example C1: Synthesis of N- (4-bromophenyl) -2-chloroacetamide (4b) (1)

4-Bromoaniline (1.8025 g, 10.48 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Chloroacetyl chloride (1.0934 g, 9.68 mmol) was dissolved in 5 mL of DMAC at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution over 5 minutes with stirring at 0 ° C., and then the mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 1.5 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture to form a white precipitate. The mixture was stirred at 23 ° C. overnight. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 2.1606 g of the title compound 4b (white solid) (yield: 90%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4b: Melting point: 178-179 ° C (white powder), 69-75 ° C (colorless plate, recrystallized from methanol). ¹ H-NMR (400 MHz, DMSO-d ₆ ): 10.430 (1H, s) 7.567 ( . 2H, d, J = 8.8 Hz), 7.515 (2H, d, J = 9.2 Hz), 4.255 (2H, s) 13 C-NMR (100 MHz, DMSO-d 6): 164.79, 137.83, 131.68, 121.25 , 115.47, 43.52. Analysis result: C ₈ H ₇ BrClNO, Calculated value: C, 38.67; H, 2.84; N, 5.64, Measured value: C, 38.53; H, 2.98; N, 5.62. HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₈ H ₇ BrClNONa, 269.9292, measured value: 269.9294.

Example C2: Synthesis of N- (4-bromophenyl) -2-chloroacetamide (4b) (2)

4-Bromoaniline (1.8398 g, 10.69 mmol) was dissolved in 5 mL of DMF to make an amine solution. Chloroacetyl chloride (1.1276 g, 9.98 mmol) was dissolved in 5 mL of DMF at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution over 5 minutes with stirring at 0 ° C., and then the mixture was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 1.5 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture to form a white precipitate. The mixture was stirred at 23 ° C. for 17 hours. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 2.1918 g of the title compound 4b (white solid) (yield: 88%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4b: ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.427 (1H, s), 7.572 (2H, d, J = 8.8 Hz), 7.512 (2H, d, J = 8.8 Hz), 4.255 (2H, s). Analysis result: C ₈ H ₇ BrClNO, calculated value: C, 38.67; H, 2.84; N, 5.64, measured value: C, 38.53; H, 2.98; N, 5.62.

Example C3: Synthesis of N- (4-bromophenyl) -2-chloroacetamide (4b) (3)

4-Bromoaniline (1.7196 g, 10.00 mmol) was dissolved in 5 mL of DMPU to prepare an amine solution. Chloroacetyl chloride (1.1222 g, 9.94 mmol) was dissolved in 5 mL of DMPU to make an acid chloride solution. After adding the amine solution to the pre-cooled acid chloride solution over 2 minutes, the mixture was stirred at 0 ° C. for 10 minutes. A precipitate was not formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 1.5 hours. A precipitate was not formed. Then 80 mL of water was added to the mixture to form a white precipitate. The resulting precipitate was collected by suction filtration and the solid was washed with water. Then, it was dried in vacuum to obtain 2.0077 g of the title compound 4b (white solid) (yield: 81%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4b: Analysis result: C ₈ H ₇ BrClNO, calculated value: C, 38.67; H, 2.84; N, 5.64, measured value: C, 38.59; H, 2.99; N, 5.68.

Example C4: Synthesis of N- (4-bromophenyl) -2-chloroacetamide (4b) (4)

4-Bromoaniline (1.8148 g, 10.55 mmol) was dissolved in 5 mL of TMU, and this was used as an amine solution. Chloroacetyl chloride (1.1526 g, 10.21 mmol) was dissolved in 5 mL of TMU at room temperature to obtain an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 5 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring and cooling at 5 ° C. over 5 minutes, and then the mixture was stirred at 5 ° C. for 10 minutes. A precipitate was not formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 1.5 hours. A precipitate was not formed. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture to form a white precipitate. The mixture was stirred at 23 ° C. overnight. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 2.2709 g of the title compound 4b (white solid) (yield: 90%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4b: Melting point: 178-179 ° C (white powder). ¹ H-NMR (400 MHz, DMSO-d ₆ ): 10.423 (1H, s), 7.571 (2H, d, J = 8.8 Hz), 7.510 (2H, d, J = 9.2 Hz), 4.253 (2H, s). ¹³ C-NMR (100 MHz, DMSO-d ₆ ): 164.75, 137.81, 131.64, 121.23, 115.45, 43.49. Analysis results: C ₈ H ₇ BrClNO, Calculated value: C, 38.67; H, 2.84; N, 5.64; Measured value: C, 38.55; H, 2.95; N, 5.65.HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₈ H ₇ BrClNONa, 269.9292, measured value: 269.9297.

Example C5: Synthesis of N- (4-bromophenyl) -2-chloroacetamide (4b) (5)

4-Bromoaniline (1.8394 g, 10.69 mmol) was dissolved in 5 mL of DMI to make an amine solution. Chloroacetyl chloride (1.1451 g, 10.14 mmol) was dissolved in 5 mL of DMI at room temperature to obtain an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution over 5 minutes with stirring and cooling at 0 ° C. The mixture turned yellow. The mixture was stirred at 0 ° C. for 10 minutes. A precipitate was not formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 1.5 hours. A precipitate was not formed. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture to form a white precipitate. The mixture was stirred at 23 ° C. overnight. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 2.3506 g of the title compound 4b (white solid) (yield: 93%). The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4b: Melting point: 174-177 ° C.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 10.426 (1H, s), 7.571 (2H, d, J = 9.2 Hz), 7.514 (2H, d, J = 9.2 Hz), 4.255 (2H, s ¹³ C-NMR (100 MHz, DMSO-d ₆ ): 164.78, 137.83, 131.67, 121.26, 115.47, 43.52. Analytical results: C ₈ H ₇ BrClNO, calculated values: C, 38.67; H, 2.84; N, 5.64, measured values: C, 38.56; H, 2.99; N, 5.58. HRMS (ESI-TOF, [N + Na] ⁺ ): calculated value: C ₈ H ₇ BrClNONa, 269.9292, measured value: 269.9330.

The procedures and yields of Examples C1 to C5 (a: yield by precipitation method) are summarized in Table 3.

Example D: Synthesis of carboxamide compound (4)
In Example D, either an aliphatic amine or an aromatic amine is combined as an amine and either a fatty acid chloride or an aromatic acid chloride is combined as an acid chloride, and the combination is reacted in an amide solvent to obtain a carboxylic acid amide compound. Synthesized.

Example D1: Synthesis of 2-chloro-N- (4-methoxybenzyl) acetamide (4a) Synthesized as described in Example A1 above.

Example D2: Synthesis of N- (4-bromophenyl) -2-chloroacetamide (4b) Synthesized as described in Example C1 above.

Example D3: Synthesis of N, N-dibenzyl-2-chloroacetamide (4c)

Dibenzylamine (2.0800 g, 10.54 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Chloroacetyl chloride (1.1269 g, 9.98 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. The amine solution was added to the pre-cooled acid chloride solution at 0 ° C. (on ice water bath) over 4 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 20 mL of water was added to the mixture. An oily component was produced. The whole was extracted with ethyl acetate (100 mL total) and the combined organic fractions were washed with 200 mL brine. The organic fraction was evaporated to give a colorless viscous oil which was subjected to flash column chromatography with ethyl acetate: n-hexane (1: 4) to give 2.3008 g of the title compound 4c (colorless oil). Obtained (yield: 84%). The product was pure enough to give a satisfactory combustion analysis without further purification.

4c: ¹ H-NMR (400 MHz, CDCl ₃ ): 7.392-7.148 (10H, m), 4.613 (2H, s), 4.509 (2H, s), 4.141 (2H, s). ¹³ C-NMR (100 MHz,): 167.28, 136.32, 135.60, 129.08, 128.69, 128.19, 127.94, 127.64, 126.40, 50.23, 48.60, 41.31.
Analytical results: C ₁₆ H ₁₆ ClNO, calculated values: C, 70.20; H, 5.89; N, 5.12, measured values: C, 70.27; H, 6.04; N, 5.10.HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₆ H ₁₆ ClNONa ⁺ : 296.08126, measured value: 296.08137.

Example D4: Synthesis of 2-chloro-1- (3,4-dihydroisoquinolin-2 (1H) -yl) ethane-1-one (4d)

1,2,3,4-Tetrahydroisoquinoline (1.3964 g, 10.484 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Chloroacetyl chloride (1.1255 g, 9.966 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. The amine solution was added to the pre-cooled acid chloride solution (0 ° C. in an ice water bath) over 4 minutes, and the whole was stirred at 0 ° C. for 10 minutes. A yellow precipitate was formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 3 hours. Completion of the reaction was confirmed by thin layer chromatography. Then, 30 mL of water and 2 mL of 2M aqueous HCl were added to the mixture. The mixture was extracted four times with 25 mL of ethyl acetate / n-hexane (v / v 2/1), and the organic layer was washed twice with 50 mL of water. The organic fraction was dried using magnesium sulfate and the solvent was evaporated to give 1.8638 g of the title compound 4d (pale yellow solid) (yield: 89%). The product was pure enough to give a satisfactory combustion analysis without further purification.

4d: Melting point: 50-51 ℃ (colorless plate, recrystallized from methanol).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.249 (4H, m), 4.231 (2H, s), 3.833 (2H, t, J = 6.7 Hz), 2.744 (2H, t, J = 6.3 Hz), 2.001 (2H, t, J = 6.7 Hz). ¹³ C-NMR (100 MHz, CDCl ₃ ): 166.2, 138.5, 128.8, 126.7, 126.2, 123.8, 44.0, 42.0, 26.7, 23.9.
Analytical results: C ₁₁ H ₁₂ ClNO, calculated values: C, 63.01; H, 5.77; N, 6.68, measured values: C, 62.87; H, 5.84; N, 6.68. HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₁ H ₁₂ ClNNaO ⁺ : 232.0500, measured value: 232.0505.

Example D5: Synthesis of 2-chloro-N- (2-chlorobenzyl) acetamide (4e)

2-Chlorobenzylamine (1.4868 g, 10.500 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Chloroacetyl chloride (1.1367 g, 10.065 mmol) was dissolved in 5 mL of DMAC at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 5 minutes, and the whole was stirred at 0 ° C. for 14 minutes. A white precipitate was formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 1.5 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 14 hours. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 1.3640 g of the title compound 4e (white solid) (yield: 62%). The product was pure enough to give a satisfactory combustion analysis without further purification.

4e: Melting point: 76-77 ° C (white powder), 75-77 ° C (colorless needles, recrystallized from methanol). ¹ H-NMR (400 MHz, CDCl ₃ ): 7.414-7.359 (2H, m), 7.270 (1H, d, d, J = 3.9, 3.5 Hz), 7.247 (1H, d, d, J = 3.3, 3.3 Hz), 7.068 (1H, br, s), 4.587 (2H, d, J = 6.1 Hz ), 4.086 (2H, s). ¹³ C-NMR (100 MHz, CDCl ₃ ): 165.96, 134.89, 133.89, 130.35, 129.81, 129.42, 127.33, 42.75, 41.95. Analytical results: C ₉ H ₉ Cl ₂ NO, Calculated value: C, 49.57; H, 4.16; N, 6.42; Measured value: C, 49.37; H, 4.18; N, 6.43. HRMS (ESI-TOF, [N + H] ⁺ ): Calculated value: C ₉ H ₁₀ Cl ₂ NO ⁺ : 218.0134, measured value: 218.0137.

Example D6: Synthesis of N- (4-methoxybenzyl) -2-phenylacetamide (4f)

4-Methoxybenzylamine (1.4389 g, 10.389 mmol) was dissolved in 5 mL of DMAC at room temperature to obtain an amine solution. 2-Phenylacetyl chloride (1.5344 g, 9.925 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 4 minutes, and then the whole was stirred at 0 ° C. for 12 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture. The mixture was stirred at 23 ° C. for 18 hours. The mixture was extracted 4 times with 20 mL dichloromethane and the combined organic fractions were washed 3 times with 50 mL water. The organic fraction was dried with magnesium sulfate and the solvent was evaporated to give a white solid which was dried in vacuo (2.0831 g, 82%). The solid was washed with 100 mL of water, filtered and dried in vacuo to give 1.5137 g of the title compound 4f (white solid) (yield: 60%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4f: Melting point: 139-140 ℃ (colorless needles, recrystallized from methanol).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.366-7.294 (5H, m), 7.107 (2H, d, d, d, J = 8.7, 2.9, 2.1 Hz), 6.824 (2H, d, d, d , J = 8.7, 2.9, 2.0 Hz), 4.345 (2H, d, J = 5.7 Hz), 3.782 (3H, s), 3.617 (2H, s). ¹³ C-NMR (100 MHz, CDCl ₃ ): 170.72 , 158.90, 134.79, 130.17, 129.38, 128.98, 128.84, 127.31, 113.98, 55.23, 43.78, 43.04. Analytical result: C ₁₆ H ₁₇ NO ₂ , calculated value: C, 75.27; H, 6.71; N, 5.49, measured value : C, 75.21; H, 6.77; N, 5.47. HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₆ H ₁₇ NO ₂ + Na ⁺ : 278.11515, measured value: 278.11732.

Example D7: Synthesis of N- (2,2-diphenylethyl) benzamide (4 g)

2,2-diphenylethane-1-amine (2.2351 g, 11.33 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Benzoyl chloride (1.4247 g, 10.14 mmol) was dissolved in 5 mL of DMAC at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 8 minutes, and the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 1.5 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 20 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. overnight. The solid was filtered off with suction and washed with 100 mL of water. Subsequently, it was dried in vacuum to obtain 2.0365 g of the title compound (white solid) (yield: 67%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4g: Melting point: 144-145 ℃ (precipitate, white powder), 145-146 ℃ (colorless needles, recrystallized from methanol).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.571 (2H, d, J = 7.2 Hz), 7.44 (1H, t, t, J = 7.4, 1.2 Hz), 7.372-7.213 (12H, m), 4.325 . (1H, t, J = 8.0 Hz), 4.089 (2H, d, d, J = 8.0 Hz, 6.0 Hz) 13 C-NMR (100 MHz, CDCl 3): 167.60, 141.95, 134.70, 131.53, 128.93, 128.65, 128.21, 127.05, 126.90, 50.65, 44.38. Analysis result: C ₂₁ H ₁₉ NO, calculated value: C, 83.69; H, 6.35; N, 4.65, measured value: C, 83.40; H, 6.50; N, 4.66 HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value:
C ₂₁ H ₁₉ NONa, 324.1359, measured value: 324.1363.

Example D8: Synthesis of N- (2-chlorobenzyl) benzamide (4h)

2-Chlorobenzylamine (1.4838 g, 10.479 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Benzoyl chloride (1.4000 g, 9.960 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. The amine solution was added to the pre-cooled acid chloride solution at 0 ° C. over 3 minutes, and the whole was stirred at 0 ° C. for 10 minutes. A white precipitate was formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 4 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 40 mL of water was added to the mixture. A white precipitate was formed. The whole was stirred at 23 ° C. for 14 hours. The resulting precipitate was collected by suction filtration and the solid was washed with 70 mL of water. Then, it was dried in vacuum to obtain 1.9768 g of the title compound 4h (white solid) (yield: 81%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4h: Melting point: 119-121 ° C (colorless plate, recrystallized from methanol).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.786 (2H, d, J = 7.0 Hz), 7.525-7.739 (5H, m), 7.255-7.237 (2H, m), 6.621 (1H, br, s) , 4.732 (2H, d, J = 6.0 Hz) 13 C-NMR (100 MHz, CDCl 3):. 167.5, 135.7, 134.4, 133.9, 131.8, 130.6, 129.7, 129.2, 128.8, 127.3, 127.1, 42.2.
Analytical result: C ₁₄ H ₁₂ ClNO, calculated value: C, 68.44; H, 4.92; N, 5.70, measured value: C, 68.23; H, 5.15; N, 5.73.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₄ H1 ₂ ClNNaO ⁺ : 268.0500, measured value: 268.0513.

Example D9: Synthesis of N, N-dibenzyl-4-fluorobenzamide (4i)

Dibenzylamine (2.0790 g, 10.54 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. 4-Fluorobenzoyl chloride (1.5871 g, 10.19 mmol) was dissolved in 5 mL of DMAC to obtain an acid chloride solution. After adding the amine solution to the pre-cooled acid chloride solution over 3 minutes, the whole was stirred at 0 ° C. for 3 minutes. A white precipitate was formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 18 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture. A white precipitate was formed. The resulting precipitate was collected by suction filtration and the solid was washed with water. It was then dried in vacuum. It was contaminated with p-fluorobenzene acid. For this, the solid was dissolved in 100 mL dichloromethane and the organic layer was washed with 50 mL saturated aqueous sodium bicarbonate and 40 mL brine. Drying with magnesium sulfate and evaporation of the solvent gave 2.2358 g of the title compound 4i (white powder) (yield: 70%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4i: Melting point. 93-95 ° C (white powder). ¹ H-NMR (400 MHz, CDCl ₃ ): 7.497 (2H, d, d, J = 8.8, 5.2 Hz), 7.377-7.137 (10H, m), 7.051 (2H, t, J = 8.8 Hz), 4.697 (2H, s), 4.406 (2H, s) 13 C-NMR (100 MHz, CDCl 3):. 171.29, 163.3 (d, 1 J CF = 248Hz) , 136.72, 136.24, 132.13, 132.09, 129.02, 128.94, 128.80, 128.39, 127.62, 126.83, 115.6 ( ² J _CF = 22Hz), 51.57, 47.15. Analytical result: C ₂₁ H ₁₈ FNO, calculated value: C, 78.98; H, 5.68; N, 4.39, measurements: C, 78.73; H, 5.92; N, 4.39.

Example D10: Synthesis of N- (2-chlorobenzyl) -4-fluorobenzamide (4j)

2-Chlorobenzylamine (1.4865 g, 10.498 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. 4-Fluorobenzoyl chloride (1.5893 g, 10.024 mmol) was dissolved in 5 mL of DMAC at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 5 minutes, and the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture. A white precipitate was formed. The whole was stirred at 23 ° C. for 13 hours. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 2.0227 g of the title compound 4j (white solid) (yield: 77%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4j: Melting point: 107-108 ℃ (white powder), 107-109 ℃ (colorless prism, recrystallized from methanol).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.791 (2H, d, d, d, d, J = 8.9, 5.3, 3.0, 2.2 Hz), 7.446 (1H, d, d, J = 5.8, 3.4 Hz ), 7.385 (1H, d, d, J = 5.6, 3.6 Hz), 7.266-7.223 (2H, m), 7.094 (2H, d, d, J = 8.6, 8.6 Hz), 6.660 (1H, s), 4.700 (2H, s). ¹³ C-NMR (100 MHz, CDCl ₃ ): 166.1, 165.1 (d, ¹ J _CF = 285 Hz), 135.6, 133.8, 130.5 (d, ⁴ J _CF = 3.0 Hz), 130.5 , 129.7, 129.5 (d, ³ J _CF = 9.3 Hz), 129.2, 127.3, 115.7 (d, ² J _CF = 22 Hz), 42.2. Analysis result: C ₁₄ H ₁₁ ClFNO, calculated value: C, 63.77; H , 4.20; N, 5.31, measured values: C, 63.63; H, 4.40; N, 5.31.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated: C ₁₄ H ₁₁ ClFNNaO ⁺ : 286.0405, Found: 286.0415.

Example D11: Synthesis of 6-chloro-N- (4-methoxybenzyl) nicotinamide (4k)

4-Methoxybenzylamine (0.8560 g, 6.240 mmol) was dissolved in 3 mL of DMAC at room temperature to obtain an amine solution. 6-chloronicotinoyl chloride (1.0476 g, 5.952 mmol) was dissolved in 3 mL of DMAC, and this was used as an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 3 minutes, and the whole was stirred at 0 ° C. for 4 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 0.5 hour. Completion of the reaction was confirmed by thin layer chromatography. Then 20 mL of water was added to the mixture. A white precipitate was formed. The whole was stirred at 23 ° C. for 19 hours. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 1.1792 g of the title compound 4k (white solid) (yield: 72%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4k: Melting point: 139 ° C (colorless powder) (recrystallized from methanol).
¹ H-NMR (400 MHz, CDCl ₃ ): 8.731 (1H, d, d, J = 2.5, 0.7 Hz), 8.084 (1H, d, d, J = 8.3, 2.5 Hz), 7.390 (1H, d, d, J = 8.3, 0.7 Hz), 7.257 (2H, d, d, d, J = 8.3, 3.2, 1.9 Hz), 6.871 (2H, d, d, d, J = 8.8, 2.9, 2.0 Hz), 6.631 (1H, br), 4.557 (2H, d, J = 5.4 Hz), 3.796 (3H, s) 13 C-NMR (100 MHz, CDCl 3):. 164.49, 159.42, 154.36, 148.05, 140.16, 138.18, 129.55, 129.12, 124.52, 114.372, 55.45, 43.97.
Analytical result: C ₁₄ H ₁₃ ClN ₂ O ₂ , calculated value: C, 60.77; H, 4.74; N, 10.12, measured value: C, 60.68; H, 4.87; N, 10.10.
HRMS (ESI-TOF, [N + H] ⁺ ): Calculated value: C ₁₄ H ₁₄ ClN ₂ O ₂ ⁺ : 277.0738, measured value: 277.0731.

Example D12: Synthesis of N- (4-methoxybenzyl) benzamide (41)

4-Methoxybenzylamine (1.4443 g, 10.528 mmol) was dissolved in 5 mL of DMAC to obtain an amine solution. Benzoyl chloride (1.4187 g, 10.093 mmol) was dissolved in 5 mL of DMAC at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 4 minutes. A white precipitate was formed. The whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 1.5 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture. A white precipitate dissolved and formed again. The mixture was stirred at 23 ° C. for 17 hours. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 1.2393 g of the title compound 4l (white solid) (yield: 51%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4l: Melting point: 96-98 ℃ (precipitate, colorless fine needles), 101 ℃ (colorless needles, recrystallized from methanol).
¹ H-NMR (400 MHz, CDCl ₃ ): 8.127 (1H, d, d, J = 9.0, 5.4 Hz), 7.790 (2H, d, d, J = 8.9, 5.3 Hz), 7.285 (2H, d, d, d, J = 8.7, 3.0, 2.1 Hz), 7.177-7.072 (3H, m), 6.891 (2H, d, d, d, J = 8.7, 3.0, 2.1 Hz), 4.573 (2H, d, J = 5.4 Hz), 3.808 (3H , s) 13 C-NMR (100 MHz, CDCl 3):. 167.25, 159.04, 134.38, 131.43, 130.23, 129.24, 128.50, 126.91, 114.08, 55.26, 43.56.
Analytical result: C ₁₅ H ₁₅ NO ₂ , calculated value: C, 74.67; H, 6.27; N, 5.81, measured value: (precipitate): C, 74.66; H, 6.38; N, 5.70, measured value: (crystal ): C, 74.46; H, 6.38; N, 5.83.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₅ H ₁₅ NO ₂ + Na ⁺ : 264.09950, measured value: 264.09937.

Example D13: Synthesis of 4-fluoro-N- (4-methoxybenzyl) benzamide (4m)

4-Methoxybenzylamine (1.4391 g, 10.490 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. 4-Fluorobenzoyl chloride (1.5893 g, 10.024 mmol) was dissolved in 5 mL of DMAC at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 4 minutes. A white precipitate was formed. The whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 1.5 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture. A white precipitate dissolved once and formed again. The mixture was stirred at 23 ° C. for 18 hours. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 1.7441 g of the title compound 4m (white solid) (yield: 67%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4m: Melting point: 117-118 ° C (colorless plate, recrystallized from methanol).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.778 (2H, d, J = 7.0 Hz), 7.497 (1H, t, J = 7.3 Hz), 7.420 (2H, d, d, J = 7.8, 5.4 Hz) ), 7.290 (2H, d, J = 8.8 Hz), 6.889 (2H, d, J = 8.7 Hz), 4.580 (2H, d, J = 5.6 Hz), 3.806 (3H, s). 13 C-NMR ( 100 MHz, CDCl ₃ ): 166.18, 165.92, 163.42, 159.12, 130.58, 130.55, 130.08, 129.28, 129.20, 115.65, 115.43, 114.13, 55.28, 43.66.
Analytical result: C ₁₅ H ₁₄ FNO ₂ , calculated value: C, 69.49; H, 5.44; N, 5.40, measured value: (crystal): C, 69.37; H, 5.63; N, 5.44.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₅ H _14F NO ₂ + Na ⁺ : 282.09008, measured value: 282.008946.

Example D14: Synthesis of 2-chloro-N-methyl-N-phenylacetamide (4n)

N-methylaniline (1.1122 g, 10.379 mmol) was dissolved in 5 mL of DMAC to obtain an amine solution. Chloroacetyl chloride (1.1219 g, 9.934 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. After adding the amine solution to the pre-cooled acid chloride solution over 3 minutes, the whole was stirred at 0 ° C. for 10 minutes. A white precipitate was formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 5 hours. Then 30 mL of water was added to the mixture. A white precipitate appeared. The mixture was stirred at 23 ° C. for 1 hour. The resulting precipitate was collected by suction filtration and the solid was washed with 60 mL of water. Then, it was dried in vacuum to obtain 1.1619 g of the title compound 4n (white solid) (yield: 64%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4n: Melting point: 67-68 ℃ (colorless plate, recrystallized from toluene).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.459 (2H, d, d, J = 7.7, 7.0 Hz), 7.270-7.255 (1H, m), 7.260-7.240 (2H, m), 3.851 (2H, . s), 3.322 (3H, s) 13 C-NMR (100 MHz, CDCl 3): 166.4, 142.8, 130.2, 128.7, 127.2, 41.7, 38.1.
Analytical result: C ₉ H ₁₀ ClNO, calculated value: C, 58.87; H, 5.49; N, 7.63, measured value: C, 58.78; H, 5.56; N, 7.60 (precipitate).
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₉ H ₁₀ ClNNaO ⁺ : 206.0343, measured value: 206.0345.

Example D15: Synthesis of 2-chloro-1- (indolin-1-yl) ethane-1-one (4o)

Indoline (1.2549 g, 10.53 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Chloroacetyl chloride (1.1235 g, 9.95 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. The amine solution was added to the pre-cooled acid chloride solution over 5 minutes. A large amount of white precipitate formed immediately. The resulting precipitate was collected by suction filtration and the solid was dried in vacuo to give 1.7290 g of the title compound 4o (white solid) (yield: 89%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4o: Melting point. 135-136 ° C (colorless needles).
¹ H-NMR (400 MHz, CDCl ₃ ): 8.202 (1H, d, J = 8.0 Hz), 7.213 (2H, d, d, J = 8.8, 8.0 Hz), 7.060 (1H, d, d, J = . 7.6, 7.2 Hz), 4.153-4.111 (4H, m), 3.225 (2H, t, J = 8.4 Hz) 13 C-NMR (100 MHz, CDCl 3): 163.89, 142.40, 131.13, 127.61, 124.60, 124.43 , 117.23, 47.77, 43.09, 28.11.
Analytical result: C ₁₀ H ₁₀ ClNO, calculated value: C, 61.39; H, 5.15; N, 7.16, measured value: C, 61.13; H, 5.26; N, 7.15.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₀ H ₁₀ ClNNaO ⁺ , 218.03431, measured value: 218.03411.

Example D16: Synthesis of N- (4-bromophenyl) -4-fluorobenzamide (4p)

4-Bromoaniline (1.7920 g, 10.417 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. 4-Fluorobenzoyl chloride (1.5672 g, 9.884 mmol) was dissolved in 5 mL of DMAC at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring and cooling at 0 ° C. over 4 minutes, and the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 3 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 15 hours. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 2.7391 g of the title compound 4p (white solid) (yield: 94%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4p: Melting point: 168-176 ° C (colorless needles, recrystallized from methanol).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.878 (2H, d, d, J = 8.9, 5.2 Hz), 7.741 (1H, br, s), 7.511 (4H, d, d, d, d, J = 10.4, 9.1, 2.4, 2.4 Hz), 7.177 (2H, d, d, J = 8.8, 8.4 Hz) 13 C-NMR (100 MHz, DMSO-d 6):. 164.52, 164.13 (1 J CF = 248 Hz), 138.47, 131.44, 131.12, 131.09, 130.48, 130.39, 122.23, 115.40, 115.4 ( ² J _CF = 22 Hz).
Analytical result: C ₁₃ H ₉ BrFNO, calculated value: C, 53.09; H, 3.08; N, 4.76., Measured value: C, 53.08; H, 3.34; N, 4.73. HRMS (ESI-TOF, [N + H] ⁺ ): Calculated value: C ₁₃ H ₁₀ BrFNO ⁺ , 293.9924, measured value: 293.9920.

Example D17: Synthesis of (4-fluorophenyl) (indoline-1-yl) methanone (4q)

Indoline (1.2728 g, 10.68 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. 4-Fluorobenzoyl chloride (1.6248 g, 10.25 mmol) was dissolved in 5 mL of DMAC at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution over 5 minutes with stirring at 0 ° C. A white precipitate formed immediately. The whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 20 mL of water was added to the mixture. The preformed precipitate was dissolved once and another white precipitate was formed. The mixture was stirred at 23 ° C. overnight. The solid was filtered off with suction and washed with 100 mL of water. Subsequently, it was dried in vacuum to obtain 2.2605 g of the title compound 4q (white solid) (yield: 91%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4q: Melting point: 104-105 ℃ (light red powder), 101-102 ℃ (colorless rod, recrystallized from methanol).
¹ H-NMR (400 MHz, CDCl ₃ ): 8.850-7.600 (1H, br), 7.500 (2H, d, d, J = 8.4, 5.6 Hz), 7.154 (2H, d, d, J = 11.6, 7.6 Hz), 7.057 (2H, d, d, J = 8.6, 8.6 Hz), 6.958 (1H, d, J = 6.4 Hz), 4.010 (2H, br), 3.050 (2H, t, J = 8.4 Hz). ¹³ C-NMR (400 MHz, CDCl ₃ ): 168.0, 163.9 (d, ¹ J _CF = 249 Hz), 142.6, 133.1, 132.5, 129.7, 129.6, 127.3, 125.1, 124.1, 115.7 (d, ² J _CF = 22 Hz), 50.8, 28.2.
Analytical result: C ₁₅ H ₁₂ FNO, calculated value: C, 74.68; H, 5.01; N, 5.81, measured value: C, 74.47; H, 5.03; N, 5.88
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₅ H ₁₂ FNNaO ⁺ : 264.0795, measured value: 264.0791

Example D18: Synthesis of (6-chloropyridin-3-yl) (indoline-1-yl) methanone (4r)

Indoline (0.7543 g, 6.330 mmol) was dissolved in 3 mL of DMAC to prepare an amine solution. 6-Chloronicotinoyl chloride (1.0557 g, 5.998 mmol) was dissolved in 3 mL of DMAC at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 3 minutes, and the whole was stirred at 0 ° C. for 4 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 45 minutes. Completion of the reaction was confirmed by thin layer chromatography. Then 20 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 17 hours. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 1.3105 g of the title compound 4r (white solid) (yield: 84%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4r: Melting point: 132-134 ° C (colorless prism, recrystallized from methanol)
¹ H-NMR (400 MHz, CDCl ₃ ): 8.613 (1H, d, J = 2.0 Hz), 8.188 (1H, br, s), 7.873 (1H, d, d, J = 8.2, 2.4 Hz), 7.442 (1H, d, d, J = 8.2, 0.7 Hz), 7.245 (2H, d, J = 7.8 Hz), 7.079 (1H, br, s), 4.087 (2H, br, s), 3.167 (2H, t ¹³ C-NMR (100 MHz, CDCl ₃ ): 165.2, 153.3, 148.5, 142.3, 137.9, 131.8, 127.6, 125.2, 124.8, 124.5, 50.8, 28.3.
Analytical result: C ₁₄ H ₁₁ ClN ₂ O, calculated value: C, 65.00; H, 4.29; N, 10.83, measured value: C, 64.62; H, 4.50; N, 10.85.
HRMS (ESI-TOF, [N + H] ⁺ ): Calculated value: C ₁₄ H ₁₂ ClN ₂ O ⁺ : 259.0633, measured value: 259.0647.

The chemical structure of the compounds synthesized in Examples D1 to D18, the stirring temperature and time, and the yield (a: the yield by precipitation method, b: the yield by column chromatography (oily substance), c: solidification after extraction) Table 4 shows.

Example E: Synthesis of carboxamide compound (5)
In Example E, various weakly basic amines and neutral amines and acid chlorides were reacted in an amide solvent to synthesize carboxylic acid amide compounds.
Example E1: Synthesis of isobutyl 4-benzamide benzoate (5a-1)

4-Butyl isobutyl 4-aminobenzoate (1.9390 g, 10.03 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Benzoyl chloride (1.4072 g, 10.1 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. After adding the amine solution to the pre-cooled acid chloride solution over 3 minutes, the whole was stirred at 0 ° C. for 20 minutes. A white precipitate was formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2.5 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 40 mL of water was added to the mixture. The resulting precipitate was collected by suction filtration and the solid was washed with water. Then, it was dried in vacuum to obtain 2.8470 g of the title compound 5a-1 (white solid) (yield: 96%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

5a-1: Melting point. 128.5-129.0 ℃ (colorless needles).
¹ H-NMR (400 MHz, CDCl ₃ ): 8.064 (3H, d, J = 6.8 Hz), 7.882 (2H, d, J = 6.8 Hz), 7.750 (2H, d, J = 8.8 Hz), 7.573 ( 1H, d, d, J = 7.6, 7.2 Hz), 7.495 (2H, d, d, J = 8.4, 8.0 Hz), 4.097 (2H, d, J = 6.4 Hz), 2.088 (1H, sep, J = . 6.8 Hz), 1.023 (6H , d, J = 6.8 Hz) 13 C-NMR (100 MHz, CDCl 3): 166.12, 165.80, 142.04, 134.53, 132.20, 130.83, 128.88, 127.07, 126.20, 119.18, 70.96, 27.89, 19.20
Analytical result: C ₁₈ H ₁₉ NO ₃ , calculated value: C, 72.71; H, 6.44; N, 4.71, measured value: C, 72.42; H, 6.57; N, 4.77.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated: C ₁₈ H ₁₉ NO ₃ + Na ⁺ , 320.12571, measured: 320.12618.

Example E2: Synthesis of isopropyl 4-benzamide benzoate (5a-2)

Isopropyl 4-aminobenzoate (1.8565 g, 10.359 mmol) was dissolved in 5 mL of DMAC to obtain an amine solution. Benzoyl chloride (1.3828 g, 9.873 mmol) was dissolved in 5 mL of DMAC at room temperature to form an acid chloride solution. The amine solution was added to the pre-cooled acid chloride solution over 3 minutes with stirring at 0 ° C., and the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 3 hours. 30 mL of water was added to the mixture. The mixture was extracted 4 times with 20 mL of dichloromethane, the combined organic fractions were washed 3 times with 50 mL of water, and the organic fractions were dried over magnesium sulfate. The organic solvent was evaporated to give a white solid and dried in vacuo to give 2.6013 g of the title compound 5a-2 (white solid) (yield: 93%). The product was pure enough to give a satisfactory combustion analysis without further purification.

5a-2: ¹ H NMR (400 MHz, CDCl ₃ ): 8.210 (1H, s), 8.028 (2H, d, J = 8.6 Hz), 7.872 (2H, d, J = 7.4 Hz), 7.745 (2H, d, J = 8.6 Hz), 7.552 (1H, d, d, J = 7.2, 7.1 Hz), 7.467 (2H, d, d, J = 7.8, 7.7 Hz), 5.232 (1H, sep, J = 6.2 Hz ), 1.365 (6H, d, J = 6.2 Hz) ¹³ C NMR (100 MHz, CDCl ₃ ): 166.05, 165.79, 142.16, 134.68, 132.29, 130.90, 128.97, 127.24, 126.70, 119.31, 68.46, 22.10.
Analytical result: C ₁₇ H ₁₇ NO ₃ , calculated value: C, 72.07; H, 6.05; N, 4.94, measured value: C, 71.89; H, 6.16; N, 4.98.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₇ H ₁₇ NNaO ₃ ⁺ : 306.1101, measured value: 306.1115.

Example E3: Synthesis of methyl 2-benzamide benzoate (5b)

Methyl anthranilate (1.5264 g, 10.10 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Benzoyl chloride (1.4040 g, 9.99 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. The amine solution was added to the pre-cooled acid chloride solution over 2 minutes, and the whole was stirred at 0 ° C. for 10 minutes. A white precipitate was formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 1.5 hours. Completion of the reaction was confirmed by thin layer chromatography. 50 mL of water was added to the mixture. The resulting precipitate was collected by suction filtration and the solid was washed with water. Then, it was dried in vacuum to obtain 2.2723 g of the title compound 5b (white solid) (yield: 89%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

5b: Melting point. 99-100 ° C (white powder).
¹ H-NMR (400 MHz, CDCl ₃ ): 12.044 (1H, s), 8.931 (1H, s), 8.068 (3H, d, d, J = 10.0, 8.8 Hz), 7.068 (1H, d, d, d, J = 8.8, 7.2, 1.6 Hz), 7.563-7.511 (3H, m), 7.123 (1H, d, d, J = 8.0, 7.6 Hz), 3.962 (3H, s). 13 C-NMR (100 _{MHz, CDCl 3): 169.04,} 165.69, 141.85, 134.81, 131.92, 130.92, 128.78, 127.35, 122.58, 120.43, 115.12, 52.45.
Analytical result: C ₁₅ H ₁₃ NO ₃ , calculated value: C, 70.58; H, 5.13; N, 5.49, measured value: C, 70.41; H, 5.24; N, 5.51.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated: C ₁₅ H ₁₃ NO ₃ + Na ⁺ , 278.07876, Found: 278.07938.

Example E4: Synthesis of N- (2-nitrophenyl) benzamide (5c)

2-Nitroaniline (1.4482 g, 10.485 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Benzoyl chloride (1.4035 g, 9.985 mmol) was dissolved in 5 mL of DMAC at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 3 minutes and cooled, and then the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 4 hours. Completion of the reaction was confirmed by thin layer chromatography. 30 mL of water was added to the mixture. A yellow precipitate was formed. The whole was stirred at 23 ° C. for 21 hours. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to give 2.120 g of the title compound 5c (white solid) (yield: 87%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

5c: Melting point: 94 ° C (yellow needles).
¹ H-NMR (400 MHz, CDCl ₃ ): 9.015 (1H, d, d, J = 8.5, 1.3 Hz), 8.288 (1H, d, d, J = 8.5, 1.5 Hz), 8.005 (2H, d, J = 6.9 Hz), 7.725 (1H, t, d, J = 7.9, 1.5 Hz), 7.617 (1H, d, d, J = 7.4, 7.2 Hz), 7.548 (2H, d, d, J = 7.6, . 7.0 Hz), 7.231 (1H , d, d, d, J = 7.9, 7.8, 1.3 Hz) 13 C-NMR (100 MHz, CDCl 3): 165.92, 136.61, 136.37, 135.51, 134.19, 132.81, 129.21, 127.52, 126.08, 123.47, 122.29.
Analytical result: C ₁₃ H ₁₀ N ₂ O ₃ , calculated value: C, 64.46; H, 4.16; N, 11.56, measured value: C, 64.22; H, 4.38; N, 11.51.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated: C ₁₃ H ₁₀ N ₂ NaO ₃ ⁺ : 265.0584, Found: 265.0587.

Example E5: Synthesis of N- (3-nitrophenyl) benzamide (5d)

3-Nitroaniline (1.3863 g, 10.04 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Benzoyl chloride (1.4071 g, 10.1 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. After adding the amine solution to the pre-cooled acid chloride solution over 1 minute, the whole was stirred at 0 ° C. for 20 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 1.5 hours. 20 mL of water was added to the mixture. A white precipitate was formed. The resulting precipitate was collected by suction filtration and the solid was washed with water. Then, it was dried in vacuum to obtain 2.3405 g of the title compound 5d (white solid) (yield: 97%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

5d: Melting point: 158-159 ° C (colorless fine needles).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 10.717 (1H, s), 8.835 (1H, d, d, J = 2.0, 2.0 Hz), 8.220 (1H, d, d, d, J = 8.0 , 2.4, 0.8 Hz), 8.020 (2H, d, J = 8.0 Hz), 8.969 (1H, d, d, d, J = 8.0, 2.4, 0.8 Hz), 7.645 (2H, d, d, J = 7.2 , 6.8 Hz), 7.578 (2H , d, d, J = 7.2, 6.8 Hz) 13 C-NMR (100 MHz, DMSO-d 6):. 166.04, 147.89, 140.39, 134.24, 132.03, 130.02, 128.50, 127.78 , 126.13, 118.09, 114.32.
Analytical result: C ₁₃ H ₁₀ N ₂ O ₃ , calculated value: C, 64.46; H, 4.16; N, 11.56, measured value: C, 64.66; H, 4.38; N, 11.65.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated: C ₁₃ H ₁₀ N ₂ O ₃ + Na ⁺ : 265.05836, Found: 265.05828.

Example E6: Synthesis of N- (4-nitrophenyl) benzamide (5e)

4-Nitroaniline (1.4101 g, 10.20 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Benzoyl chloride (1.4028 g, 9.98 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. The amine solution was added to the pre-cooled acid chloride solution over 3 minutes, and the whole was stirred at 0 ° C. for 2 hours. 50 mL of water was added to the mixture. A white precipitate was formed. The resulting precipitate was collected by suction filtration and the solid was washed with water. Then, it was dried in vacuum to obtain 2.3573 g of the title compound 5e (white solid) (yield: 98%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

5e: Melting point: 201-202 ° C (light green powder).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 10.820 (1H, br s), 8.279 (2H, d, J = 9.2 Hz), 8.079 (2H, d, J = 9.2 Hz), 8.079 (2H, d, J = 9.6 Hz), 7.990 (2H, d, J = 7.6 Hz), 7.654 (2H, d, d, J = 7.2, 7.2 Hz), 7.572 (2H, d, d, J = 8.0, 8.0 Hz ¹³ C-NMR (100 MHz, DMSO-d ₆ ): 166.29, 145.51, 142.46, 134.23, 132.18, 128.52, 127.92, 124.80, 119.83.
Analytical result: C ₁₃ H ₁₀ N ₂ O ₃ , calculated value: C, 64.46; H, 4.16; N, 11.56, measured value: C, 64.26; H, 4.29; N, 11.60.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₃ H ₁₀ N ₂ O ₃ + Na ⁺ : 265.05836, measured value: 265.05815.

Example E7: Synthesis of N- (4-cyanophenyl) benzamide (5f)

4-Aminobenzonitrile (1.2370 g, 10.471 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Benzoyl chloride (1.4051 g, 9.996 mmol) was dissolved in 5 mL of DMAC at room temperature to form an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring and cooling at 0 ° C. over 4 minutes, and the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. Completion of the reaction was confirmed by thin layer chromatography. 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 15 hours. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 2.1417 g of the title compound 5f (white solid) (yield: 96%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

5f: Melting point: 165-167 ° C (colorless powder, recrystallized from methanol).
¹ H-NMR (400 MHz, CDCl ₃ ): 8.027 (1H, be, s), 7.876 (2H, d, J = 7.0 Hz), 7.801 (2H, d, J = 8.9 Hz), 7.662 (2H, d , J = 8.8 Hz), 7.601 (1H, d, d, J = 7.6, 7.3 Hz), 7.518 (2H, d, d, J = 7.7, 7.2 Hz). ¹³ C-NMR (100 MHz, CDCl ₃ ) : 166.2, 143.5, 134.4, 133.1, 132.1, 128.5, 127.9, 120.2, 119.1, 105.3.
Analytical results: C ₁₄ H ₁₀ N ₂ O, calculated values: C, 75.66; H, 4.54; N, 12.60, measured values: C, 75.63; H, 4.69; N, 12.62. HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₄ H ₁₀ N ₂ NaO ⁺ : 245.0685, measured value: 245.0688.

Example E8: Synthesis of N- (benzylcarbamoyl) benzamide (5 g)

1-Benzylurea (1.5162 g, 10.10 mmol) was suspended in 5 mL of DMAC, and this was used as a urea suspension. Benzoyl chloride (1.4118 g, 10.04 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. The acid chloride solution was added to the urea suspension over 3 minutes at 23 ° C., and the whole was stirred at 23 ° C. for 7.5 hours. A clear solution was obtained. Completion of the reaction was confirmed by thin layer chromatography. 40 mL of water was added to the mixture. The resulting precipitate was collected by suction filtration and the solid was washed with water. Then, it was dried in vacuum to obtain 1.2965 g of the title compound (white solid) (yield: 51%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

5g: Melting point. 168-169 ° C (colorless cube, recrystallized from methanol).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 10.790 (1H, s), 9.093 (1H, s), 7.977 (2H, d, J = 7.2 Hz), 7.621 (1H, d, d, J = 7.6, 7.2 Hz), 7.507 (2H, d, d, J = 8.0, 7.6 Hz), 7.357-7.244 (5H, m), 4.462 (2H, d, J = 6.0 Hz). ¹³ C-NMR (100 MHz , DMSO-d ₆ ): 168.28, 153.66, 139.24, 132.76, 132.56, 128.49, 128.43, 128.16, 127.26, 126.96, 42.74.
Analytical result: C ₁₅ H ₁₄ N ₂ O ₂ , calculated value: C, 70.85; H, 5.55; N, 11.02, measured value: C, 70.72; H, 5.60; N, 11.01.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated: C ₁₅ H ₁₄ N ₂ O ₂ + Na ⁺ , 277.09475, measured: 277.09563.

Example E9: Synthesis of N-carbamoylbenzamide (5h)

Urea (603.4 mg, 10.05 mmol) was suspended in 8 mL of DMAC, and this was used as a urea suspension. Benzoyl chloride (1.4109 g, 10.04 mmol) was dissolved in 2 mL of DMAC to make an acid chloride solution. After the acid chloride solution was added to the preheated 70 ° C. urea suspension over 2 minutes, the whole was heated at 70 ° C. with stirring for 2 hours. A clear solution was obtained. Completion of the reaction was confirmed by thin layer chromatography. After the mixture was cooled to room temperature, 100 mL of water was added to the reaction vessel. The resulting precipitate was collected by suction filtration and the solid was washed with water. Then, it was dried in vacuum to obtain 991.9 mg of the title compound 5h (white solid) (yield: 60%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

5h: Melting point. 169-172 ° C (colorless fine needles).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 10.547 (1H, s), 8.059 (1H, br, s), 7.961 (2H, d, J = 7.2 Hz), 7.613 (1H, d, d, J = 7.6, 7.2 Hz), 7.499 (2H, d, d, J = 8.0, 7.6 Hz), 7.047 (1H, br, s) ¹³ C-NMR (100 MHz, DMSO-d ₆ ): 168.13, 154.19, 132.72, 132.69, 128.48, 128.13
Analytical result: C ₈ H ₈ N ₂ O ₂ , calculated value: C, 58.53; H, 4.91; N, 17.06, measured value: C, 58.25; H, 5.07; N, 17.15.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated: C ₈ H ₈ N ₂ O ₂ + Na ⁺ , 187.04780, Found: 187.004842.

Table 5 shows the chemical structure, stirring temperature and time, and yield (a: yield by precipitation method) of the compounds synthesized in Examples E1 to E9.

Example F: Synthesis of carboxylic acid amide compound (6)
In Example F, various zwitterionic molecules and acid chlorides were reacted in an amide solvent to synthesize a carboxylic acid amide compound.

Example F1: Synthesis of 2-benzamide benzoic acid (6a)

Anthranilic acid (1.3716 g, 10.00 mmol) was dissolved in 5 mL of DMAC to prepare an anthranilic acid solution. Benzoyl chloride (1.4057 g, 10.00 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. The anthranilic acid solution was added to the pre-cooled acid chloride solution at 0 ° C. (on ice water bath) over 5 minutes. A white precipitate was formed. The whole was stirred at 0 ° C. for 5 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 1.5 hours. 40 mL of water was added to the mixture. A white precipitate was formed. The resulting precipitate was collected by suction filtration and the solid was washed with water. Then, it was dried in vacuum to obtain 2.2910 g of the title compound 6a (white solid) (yield: 95%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

6a: Melting point. 182.2-183 ° C (colorless fine needles).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 13.817 (1H, brs), 12.204 (1H, s), 8.742 (1H, d, d, J = 8.6, 1.2 Hz), 8.082 (1H, d, d, J = 7.8, 2.0Hz), 7.981 (2H, d, d, J = 7.8, 1.2Hz), 7.683 (1H, t, d, J = 8.0, 1.6 Hz), 7.647 (1H, t, d, J = 7.2, 1.6Hz), 7.608 (2H, t, d, J = 6.8, 1.6 Hz), 7.227 (1H, t, d, J = 7.4, 1.2Hz).
¹³ C-NMR (100 MHz, DMSO-d ₆ ): 170.04, 164.70, 141.14, 134.54, 134.35, 132.20, 131.30, 129.00, 127.03, 122.95, 119.89, 116.51.
Analytical result: C ₁₄ H ₁₁ NO ₃ , calculated value: C, 69.70; H, 4.60; N, 5.81, measured value: C, 69.93; H, 4.82; N, 5.90.
HRMS (ESI-TOF, [NH ] -): _{_{_{Calculated: C 14 H 10 NO 3 -H}}} -, 240.06662, found: 240.06760.

Example F2: Synthesis of 2-benzamide benzoic acid (6a)

Anthranilic acid (1.3740 g, 10.00 mmol) was dissolved in 5 mL of DMPU to prepare an anthranilic acid solution. Benzoyl chloride (1.4063 g, 10.00 mmol) was dissolved in 5 mL of DMPU to make an acid chloride solution. The anthranilic acid solution was added to the precooled acid chloride solution at 0 ° C. (on an ice-water bath) over 4 minutes, and then the whole was stirred at 0 ° C. for 3 minutes. A precipitate was not formed. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 1.5 hours. A precipitate was not formed. 40 mL of water was added to the mixture. A white precipitate was formed. The resulting precipitate was collected by suction filtration and the solid was washed with water. Then, it was dried in vacuum to obtain 2.3272 g of the title compound 6a (white solid) (yield: 96%). The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

Measured value: analysis result: C ₁₄ H ₁₁ NO ₃ , calculated value: C, 69.70; H, 4.60; N, 5.81, measured value: C, 69.32; H, 4.84; N, 5.72.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 13.810 (1H, brs), 12.190 (1H, s), 8.727 (1H, d, d, J = 8.4, 0.8 Hz), 8.070 (1H, d, d, J = 7.8, 1.4 Hz), 7.969 (2H, d, J = 7.6 Hz), 7.697-7.579 (4H, m), 7.219 (1H, t, d, J = 7.4, 1.2 Hz).
¹³ C-NMR (100 MHz, DMSO-d ₆ ): 170.03, 164.71, 141.13, 134.54, 134.35, 132.21, 131.30, 129.01, 127.03, 122.97, 119.89, 116.53.

Example F3: Synthesis of benzoylglycine (6b)

Benzoyl chloride (1.4039 g, 9.99 mmol) was dissolved in 5 mL of DMAC to obtain an acid chloride solution. Pure glycine (748.0 mg, 9.96 mmol) was added to the pre-cooled acid chloride solution at 0 ° C. (on ice water bath) over 1 minute and the whole was stirred at 0 ° C. for 20 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 4 hours. Completion of the reaction was confirmed by thin layer chromatography. To the mixture was added 11 mL of water. The resulting precipitate was collected by suction filtration and dried in vacuo to give 1.2561 g of the title compound 6b (white solid) (yield: 70%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

6b: Melting point. 190.5-190.7 ℃ (colorless fine needles).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 12.611 (1H, br, s), 8.847 (1H, t, J = 5.8 Hz), 7.881 (2H, d, J = 7.2 Hz), 7.551 (1H , d, d, J = 7.6, 7.2 Hz), 7.483 (2H, d, d, J = 7.6, 6.8 Hz), 3.938 (2H, d, J = 6.0 Hz). ¹³ C-NMR (100 MHz, DMSO -d ₆ ): 171.39, 166.51, 133.86, 131.46, 128.39, 127.27, 41.25.
Analytical results: C ₉ H ₉ NO ₃ + 0.1H ₂ O, calculated values: C, 59.73; H, 5.12; N, 7.74, measured values: C, 59.85; H, 5.02; N, 7.87. HRMS (ESI-TOF , [NH] ^-): _{_{_{^{calculated: C 9 H 8 NO 3 -}}}} , 178.05097, found: 178.05185.

Example F4: Synthesis of benzoyl-L-phenylalanine (6c)

Benzoyl chloride (1.4031 g, 9.982 mmol) was dissolved in 10 mL of DMAC at room temperature to obtain an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. Pure L-phenylalanine (1.7290 g, 10.467 mmol) was added to the acid chloride solution at 0 ° C. (on ice water bath) at 0 ° C. over 9 minutes with cooling and the whole was then added at 0 ° C. Stir for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 21 hours. 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 7 hours. The solid was filtered off with suction and washed with 150 mL of water. Then, it was dried in vacuum to obtain 2.0819 g of the title compound 6c (white solid) (yield: 77%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

6c: Melting point: 137-138 ° C (white powder).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.687 (2H, d, J = 7.0 Hz), 7.519 (1H, t, J = 7.4 Hz), 7.421 (2H, d, d, J = 7.8, 7.2 Hz ), 7.341-7.274 (3H, m), 7.213 (2H, d, J = 6.3 Hz), 6.546 (1H, d, J = 7.2 Hz), 5.082 (1H, d, d, d, J = 7.3, 7.3 , 7.3 Hz), 3.376 (1H , d, d, J = 38.6, 5.6 Hz), 3.280 (1H, d, d, J = 38.6, 5.6 Hz) 13 C-NMR (100 MHz, CDCl 3):. 174.9 , 167.9, 135.8, 133.6, 132.2, 129.6, 128.9, 128.8, 127.5, 127.2, 57.8, 37.4.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₆ H ₁₅ NNaO ₃ ⁺ : 292.0944., Measured value: 292.0959.
Analytical result: C ₁₆ H ₁₅ NO ₃ , calculated value: C, 71.36; H, 5.61; N, 5.20, measured value: C, 71.04; H, 5.80; N, 5.28.

Example F5: Optical purity of benzoylated phenylalanine (1) Synthesis of benzoyl-L-phenylalanine and methylation of the product carboxylic acid

Benzoyl chloride (1.4143 g, 10.061 mmol) was dissolved in 10 mL of DMAC at room temperature to obtain an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. After adding L-phenylalanine (1.7408 g, 10.538 mmol) to the acid chloride solution over 1 minute, the whole was stirred at 0 ° C. for 10 minutes. The ice bath was replaced with a water bath and the mixture was stirred at 23 ° C. for 22 hours. 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 2 hours. The solid was filtered off with suction and washed with 60 mL of water. Then, it was dried in vacuum to obtain 1.5603 g of benzoyl-L-phenylalanine 6c (white solid) (yield: 58%).

The obtained benzoyl-L-phenylalanine 6c (0.1234 g) was transferred to a 30 ml round bottom flask, 1.5 ml of methanol was added, and the whole was left at room temperature for 2 hours. 1.5 mL of trimethylsilyldiazomethane was added. The whole was evaporated to obtain a white solid, which was purified by column chromatography (ethyl acetate / n-hexane = 1/2) to obtain 0.0373 g of methyl benzoyl-L-phenylalaninate (white solid).

(2) Synthesis of benzoyl-D-phenylalanine and methylation of the product carboxylic acid

Benzoyl chloride (1.4104 g, 10.034 mol) was dissolved in 10 mL of DMAC at room temperature to obtain an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. After adding D-phenylalanine (1.7035 g, 10.1212 mmol) to the acid chloride solution over 1 minute, the whole was stirred at 0 ° C for 10 minutes. The ice bath was replaced with a water bath and the mixture was stirred at 23 ° C. for 19 hours. 40 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 2 hours. The solid was filtered off with suction and washed with 60 mL of water. Then, it was dried in vacuum to obtain 1.6957 g of benzoyl-D-phenylalanine 6c ′ (white solid) (yield: 63%).

The obtained benzoyl-D-phenylalanine 6c ′ (0.1109 g) was transferred to a 30 ml round bottom flask, 1.5 ml of methanol was added, and the whole was left at room temperature for 2 hours. 1.5 ml of trimethylsilyldiazomethane was added. The whole was evaporated to obtain a white solid, which was purified by column chromatography (ethyl acetate / n-hexane = 1/2) to obtain 0.0479 g of methyl benzoyl-D-phenylalaninate (white solid).

(3) Analysis of optical purity Methyl benzoyl-L-phenylalaninate 6c and methyl benzoyl-D-phenylalaninate 6c ′ obtained in (1) and (2) above were diluted with 2-propanol (1 g / L ), L preparation and D preparation. In addition, an equal amount of L specimen and D specimen were mixed to prepare an LD mixed specimen. The abundance ratio of optical isomers in each sample was measured using high performance liquid chromatography (HPLC). The HPLC configuration equipment and HPLC conditions were as follows.

<HPLC configuration apparatus>
Pump: (Elite LaChorm L-2130, manufactured by Hitachi High-Technology Corporation)
UV detector: (Elite LaChorm L-2400, manufactured by Hitachi High-Technology Corporation)
Software: (Chromato-Integrator D-2500, manufactured by Hitachi High-Technology Corporation)

<HPLC conditions>
Sample volume: 10 μL
Column: Chiral column (CHIRALCEL OD-H 0.46 cmφ × 25 cm, manufactured by Daicel)
Solvent: 2-propanol: hexane = 1: 30
Flow rate: 1.0 mL / min

The HPLC chromatograms were as shown in FIGS. It was shown that two peaks (30.67 minutes, 45.55 minutes) of the chromatogram (FIG. 1) of the LD mixed preparation were derived from D-form or L-form, respectively. In the chromatogram of the L standard (FIG. 2), the peak of 1% or more of the integrated value of the peak derived from the L standard does not exist at the time corresponding to the peak of the D standard. The reaction product of the product was shown to be L-form having an optical purity of 99% or more. Similarly, in the chromatogram of the D standard (FIG. 3), it was shown that the reaction product of the D standard was D form having an optical purity of 99% or more. From these results, it was shown that phenylalanine can be benzoylated without racemization according to the production method of the present invention.

Example F6: Synthesis of benzoyl-L-valine (6d)

Benzoyl chloride (1.3990 g, 9.953 mmol) was dissolved in 10 mL of DMAC to obtain an acid chloride solution. After adding pure L-valine (1.2298 g, 10.498 mmol) to the pre-cooled acid chloride solution over 1 minute, the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 26 hours. To the mixture was added 5 mL of methanol. The mixture was stirred at 23 ° C. for 5 hours. 5 mL of 2M hydrochloric acid solution was added. The mixture was extracted 3 times with 30 mL of ethyl diethyl ether. The organic fraction was dried using magnesium sulfate, and the organic solvent was evaporated to obtain 1.8638 g of a colorless liquid. The product was purified by open column chromatography (chloroform: methanol: acetic acid = 90: 10: 1) to obtain 1.6565 g of the title compound 6d (yield: 75%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

6d: Melting point: 133-136 ° C (colorless rod).
¹ H-NMR (400 MHz, CDCl ₃ ): 9.393 (1H, br, s), 7.812 (2H, d, J = 6.9 Hz), 7.535 (1H, d, d, J = 7.5, 7.2 Hz), 7.458 (2H, d, d, J = 7.6, 7.5 Hz), 6.644 (1H, d, J = 8.4 Hz), 4.810 (1H, d, d, J = 8.5, 4.8 Hz), 2.414-2.334 (1H, m .), 1.056 (6H, d , d, J = 10.3, 6.9 Hz) 13 C NMR (100 MHz, CDCl 3): 175.80, 168.28, 133.88, 132.11, 128.80, 127.28, 57.70, 31.45, 19.16, 17.94
Analytical results: C ₁₂ H ₁₅ NO ₃ , calculated values: C, 65.14; H, 6.83; N, 6.33, measured values: C, 64.97; H, 6.93; N, 6.43. HRMS (ESI-TOF, [N + Na ] ⁺ ): Calculated value: C ₁₂ H ₁₅ NNaO ₃ ⁺ : 244.0944, measured value: 244.0947.

The chemical structures of the compounds synthesized in Examples F1, F3, F4 and F6, the stirring temperature and time, and the yield (a: the yield by the precipitation method, b: the yield by the extraction method) are as shown in Table 6.

Example G: Synthesis of amide compound (7)
In Example G, a selective carboxylic acid amide compound was synthesized by reacting two kinds of amines having different basicities with an acid chloride in an amide solvent.
Example G1: Synthesis of N-phenylbenzamide (4s)

Aniline (0.9779 g, 10.500 mmol) was dissolved in 5 mL of DMAC at room temperature to obtain an amine solution. Benzoyl chloride (1.4129 g, 10.52 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 0 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring at 0 ° C. over 3 minutes, and the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 2 hours. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 2 hours. The solid was filtered off with suction and washed with 100 mL of water. Then, it was dried in vacuum to obtain 1.8857 g of the title compound 4s (white solid) (yield: 95%). The precipitate was pure enough to give a satisfactory combustion analysis without further purification.

4s: Melting point: 164-166 ° C (colorless plate, recrystallized from methanol).
¹ H NMR (400 MHz, CDCl ₃ ): 7.877 (2H, d, J = 6.9 Hz), 7.807 (1H, br, s), 7.647 (2H, d, J = 8.4 Hz), 7.562 (1H, t, J = 7.3 Hz), 7.497 (2H, d, d, J = 7.6, 7.0 Hz), 7.384 (2H, d, d, J = 8.5, 7.5 Hz), 7.162 (1H, t, J = 7.4 Hz). ¹³ C NMR (100 MHz, CDCl ₃ ): 165.84, 138.05, 135.17, 132.02, 129.28, 128.97, 127.15, 124.74, 120.31.
Analytical result: C ₁₃ H ₁₁ NO, calculated value: C, 79.17; H, 5.62; N, 7.10, measured value: C, 78.92; H, 5.85; N, 7.13.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₃ H ₁₁ NNaO ⁺ : 220.0733, measured value: 220.0703.

Example G2: Synthesis of N- (4-methoxybenzyl) benzamide (4l) and N-phenylbenzamide (4s)

A 30 mL round bottom flask equipped with a stir bar was charged with aniline (0.4918 g, 5.281 mmol) and 4-methoxybenzylamine (0.7054 g, 5.142 mmol). The flask was immersed in an ice water bath (0 ° C.). DMAC 5 mL and acetic acid (1.2331 g, 20.535 mmol) were added with stirring. Next, an acid chloride solution in which benzoyl chloride (0.7039 g, 5.008 mmol) was dissolved in 5 mL of DMAC at room temperature was added at 0 ° C. over 7 minutes, and then the whole was stirred at 0 ° C. for 25 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 3 hours. 30 mL of water was added. A white precipitate was formed. The mixture was stirred at 23 ° C. for 1 hour. The solid was filtered off with suction and washed with 60 mL of water. Dry in vacuum. The mixture of amide products was separated by column chromatography (ethyl acetate: n-hexane = 1: 4). There were obtained 0.7727 g (yield: 78%) of the title compound 4s (white solid) and 0.0944 g (yield: 7.8%) of the title compound 4l (white solid). The ratio of 4s to 4l was determined by integration of ¹ H-NMR signal in the comparison between amide 4s (see Example G1) and 4l (see Example D12) (hereinafter the same).

¹ H-NMR (400 MHz, CDCl ₃ ): 7.877 (2H (4s), d, J = 6.9 Hz), 7.850-7.766 (1H (4s), 2H (4k), m), 7.647 (2H (4s) , d, d, J = 8.4, 1.1 Hz), 7.562 (1H (4s), t, J = 7.3 Hz), 7.520-7.261 (4H (4s), 5H (4k), m), 7.292 (2H (4k ), d, J = 8.8 Hz), 7.162 (1H (4s), t, J = 7.4 Hz), 6.889 (2H (4k), d, J = 8.7 Hz), 4.584 (2H (4k), d, J = 5.6 Hz), 3.807 (3H (4k), s)

Example G3: Synthesis of N- (4-methoxybenzyl) benzamide (4l) and N-phenylbenzamide (4s)

A 30 mL round bottom flask equipped with a stir bar was charged with aniline (0.4865 g, 5.224 mmol) and 4-methoxybenzylamine (0.7059 g, 5.146 mmol). The flask was immersed in an ice water bath (0 ° C.). DMAC 5 mL and acetic acid (3.0567 g, 50.903 mmol) were added with stirring. Then, an acid chloride solution in which benzoyl chloride (0.7048 g, 5.014 mmol) was dissolved in 5 mL of DMAC at room temperature was added over 3 minutes, and the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 3 hours. 40 mL of water was added. A white precipitate was formed. The mixture was stirred at 23 ° C. for 3 hours. The solid was filtered off with suction and washed with 80 mL of water. Dry in vacuum. 0.9090 g (yield: 92%) of the title compound 4s (white solid) was obtained. N- (4-methoxybenzyl) benzamide (4l) could not be detected. The product was pure enough to give a satisfactory combustion analysis without further purification. The product was identical to the real compound in terms of ¹ H-NMR (CDCl ₃ ) and combustion analysis.

4s: ¹ H NMR (400 MHz, CDCl ₃ ): 7.873 (2H, d, J = 7.0 Hz), 7.832 (1H, br, s), 7.644 (2H, d, J = 8.5 Hz), 7.557 (1H, t, J = 7.3 Hz), 7.491 (2H, d, d, J = 7.6, 7.0 Hz), 7.379 (2H, d, d, J = 8.5, 7.5 Hz), 7.159 (1H, t, J = 7.4 Hz Analysis result: C ₁₃ H ₁₁ NO, calculated value: C, 79.17; H, 5.62; N, 7.10, measured value: C, 78.96; H, 5.81; N, 7.09.

Example G4: Synthesis of N- (4-methoxybenzyl) benzamide (4l) and N-phenylbenzamide (4s)

In a 30 mL round bottom flask equipped with a stir bar, aniline (0.5023 g, 5.394 mmol) and 4-methoxybenzylamine (0.7061 g, 5.147 mmol) were placed. The flask was immersed in an ice water bath (0 ° C.). DMAC 5 mL and triethylamine (2.0340 g, 18.628 mmol) were added with stirring. Next, an acid chloride solution in which benzoyl chloride 3b (0.7098 g, 5.050 mmol) was dissolved in 5 mL of DMAC at room temperature was added over 5 minutes, and then the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 3 hours. 30 mL of water was added. A white precipitate was formed. The mixture was stirred at 23 ° C. for 15 hours. The solid was filtered off with suction and washed with 100 mL of water. Dry in vacuum. The mixture of amide products was separated by column chromatography (ethyl acetate: n-hexane = 1: 4). 0.2794 g (yield: 28%) of the title compound 4s (white solid) and 0.7317 g (yield: 60%) of the title compound 4l (white solid) were obtained.

¹ H-NMR (400 MHz, CDCl ₃ ): 7.880 (2H (4s), d, J = 6.9 Hz), 7.870-7.766 (1H (4s), 2H (4k), m), 7.650 (2H (4s) , d, d, J = 8.6, 1.0 Hz), 7.564 (1H (4s), t, J = 7.3 Hz), 7.520-7.364 (4H (4s), 3H (4k), m), 7.292 (2H (4k ), d, J = 8.8 Hz), 7.162 (1H (4s), t, J = 7.4 Hz), 6.891 (2H (4k), d, J = 8.7 Hz), 4.587 (2H (4k), d, J = 5.6 Hz), 3.808 (3H (4k), s)

Example G5: Synthesis of N- (4-methoxybenzyl) benzamide (4l) and N-phenylbenzamide (4s)

4-methoxybenzylamine (0.4849 g, 5.207 mmol) and aniline (0.6940 g, 5.059 mmol) were placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). 5 mL of DMAC was added with stirring. Then, an acid chloride solution in which benzoyl chloride (0.7000 g, 4.980 mmol) was dissolved in 5 mL of DMAC at room temperature was added at 0 ° C. over 5 minutes, and the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 3 hours. 40 mL of water was added. A white precipitate was formed. The mixture was stirred at 23 ° C. for 2 hours. The solid was filtered off with suction and washed with 100 mL of water. Dry in vacuum. The precipitate contained only a mixture of amide products. 0.6482 g (yield: 66%) of the title compound 4s (white solid) and 0.3298 g (yield: 27%) of the title compound 4l (white solid) were obtained.

¹ H-NMR (400 MHz, CDCl ₃ ): 7.878 (2H (4s), d, J = 6.9 Hz), 7.870-7.765 (1H (4s), 2H (4k), m), 7.648 (2H (4s) , d, d, J = 8.6, 1.1 Hz), 7.563 (1H (4s), t, J = 7.3 Hz), 7.519-7.358 (4H (4s), 3H (4k), m), 7.290 (2H (4k ), d, J = 8.7 Hz), 7.162 (1H (4s), t, J = 7.4 Hz), 6.890 (2H (4k), d, J = 8.7 Hz), 4.586 (2H (4k), d, J = 5.5 Hz), 3.808 (3H (4k), s)

The procedures and yields of Examples G2 to G5 are summarized in Table 7.

Example G6: Synthesis of N- (4-nitrophenyl) benzamide (P1) and N- (4-methoxybenzyl) benzamide (P2)

4-methoxybenzylamine (0.7928 g, 5.779 mmol) and 4-nitroaniline (0.7934 g, 5.744 mmol) were placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). DMAC 5 mL and trifluoroacetic acid (2 mL, 26.118 mmol) were added with stirring. Next, an acid chloride solution in which benzoyl chloride (0.7729 g, 5.498 mmol) was dissolved in 3 mL of DMAC at room temperature was added at 0 ° C. over 5 minutes, and then the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 24 hours. 40 mL of water was added. A white precipitate was formed. The mixture was stirred at 23 ° C. for 2 hours. The solid was filtered off with suction and washed with 100 mL of water. Dry in vacuum. The precipitate contained only the title compound P1. There were obtained 1.1658 g (yield: 88%) of the title compound P1 (white solid).

¹ H-NMR (400 MHz, DMSO-d ₆ ): 8.280 (2H, d, J = 9.3 Hz), 8.057 (2H, d, J = 9.4 Hz), 7.987 (2H, d, J = 7.0 Hz), 7.648 (1H, t, J = 7.3 Hz), 7.572 (2H, dd, J = 7.7, 7.0 Hz)
Analytical result: C ₁₃ H ₁₀ N ₂ O ₃ , calculated value: C, 64.46; H, 4.16; N, 11.56, measured value: C, 64.31; H, 4.31; N, 11.50

Example G7: Synthesis of N- (4-bromophenyl) benzamide (P3) and N- (2-chlorobenzyl) benzamide (P4)

2-Chlorobenzylamine (0.6995 g, 4.940 mmol) and 4-bromoaniline (0.8589 g, 4.995 mmol) were placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). DMAC 5 mL and trifluoroacetic acid (2 mL, 26.118 mmol) were added with stirring. Subsequently, an acid chloride solution in which benzoyl chloride (0.6731 g, 4.788 mmol) was dissolved in 3 mL of DMAC at room temperature was added at 0 ° C. over 5 minutes, and the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 4 hours. 40 mL of water was added. A white precipitate was formed. The mixture was stirred at 23 ° C. for 2 hours. The solid was filtered off with suction and washed with 100 mL of water. Dry in vacuum. The precipitate contained only the title compound P3. 1.285 g (yield: 96%) of the title compound P3 (white solid) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 10.373 (1H, s), 7.948 (2H, d, J = 7.0 Hz), 7.775 (2H, d, J = 9.0 Hz), 7.606 (1H, t , J = 7.3 Hz), 7.523-7.518 (4H, m)
Analytical result: C ₁₃ H ₁₀ BrNO, calculated value: C, 56.55; H, 3.65; N, 5.07, measured value: C, 56.39; H, 3.79; N, 4.84

Example H: Synthesis of Carbamate Compound In Example H, a carbamate compound was synthesized by reacting various amines with a carboxylic acid ester chloride in an amide solvent.

Example H1: Synthesis of methyl dibenzylcarbamate

Methyl chloroformate (0.9470 g, 10.12 mmol) was dissolved in 5 mL of DMAC to obtain an acid chloride solution. Dibenzylamine (2.0735 g, 10.510 mmol) was dissolved in 5 mL of DMAC at room temperature to obtain an amine solution. The amine solution was transferred to a 30 mL round bottom flask and the whole was cooled to 1 ° C. in an ice water bath. The acid chloride solution was added to the amine solution with stirring and cooling at 1 ° C. over 5 minutes. A white precipitate was formed. The whole was stirred at 1 ° C. for 10 minutes. The ice bath was removed and the mixture was stirred at room temperature for 1296 minutes. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture. The whole was stirred at 23 ° C. for 22 hours. The mixture was extracted three times with 20 mL ethyl acetate and the combined organic fractions were washed once with 20 mL brine and once with 40 mL water. The organic fraction was dried with magnesium sulfate and evaporated at 19-35 ° C. for 19 minutes. A liquid like white miso soup appeared. The oil was dried under vacuum for 5 hours. 10 mL of ethyl acetate was added to the product and washed with 17 mL of water three times. The organic fraction was dried with magnesium sulfate and evaporated at 44 ° C. for 20 minutes. A colorless oil appeared. The oil was dried under vacuum for 17 hours to give 0.7338 g of the title compound (colorless liquid) (yield: 29%).

¹ H NMR (400 MHz, CDCl ₃ ): 7.341-7.206 (10H, m), 4.418 (4H, s), 3.795 (3H, s) ¹³ C NMR (100 MHz, CDCl ₃ ): 170.74, 137.41, 130.19, 129.04, 128.65, 127.45, 53.03, 38.11, 35.24, 21.64
Analytical result: C ₁₆ H ₁₇ NO ₂ , calculated value: C, 75.27; H, 6.71; N, 5.49, measured value: C, 75.27; H, 6.82; N, 5.50
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₆ H ₁₇ NNaO ₂ ⁺ : 278.1152, measured value: 278.1169

Example H2: Synthesis of methyl indoline-1-carboxylate

Methyl chloroformate (0.9461 g, 10.12 mmol) was dissolved in 5 mL of DMAC at room temperature to obtain an acid chloride solution. Indoline (1.2503 g, 10.492 mmol) was dissolved in 5 mL of DMAC to make an amine solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 1 ° C. in an ice water bath. The amine solution was added to the acid chloride solution over 5 minutes with stirring at 1 ° C. A pale yellow precipitate was formed. The whole was stirred at 1 ° C. for 10 minutes. The ice bath was removed and the mixture was stirred at room temperature for 234 minutes. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture. The pale yellow precipitate disappeared and a white precipitate appeared. The whole was stirred at 23 ° C. for 16 hours. The solid was filtered, washed with 100 mL water and dried in vacuo. 1.4343 g (yield: 81%) of a white solid was obtained. Methanol was added in a water bath (65 ° C.) until the solid disappeared, cooled at room temperature overnight, and cooled in an ice bath for 5 minutes. Crystals appeared. The crystals were filtered, washed with 40 mL water and dried under vacuum. 1.1404 g of the title compound (white solid) was obtained (yield: 64%).

Melting point: 71-72 ℃ (white powder)
Melting point (crystal): 72-74 ℃ (colorless, plate-like)
¹ H NMR (400 MHz, CDCl ₃ ): 8.287 (1H, br, s), 7.201 (1H, d, J = 7.4 Hz), 7.149 (1H, d, d, J = 8.2, 8.2 Hz), 6.937 ( 1H, d, d, d, J = 7.4, 7.4, 0.9 Hz), 3.954 (2H, t, J = 8.7 Hz), 3.7459 (3H, s), 3.094 (2H, t, J = 8.8 Hz)
¹³ C NMR (100 MHz, CDCl ₃ ): 127.57, 124.77, 122.64, 114.81, 52.63, 47.44, 27.61
Analytical result: C ₁₀ H ₁₁ NO ₂ , calculated value: C, 67.78; H, 6.26; N, 7.90
Measurements: C, 67.73; H, 6.16; N, 8.14
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₀ H ₁₁ NNaO ₂ ⁺ : 200.0682
Measurement value: 200.0684

Example H3: Synthesis of methyl dibenzylcarbamate

Methyl chloroformate (0.9441 g, 9.991 mmol) was dissolved in 5 mL of DMAC to obtain an acid chloride solution. Dibenzylamine (2.0728 g, 10.507 mmol) was dissolved in 5 mL of DMAC at room temperature to obtain an amine solution. The amine solution was transferred to a 30 mL round bottom flask and the whole was cooled to 1 ° C. in an ice water bath. The acid chloride solution was added to the amine solution with stirring and cooling at 1 ° C. over 5 minutes. A white precipitate was formed. The mixture was stirred at 1 ° C. for 10 minutes. The ice bath was removed and the mixture was stirred at room temperature for 1432 minutes. 30 mL of water was added. The precipitate disappeared. The mixture was stirred at 23 ° C. for 5 minutes. The mixture was extracted 3 times with 20 mL of dichloromethane and all organic fractions were washed 3 times with 50 mL of water. The organic fraction was dried with magnesium sulfate and evaporated at 30 ° C. for 20 minutes. A colorless liquid appeared. The liquid was dried under vacuum for 13 hours (1.6405 g, yield: 64%). 20 mL of ethyl acetate was added to the product and washed once with 100 mL of water and twice with 50 mL of water. The organic fraction was dried over magnesium sulfate, filtered and evaporated at 31 ° C. for 17 minutes. A colorless liquid appeared. The liquid was dried under vacuum for 4 hours to obtain 0.9025 g of the title compound (colorless liquid) (yield: 35%).

¹ H NMR (400 MHz, CDCl ₃ ): 7.354-7.189 (10H, m), 4.450 (2H, s,), 4.436 (2H, s), 3.801 (3H, s) ¹³ C NMR (100 MHz, CDCl ₃ ): 157.55, 137.51, 128.73, 128.29, 127.54, 53.11, 49.56, 49.03
Analytical result: C ₁₆ H ₁₇ NO ₂ , calculated value: C, 75.27; H, 6.71; N, 5.49
Measurements: C, 75.18; H, 6.59; N, 5.52
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₆ H ₁₇ NNaO ₂ ⁺ : 278.1152
Measurements: 278.1156

Example H4: Synthesis of methyl 3,4-dihydroisoquinoline-2 (1H) -carboxylate

Methyl chloroformate (0.9542 g, 10.098 mmol) was dissolved in 5 mL of DMAC at room temperature to obtain an acid chloride solution. 1,2,3,4-Tetrahydroisoquinoline (1.2406 g, 10.411 mmol) was dissolved in 5 mL of DMAC to make an amine solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 1 ° C. in an ice water bath. The amine solution was added to the acid chloride solution over 5 minutes at 1 ° C. with stirring and cooling. The whole was stirred at 1 ° C. for 10 minutes. The ice water bath was removed and the mixture was stirred at room temperature for 1200 minutes. 30 mL of water was added. The mixture was stirred at 23 ° C. for 20 hours. The mixture was extracted 3 times with 20 mL dichloromethane and the organic fraction was washed 3 times with 50 mL water. The organic fraction was dried with magnesium sulfate and evaporated at 32 ° C. for 7 minutes. A yellow oil appeared. The oil was dried under vacuum (1.3405 g, yield: 69%). The oil was purified by flash chromatography using 150 mL of ethyl acetate and 750 mL of n-hexane to give 1.0162 g of the title compound (yellow oil) (yield: 53%).

¹ H NMR (400 MHz, CDCl ₃ ): 7.656 (1H, d, J = 8.0 Hz), 7.159 (1H, d, d, J = 8.1, 7.8 Hz), 7.009 (1H, d, d, d, J = 7.4, 7.4, 1.2 Hz), 3.792 (3H, s), 3.762 (2H, d, d, J = 6.2, 6.1 Hz), 2.773 (2H, d, d, J = 6.6, 6.6 Hz), 1.944 ( 2H, d, d, J = 6.2, 6.2 Hz) ¹³ C NMR (100 MHz, CDCl ₃ ): 155.54, 138.30, 130.19, 128.75, 126.10, 124.04, 123.84, 53.01, 44.94, 27.46, 23.60
Analytical result: C ₁₁ H ₁₃ NO ₂ , calculated value: C, 69.09; H, 6.85; N, 7.32
Measurements: C, 68.54; H, 6.63; N, 7.32
Measurements: (after flash chromatography): C, 69.06; H, 6.94; N, 7.41
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₁ H ₁₃ NNaO ₂ ⁺ : 214.0839
Measurements: 214.0841

Example I: Synthesis of urea compounds

Indoline (1.2406 g, 10.411 mmol) was dissolved in 5 mL of DMAC to prepare an amine solution. Dimethylcarbamic acid chloride (1.0663 g, 9.916 mmol) was dissolved in 5 mL of DMAC at room temperature to obtain an acid chloride solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 1 ° C. in an ice water bath. The amine solution was added to the acid chloride solution with stirring and cooling at 1 ° C. over 4 minutes, and the whole was stirred at 1 ° C. for 53 minutes. The ice water bath was removed and the mixture was stirred at room temperature for 1200 minutes. Then 30 mL of water was added to the mixture. The mixture was stirred for 48 hours. Water (30 mL) was added. The mixture was stirred at 23 ° C. for 48 hours. The mixture was extracted 3 times with 27 mL of dichloromethane, the combined organic fractions were washed 3 times with 50 mL of water, the organic fractions were dried over magnesium sulfate and filtered. Fractions were evaporated at 32 ° C. for 7 minutes. A brown liquid appeared. The liquid was dried under vacuum for 12 hours. To the product was added 20 mL of ethyl acetate. The mixture was washed once with 100 mL water, washed twice with 50 mL water, dried using magnesium sulfate, and filtered. This was evaporated at 34 ° C. for 7 minutes. The liquid was dried in vacuum for 4 hours to obtain 0.4287 g of N, N-dimethylindoline-1-carboxamide (yellow oil) (yield: 23%).

¹ H NMR (400 MHz, CDCl ₃ ): 7.164 (1H, d, J = 7.8 Hz), 7.121 (1H, d, J = 8.1 Hz), 6.935 (1H, d, J = 8.0 Hz), 6.875 (1H , d, d, d, J = 7.4, 7.4, 1.0 Hz), 3.901 (2H, t, J = 8.2 Hz), 3.025 (2H, t, J = 8.3 Hz), 2.935 (6H, s) ¹³ C NMR (100 MHz, CDCl ₃ ): 160.42, 144.47, 131.55, 127.14, 124.96, 121.45, 113.43, 50.49, 38.31, 38.17, 35.32, 28.25, 21.72
Analytical result: C ₁₁ H ₁₄ N ₂ O, calculated value: C, 69.45; H, 7.42; N, 14.73, measured value: C, 69.83; H, 7.37; N, 14.34
HRMS (ESI-TOF, [N + H] ⁺ ): Calculated value: C ₁₁ H ₁₅ N ₂ O ⁺ : 191.1179, measured value: 191.1192

Example J: Synthesis of sulfonamide compound In Example J, various amines and sulfonic acid chlorides were reacted in an amide solvent to synthesize a sulfonamide compound.

Example J1: Synthesis of 1-tosylindoline

Tosyl chloride (1.9225 g, 10.084 mmol) was dissolved in 5 mL of DMAC to obtain an acid chloride solution. Indoline (1.2731 g, 10.683 mmol) was dissolved in 5 mL of DMAC at room temperature to form an amine solution. The amine solution was transferred to a 30 mL round bottom flask and the whole was cooled to 1 ° C. in an ice water bath. The acid chloride solution was added to the amine solution with stirring and cooling at 1 ° C. over 5 minutes. A white precipitate was formed. The whole was stirred at 1 ° C. for 10 minutes. The ice bath was removed and the mixture was stirred at room temperature for 1405 minutes. The precipitate disappeared 1340 minutes after removing the ice bath. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred for 49 minutes. The solid was filtered and washed with 100 mL water. Then, it was dried in vacuum to obtain 2.3810 g of the title compound (white solid) (yield: 86%).

Melting point: 97 ℃ (white, powder)
¹ H NMR (400 MHz, CDCl ₃ ): 7.669 (2H, d, d, d, J = 8.4, 2.0, 2.0 Hz), 7.637 (1H, d, J = 8.4 Hz), 7.216 (2H, d, J = 8.4 Hz), 7.174 (1H, d, J = 8.0 Hz), 7.069 (1H, d, J = 6.0 Hz), 6.963 (1H, d, d, d, J = 7.6, 7.2, 0.8 Hz), 3.905 (2H, t, J = 8.4 Hz), 2.877 (2H, t, J = 8.4 Hz) ¹³ C NMR (100 MHz, CDCl ₃ ): 144.14, 142.12, 134.14, 131.88, 129.76, 127.82, 127.43, 125.21, 123.82 , 115.13, 50.05, 27.99, 21.64
Analysis result: C ₁₅ H ₁₅ NO ₂ S, calculated value: C, 65.91; H, 5.53; N, 5.12
Analysis result: C ₁₅ H ₁₅ NO ₂ S 0.106H ₂ O, calculated value: C, 65.45; H, 5.57; N, 5.09
Measurements: C, 65.45; H, 5.56; N, 5.10
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₅ H ₁₅ NNaO ₂ S ⁺ : 296.07156
Measurement value: 296.0693

Example J2: Synthesis of 1-tosylindoline

Tosyl chloride (1.9063 g, 9.999 mmol) was dissolved in 5 mL of DMAC to obtain an acid chloride solution. Indoline (1.2568 g, 10.469 mmol) was dissolved in 5 mL of DMAC at room temperature to make an amine solution. The amine solution was transferred to a 30 mL round bottom flask and the whole was heated to 47 ° C. in an oil bath. The acid chloride solution was added to the amine solution with stirring and heating at 47 ° C. over 5 minutes. A white precipitate was formed. The whole was stirred at 47 ° C. for 144 minutes. Completion of the reaction was confirmed by thin layer chromatography. The oil bath was removed and the mixture was stirred at room temperature for 6 minutes. The mixture was cooled on an ice water bath at 1 ° C. for 5 minutes. 30 mL of water was added. A white precipitate appeared. The mixture was stirred for 1144 minutes. The solid was filtered, washed with 100 mL water and dried under vacuum to give 2.2927 g of the title compound (white solid) (yield: 84%).

Melting point: 97 ° C (white, powder)
¹ H NMR (400 MHz, CDCl ₃ ): 7.671 (2H, d, d, d, J = 8.4, 2.0, 1.8 Hz), 7.640 (1H, d, J = 8.0 Hz), 7.219 (2H, d, J = 8.4 Hz), 7.177 (1H, d, J = 8.0 Hz), 7.072 (1H, d, J = 6.8 Hz), 6.963 (1H, t, d, J = 8.4, 1,2 Hz), 3.907 (2H , t, J = 8.4 Hz), 2.881 (2H, t, J = 8.4 Hz) ¹³ C NMR (100 MHz, CDCl ₃ ): 144.16, 142.12, 134.13, 131.88, 129.77, 127.83, 127.45, 125.22, 123.83, 115.14 , 50.06, 28.00, 21.66
Analysis result: C ₁₅ H ₁₅ NO ₂ S, calculated value: C, 65.91; H, 5.53; N, 5.12
Measurements: C, 65.76; H, 5.61; N, 5.16
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₅ H ₁₅ NNaO ₂ S ⁺ : 296.0712
Measurements: 296.0704

Example J3: Synthesis of 1-tosylindoline

Tosyl chloride (1.9130 g, 10.035 mmol) was dissolved in 5 mL of DMAC to obtain an acid chloride solution. Indoline (1.2473 g, 10.467 mmol) was dissolved in 5 mL of DMAC at room temperature to make an amine solution. The amine solution was transferred to a 30 mL round bottom flask and the whole was cooled to 1 ° C. in an ice water bath. The acid chloride solution was added to the amine solution with stirring and cooling at 1 ° C. over 5 minutes. A brown precipitate was formed. The whole was stirred at 1 ° C. for 161 minutes. Completion of the reaction was confirmed by thin layer chromatography. The ice bath was removed and 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 1136 minutes. The solid was filtered and washed with 100 mL water. It was then dried in vacuo to give the title compound (white solid) 2.0540 (yield: 75%). Methanol was added on a 65 ° C. water bath until the solid disappeared, cooled at room temperature overnight, and cooled on an ice bath for 5 minutes. Crystals appeared. The crystals were filtered, washed with 40 mL of water and dried under vacuum to give 1.4759 g of the title compound (white solid) (Yield: 54%).

Melting point: 98 ° C (white, powder)
Melting point (crystal): 98-99 ℃ (colorless, prismatic)
¹ H NMR (400 MHz, CDCl ₃ ): 7.673 (2H, d, d, d, J = 8.4, 2.0, 2.0 Hz), 7.640 (1H, d, J = 8.0 Hz), 7.221 (2H, d, J = 8.2 Hz), 7.179 (1H, d, J = 8.0 Hz), 7.073 (1H, d, J = 6.8 Hz), 6.967 (1H, t, d, J = 7.6, 0.9 Hz), 3.908 (2H, t , J = 8.0 Hz), 2.874 (2H, t, J = 8.4 Hz) ¹³ C NMR (100 MHz, CDCl ₃ ): 144.15, 121.13, 134.15, 131.88, 129.77, 127.85, 127.46, 125.22, 123.83, 115.16, 50.07 , 28.01, 21.67
Analysis result: C ₁₅ H ₁₅ NO ₂ S, calculated value: C, 65.91; H, 5.53; N, 5.12
Measurements: C, 65.80; H, 5.60; N, 5.09
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₅ H ₁₅ NNaO ₂ S ⁺ : 296.0716
Measurements: 296.0722

Example J4: Synthesis of N- (4-methoxyphenyl) -4-methylbenzenesulfonamide

Tosyl chloride (1.9050 g, 9.993 mmol) was dissolved in 5 mL of DMAC to obtain an acid chloride solution. 4-Methoxybenzylamine (1.4479 g, 10.555 mmol) was dissolved in 5 mL of DMAC at room temperature to obtain an amine solution. The amine solution was transferred to a 30 mL round bottom flask and the whole was heated to 65 ° C. in an oil bath. The acid chloride solution was added to the amine solution with stirring and heating at 65 ° C. over 5 minutes. A yellow precipitate was formed. The whole was stirred at 65 ° C. for 78 minutes. Completion of the reaction was confirmed by thin layer chromatography. The oil bath was removed and the mixture was cooled at room temperature for 12 minutes. 30 mL of water was added. A white precipitate appeared. The mixture was stirred for 1051 minutes. The solid was filtered, washed with 100 mL of water and dried under vacuum to give 1.5001 g of the title compound (white solid) (Yield: 52%). Methanol was added on a 70 ° C. water bath until the solid disappeared, cooled overnight at room temperature, and cooled on an ice bath for 5 minutes. Crystals appeared. The crystals were filtered, washed with 30 mL of water and dried under vacuum to give 1.1845 g of the title compound (white solid) (Yield: 41%).

Melting point: 121-122 ° C (white, powder)
Melting point (crystal): 123-124 ℃ (colorless, needle-shaped)
¹ H NMR (400 MHz, CDCl ₃ ): 7.758 (2H, d, d, d, J = 8.4, 2.2, 2.0 Hz), 7.314 (2H, d, d, J = 8.4, 0.4 Hz), 7.106 (2H , d, d, d, J = 8.8, 2.8, 2.0 Hz), 6.801 (2H, d, d, d, J
= 8.8, 3.0, 1.8 Hz), 4.052 (2H, s), 3.776 (3H, s), 2.442 (3H, s), ¹³ C NMR (100 MHz,): 159.48, 143.46, 137.03, 129.88, 129.42, 128.37 , 127.34, 114.22, 55.43, 46.96, 21.69
Analytical result: C ₁₅ H ₁₇ NO ₃ S, calculated value: C, 61.83; H, 5.88; N, 4.81
Measurements: C, 61.30; H, 5.89; N, 4.78
Measurements: (Crystal): C, 61.57; H, 6.07; N, 4.71
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₅ H ₁₇ NNaO ₃ S ⁺ : 314.08214
Measurements: 314.08247

Example J5: Synthesis of N- (4-methoxyphenyl) -4-methylbenzenesulfonamide

Tosyl chloride (1.9090 g, 10.14 mmol) was dissolved in 5 mL of 1,3-dimethyl-2-imidazolidinone to obtain an acid chloride solution. 4-Methoxybenzylamine (1.4367 g, 10.473 mmol) was dissolved in 5 mL of 1,3-dimethyl-2-imidazolidinone at room temperature to form an amine solution. The amine solution was transferred to a 30 mL round bottom flask and the whole was heated to 65 ° C. in an oil bath. The acid chloride solution was added to the amine solution over 5 minutes with stirring at 65 ° C. A yellow precipitate was formed. The whole was stirred at 65 ° C. for 78 minutes. The oil bath was removed and the mixture was cooled at room temperature for 12 minutes. 30 mL of water was added. A white precipitate appeared. The mixture was stirred at 23 ° C. for 15 hours. The solid was filtered, washed with 100 mL of water and dried under vacuum to give 1.6481 g of the title compound (white solid) (Yield: 62%).

Melting point: 122-123 ℃ (white, powder)
¹ H NMR (400 MHz, CDCl ₃ ): 7.746 (2H, d, d, d, J = 8.3, 2.0, 1.8 Hz), 7.299 (2H, d, J = 8.4 Hz), 7.099 (2H, d, d , d, J = 8.8, 2.9, 2.1 Hz), 6.778 (2H, d, d, d, J = 8.7, 3.0, 2.1 Hz), 4.041 (2H, d, J = 4.2 Hz), 3.766 (3H, s ), 2.434 (3H, s), ¹³ C NMR (100 MHz, CDCl ₃ ): 159.41, 143.58, 137.02, 130.35, 129.84, 129.39, 128.41, 127.31, 127.17, 114.17, 55.40, 46.90, 21.95, 21.65
Analytical result: C ₁₅ H ₁₇ NO ₃ S, calculated value: C, 61.83; H, 5.88; N, 4.81
Measurements: C, 59.75; H, 5.69; N, 4.28
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₅ H ₁₇ NNaO ₃ S ⁺ : 314.08214
Measurements: 314.08239

Example J6: Synthesis of N- (4-methoxyphenyl) octane-1-sulfonamide

Octane-1-sulfonyl chloride (2.1403 g, 10.061 mmol) was dissolved in 5 mL of DMAC at room temperature to obtain an acid chloride solution. 4-Methoxybenzylamine (1.4340 g, 10.453 mmol) was dissolved in 5 mL of DMAC at room temperature to obtain an amine solution. The acid chloride solution was transferred to a 30 mL round bottom flask and the whole was cooled to 1 ° C. in an ice water bath. The amine solution was added to the acid chloride solution over 5 minutes at 1 ° C. with stirring and cooling. The whole was stirred at 1 ° C. for 10 minutes. The ice water bath was removed and the mixture was stirred in a 22 ° C. water bath for 78 minutes. Completion of the reaction was confirmed by thin layer chromatography. Then 30 mL of water was added to the mixture. A white precipitate was formed. The mixture was stirred at 23 ° C. for 15 hours. The solid was filtered and washed with 120 mL water. It was then dried in vacuo to give 2.0356 g of the title compound (white solid). The crude product was washed with n-hexane and dried under vacuum (1.3423 g, yield: 43%). Methanol was added on a 65 ° C. water bath until the solid disappeared, cooled at room temperature overnight, and cooled on an ice bath for 5 minutes. Crystals appeared. The crystals were filtered, washed with 50 mL of water and dried under vacuum to give 1.2165 g of the title compound (white solid) (Yield: 39%).

Melting point: 88-90 ℃ (white, powder)
Melting point (crystal): 90-91 ℃ (colorless, plate-like)
¹ H NMR (400 MHz, CDCl ₃ ): 7.600 (2H, d, d, d, J = 8.5, 2.9, 1.6 Hz), 6.884 (2H, d, d, d, J = 8.5, 3.0, 2.0), 4.227 (2H, s), 3.806 (3H, s), 2.913-2.873 (2H, m), 1.768-1.691 (2H, m), 1.362-1.253 (10H, m), 0.883 (3H, t, J = 6.8 (Hz) ¹³ C NMR (100 MHz, CDCl ₃ ): 159.56, 129.47, 129.08, 114.34, 55.45, 53.44, 46.87, 31.84, 29.15, 29.09, 28.36, 23.74, 22.73, 14.21
Analytical results: C ₁₆ H ₂₇ NO ₃ S, calculated values: C, 61.31; H, 8.68; N, 4.47
Measurements: C, 61.00; H, 8.54; N, 4.47
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₆ H ₂₇ NNaO ₃ S ⁺ : 336.1604
Measurements: 336.1615

Example K: Synthesis of ester compound

Benzyl alcohol (1.1240 g, 10.394 mmol) was dissolved in 5 mL of DMAC to prepare a benzyl alcohol solution. Benzoyl chloride (1.3974 g, 9.941 mmol) was dissolved in 5 mL of DMAC to make an acid chloride solution. The benzyl alcohol solution was added to the previously cooled acid chloride solution at 0 ° C. over 3 minutes, and the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 26 hours. Completion of the reaction was confirmed by thin layer chromatography. 30 mL of water was added to the mixture. The mixture was extracted three times with 30 mL of ethyl acetate and the combined organic fractions were washed twice with 50 mL of water and once with 50 mL of 0.1 M aqueous sodium hydroxide. The organic fraction was dried using magnesium sulfate, and the solvent was evaporated to obtain 1.6374 g of benzyl benzoate (colorless liquid) (yield: 78%). The product was pure enough to give a satisfactory combustion analysis without further purification.

¹ H-NMR (400 MHz, CDCl ₃ ): 8.082 (2H, d, J = 8.5 Hz), 7.554 (1H, t, 7.4 Hz), 7.463-7.310 (7H, m), 5.367 (2H, s)
Analytical result: C ₁₄ H ₁₂ O ₂ , calculated value: C, 79.23; H, 5.70, measured value: C, 79.00; H, 5.67

Example L: Synthesis of amide compound (8)
In Example L, an amine having two amino groups having different basicities in the same molecule was reacted with an acid chloride in an amide solvent to selectively form an amide bond.

Example L1: Selective synthesis of an aromatic amide (N- (4-aminomethylphenyl) -benzamide) in the presence of an aliphatic amine

4-Aminobenzylamine (0.6536 g, 5.350 mmol) was placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). DMAC 5 mL and trifluoroacetic acid (2 mL, 26.118 mmol) were added with stirring. Next, an acid chloride solution in which benzoyl chloride (0.6536 g, 4.650 mmol) was dissolved in 5 mL of DMAC at room temperature was added at 0 ° C. over 5 minutes, and then the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 4 hours. Toluene (40 mL) was added. A yellow precipitate was formed. The mixture was stirred at 23 ° C. for 1 hour. The solid was filtered off with suction and washed with 100 mL of hexane. Dry in vacuum. 1.1452 g (yield: 94%) of the title compound (yellow solid) was obtained.

Melting point: 300 ° C or higher (yellow fine needles)
¹ H-NMR (400 MHz, DMSO-d ₆ ): 10.380 (1H, s), 8.326 (3H, s, br), 7.972 (2H, d, J = 7.0 Hz), 7.819 (2H, d, J = 8.6 Hz), 7.604 (1H, t, J = 7.3 Hz), 7.536 (2H, d, d, J = 7.6, 7.1 Hz), 7.759 (2H, d, d, J = 8.6 Hz), 3.981 (2H, . q, J = 5.6 Hz) 13 C-NMR (100 MHz, DMSO-d 6): 165.62, 139.36, 134.73, 131.69, 129.42, 129.10, 128.41, 127.74, 120.30, 41.82.
Analytical results: C ₁₄ H ₁₅ N ₂ OCl, calculated values: C, 64.00; H, 5.75; N, 10.66, measured values: C, 63.88; H, 5.85; N, 10.59. HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₁₄ H ₁₄ N ₂ NaO ⁺ , 249.0998, measured value: 249.1006.

Example L2: Selective synthesis of an aromatic amide (N- (3-aminomethylphenyl) -benzamide) in the presence of an aliphatic amine

3-Aminobenzylamine (0.6536 g, 5.350 mmol) was placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). DMAC 5 mL and trifluoroacetic acid (2 mL, 26.118 mmol) were added with stirring. Next, an acid chloride solution in which benzoyl chloride (0.6536 g, 4.650 mmol) was dissolved in 5 mL of DMAC at room temperature was added at 0 ° C. over 5 minutes, and then the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 4 hours. Toluene 40 mL was added. A yellow precipitate was formed. The mixture was stirred at 23 ° C. for 1 hour. The solid was filtered off with suction and washed with 100 mL of hexane. Dry in vacuum. 1.1452 g (yield: 91%) of the title compound (yellow solid) was obtained.

Melting point: 300 ° C or higher (yellow fine needles)
¹ H-NMR (400 MHz, DMSO-d ₆ ): 10.642 (1H, s), 8.336 (3H, br, s), 7.644 (2H, d, J = 8.6 Hz), 7.441 (2H, d, J = . 8.6 Hz), 4.304 (2H , s), 3.962 (2H, q, J = 6.0Hz) 13 C-NMR (100 MHz, DMSO-d 6): 165.62, 139.36, 134.73, 131.69, 129.42, 129.10, 128.41 , 127.74, 120.30, 41.82.
Analytical results: C ₁₄ H ₁₅ N ₂ OCl, calculated values: C, 64.00; H, 5.75; N, 10.66, measured values: C, 63.88; H, 5.85; N, 10.59. HRMS (ESI-TOF, [N + H] ⁺ ): Calculated value: C ₁₄ H ₁₄ N ₂ NaO ⁺ , 249.0998, measured value: 249.1006.

Example L3: Selective synthesis of an aromatic amide (N- (4-aminomethyl-phenyl) -2-chloroacetamide) in the presence of an aliphatic amine

4-Aminobenzylamine (0.6451 g, 5.117 mmol) was placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). DMAC 5 mL and trifluoroacetic acid (2 mL, 26.118 mmol) were added with stirring. Next, an acid chloride solution in which chloroacetyl chloride (0.5572 g, 4.934 mmol) was dissolved in 5 mL of DMAC at room temperature was added at 0 ° C. over 5 minutes, and then the whole was stirred at 0 ° C. for 10 minutes. The ice water bath was replaced with a water bath and the whole was stirred at 23 ° C. for 4 hours. A 1: 1 mixed solution of toluene and hexane (40 mL) was added. A yellow precipitate was formed. The mixture was stirred at 23 ° C. for 1 hour. The solid was filtered off with suction and washed with 50 mL of toluene. Dry in vacuum. 1.0625 g (yield: 92%) of the title compound (yellow solid) was obtained.

Melting point: 300 ° C or higher (yellow fine needles)
¹ H-NMR (400 MHz, DMSO-d ₆ ): 10.642 (1H, s), 8.336 (3H, br, s), 7.644 (2H, d, J = 8.6 Hz), 7.441 (2H, d, J = . 8.6 Hz), 4.304 (2H , s), 3.962 (2H, q, J = 6.0Hz) 13 C-NMR (100 MHz, DMSO-d 6): 164.81, 138.71, 129.64, 129.23, 119.28, 43.52, 41.79 .
Analytical results: C ₉ H ₁₂ Cl ₂ N ₂ O, calculated values: C, 45.98; H, 5.14; N, 11.92, measured values: C, 46.11; H, 5.35; N, 12.08. HRMS (ESI-TOF, [ N + H] ⁺ ): Calculated value: C ₉ H ₁₃ Cl ₂ N ₂ O ⁺ , 199.0633, measured value: 199.0620.

Example M: Synthesis of amide compound (9)
In Example M, a dipeptide was synthesized by reacting two amino acids in an amide solvent.

Example M1: Synthesis of dipeptide (Phe-Val)

Fmoc-Phe-OH (0.7620 g, 1.967 mmol) was placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). 2 mL of DMAC and thionyl chloride (0.16 mL, 2.203 mmol) were added with stirring. The whole was stirred at 23 ° C. for 1 hour. L-valine methyl ester hydrochloride (0.3610 g, 2.153 mmol) was added. The whole was stirred at 23 ° C. for 4 hours. 40 mL of water was added. A white precipitate was formed. The mixture was stirred at 23 ° C. for 1 hour. The solid was filtered off with suction and washed with 60 mL of water. Dry in vacuum. 0.8895 g (yield: 90%) of the title compound (white solid) was obtained.

Melting point: 135-136 ° C (colorless powder)
¹ H-NMR (400 MHz, CDCl ₃ ): 7.756 (2H, d, J = 7.6 Hz), 7.537 (2H, d, d, J = 6.9, 6.8 Hz), 7.396 (2H, d, d, J = 7.7, 7.4 Hz), 7.317-7.155 (7H, m), 6.322 (1H, d, J = 7.3 Hz), 5.440 (1H, d, J = 7.2 Hz), 4.490-4.392 (3H, m), 4.324 ( 1H, d, d, J = 9.9, 6.6 Hz), 4.188 (1H, t, J = 7.0 Hz), 3.672 (3H, s), 3.104-3.021 (2H, m), 2.080 (1H, sept, J = . 6.7 Hz), 0.849 (3H , d, J = 6.8 Hz), 0.806 (3H, d, J = 6.7 Hz) 13 C-NMR (100 MHz, CDCl 3): 171.81, 170.88, 156.06, 143.89, 143.80, 141.40, 136.40, 129.47, 128.83, 127.86, 127.20, 125.17, 120.11, 67.28, 57.45, 56.29, 52.23, 47.19, 38.61, 31.33, 18.93, 17.91.
Analytical results: C ₃₀ H ₃₂ N ₂ O ₅ , calculated values: C, 71.98; H, 6.44; N, 5.60, measured values: C, 72.20; H, 6.56; N, 5.45. HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₃₂ H ₃₂ N ₂ NaO ₅ ⁺ , 523.2203, measured value: 523.2198.

Example M2: Synthesis of dipeptide (Phe-Phe)

Fmoc-Phe-OH (0.7796 g, 2.012 mmol) was placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). 2 mL of DMAC and thionyl chloride (0.16 mL, 2.203 mmol) were added with stirring. The whole was stirred at 23 ° C. for 2 hours. L-Phenylalanine methyl ester hydrochloride (0.4431 g, 2.054 mmol) was added. The whole was stirred at 23 ° C. for 4 hours. 40 mL of 0.5 M aqueous sodium bicarbonate solution was added. A white precipitate was formed. The mixture was stirred at 23 ° C. for 1 hour. The solid was filtered off with suction and washed with 60 mL of water. Dry in vacuum. 0.9469 g (yield: 86%) of the title compound (white solid) was obtained.

Melting point: 175-176 ° C (colorless powder)
¹ H-NMR (400 MHz, CDCl ₃ ): 7.765 (2H, d, J = 7.5 Hz), 7.523 (2H, d, d, J = 6.6, 6.1 Hz), 7.402 (2H, t, J = 7.5 Hz) ), 7.322-7.170 (10H, m), 6.951 (1H, d, J = 5.4 Hz), 4.773 (1H, t, d, J = 7.6, 6.0 Hz), 4.440-4.267 (3H, m), 4.178 ( . 1H, d, d, J = 7.0, 6.9 Hz), 3.667 (3H, s), 3.097-2.966 (4H, m) 13 C-NMR (100 MHz, CDCl 3): 171.42, 170.42, 143.86, 143.83, 141.41, 135.63, 129.51, 129.29, 129.16, 128.83, 128.67, 127.87, 127.27, 127.21, 125.14, 120.13, 120.12, 67.26, 53.44, 52.45, 47.20, 38.48, 38.00.
Analysis results: C ₃₄ H ₃₂ N ₂ O ₅ : C, 74.43; H, 5.88; N, 5.11, measured values: C, 74.41; H, 6.08; N, 5.02. HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₃₄ H ₃₂ N ₂ NaO ₅ ⁺ : 571.2203, measured value: 571.2213.

Example M3: Synthesis of dipeptide (Ala-Val)

Fmoc-Ala-OH (0.6284 g, 2.018 mmol) was placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). 2 mL of DMAC and thionyl chloride (0.16 mL, 2.203 mmol) were added with stirring. The whole was stirred at 23 ° C. for 1 hour. L-valine methyl ester hydrochloride (0.3603 g, 2.149 mmol) was added. The whole was stirred at 23 ° C. for 4 hours. 40 mL of water was added. A white precipitate was formed. The mixture was stirred at 23 ° C. for 1 hour. The solid was filtered off with suction and washed with 60 mL of water. Dry in vacuum. 0.7024 g (yield: 82%) of the title compound (white solid) was obtained.

Melting point: 157-158 ° C (colorless needles)
¹ H-NMR (400 MHz, CDCl ₃ ): 7.753 (2H, d, J = 7.5 Hz), 7.560 (2H, d, J = 7.4 Hz), 7.390 (2H, d, J = 7.6, 7.5 Hz), 7.297 (2H, d, J = 7.5, 7.4 Hz), 6.642 (1H, d, J = 8.1 Hz), 5.530 (1H, d, J = 7.7 Hz), 4.558-4.190 (5H, m), 3.721 (3H , s), 2.154 (1H, sep, J = 6.9 Hz), 1.402 (3H, d, J = 6.9 Hz), 0.911 (3H, d, J = 6.9 Hz), 0.877 (3H, d, J = 6.9 Hz) ¹³ C-NMR (100 MHz, CDCl ₃ ): 172.40, 172.30, 143.91, 143.86, 141.39, 127.84, 127.19, 125.19, 120.10, 67.28, 57.30, 50.56, 47.19, 31.33, 19.04, 18.67, 17.82.
Analytical results: C ₂₄ H ₂₈ N ₂ O ₅ : C, 67.19; H, 6.65; N, 6.60, measured values: C, 67.73; H, 6.70; N, 6.48. HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₂₄ H ₂₈ N ₂ NaO ₅ ⁺ : 447.1890, measured value: 447.1868.

Example M4: Synthesis of dipeptide (Ala-Phe)

Fmoc-Ala-OH (0.3150 g, 1.012 mmol) was placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). 1 mL of DMAC and thionyl chloride (0.08 mL, 1.101 mmol) were added with stirring. The whole was stirred at 23 ° C. for 1 hour. L-phenylalanine methyl ester hydrochloride (0.2254 g, 1.045 mmol) was added. The whole was stirred at 23 ° C. for 4 hours. 40 mL of water was added. A white precipitate was formed. The mixture was stirred at 23 ° C. for 1 hour. The solid was filtered off with suction and washed with 60 mL of water. Dry in vacuum. 0.4371 g (yield: 91%) of the title compound (white solid) was obtained.

Melting point: 125-126 ° C (colorless needles)
¹ H-NMR (400 MHz, CDCl ₃ ): 7.772 (2H, d, J = 7.5 Hz), 7.589 (2H, d, J = .7.2 Hz), 7.408 (2H, d, d, J = 7.4, 7.3 Hz), 7.317 (2H, d, d, J = 7.4, 7.4 Hz), 7.235-7.187 (3H, m), 7.072 (2H, d, J = 6.6 Hz), 6.395 (1H, d, J = 7.0 Hz ), 5.290 (1H, d, J = 5.7 Hz), 4.856 (1H, m), 4.428-4.190 (4H, m), 3.723 (3H, s), 3.186-3.053 (2H, m), 1.356 (3H, . d, J = 6.8 Hz) 13 C-NMR (100 MHz, CDCl 3): 171.99, 171.29, 155.91, 143.88, 141.33, 135.78, 129.35, 128.54, 127.78, 127.14, 125.20, 125.15, 120.01, 67.17, 61.60, 53.34, 50.40, 47.13, 37.94, 18.86, 14.13.
Analysis results: C ₂₈ H ₂₈ N ₂ O ₅ : C, 71.17; H, 5.97; N, 5.93, measured values: C, 71.30; H, 6.33; N, 5.64. HRMS (ESI-TOF, [N + H] ⁺ ): Calculated value: C ₂₈ H ₂₈ N ₂ NaO ₅ : 495.1890, measured value: 495.1882.

Example M5: Synthesis of dipeptide (Leu-Val)

Fmoc-Leu-OH (0.7058 g, 1.997 mmol) was placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). 2 mL of DMAC and thionyl chloride (0.16 mL, 2.203 mmol) were added with stirring. The whole was stirred at 23 ° C. for 1 hour. L-valine methyl ester hydrochloride (0.3552 g, 2.119 mmol) was added. The whole was stirred at 23 ° C. for 4 hours. 40 mL of 0.5 M aqueous sodium bicarbonate solution was added. A white precipitate was formed. The mixture was stirred at 23 ° C. for 1 hour. The solid was filtered off with suction and washed with 50 mL of 0.5 M aqueous sodium bicarbonate. Dry in vacuum. 0.8370 g (yield: 90%) of the title compound (white solid) was obtained.

Melting point: 135-137 ° C (colorless needles)
¹ H-NMR (400 MHz, CDCl ₃ ): 7.766 (2H, d, d, J = 7.4, 0.7 Hz), 7.578 (2H, d, J = 7.4 Hz), 7.397 (2H, d, d, J = 7.8, 7.2 Hz), 7.305 (2H, t, J = 7.4 Hz), 6.456 (1H, d, J = 7.9 Hz), 5.237 (1H, d, J = 8.3 Hz), 4.534 (1H, d, d, J = 8.8, 5.0 Hz), 4.420-4.402 (2H, m), 4.216 (2H, t, J = 7.0 Hz), 2.164 (1H, sept, J = 6.4 Hz), 1.675-1.526 (3H, m), ^{. 0.961-0.856 (12H, m) 13} C-NMR (100 MHz, CDCl 3): 172.27, 172.19, 143.84, 141.44, 127.87, 127.23, 125.17, 120.14, 120.12, 57.24, 52.32, 47.27, 41.41, 31.39, 24.78 , 2.04, 22.20, 19.05, 17.85.
Analytical results: C ₂₇ H ₃₄ N ₂ O ₅ : C, 69.51; H, 7.35; N, 6.00, found: Found: C, 69.70; H, 7.34; N, 6.00. HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₂₇ H ₃₄ N ₂ NaO ₅ ⁺ : 489.2360, measured value: 489.2362.

Example M6: Synthesis of dipeptide (Leu-Phe)

Fmoc-Leu-OH (0.7026 g, 1.988 mmol) was placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). 2 mL of DMAC and thionyl chloride (0.16 mL, 2.203 mmol) were added with stirring. The whole was stirred at 23 ° C. for 1 hour. L-phenylalanine methyl ester hydrochloride (0.5430 g, 2.341 mmol) was added. The whole was stirred at 23 ° C. for 4 hours. 40 mL of 0.5 M aqueous sodium bicarbonate solution was added. A white precipitate was formed. The mixture was stirred at 23 ° C. for 1 hour. The solid was filtered off with suction and washed with 50 mL of 0.5 M aqueous sodium bicarbonate. Dry in vacuum. 0.8264 g (yield: 81%) of the title compound (white solid) was obtained.

Melting point: 139-140 ° C (colorless needles)
¹ H-NMR (400 MHz, CDCl ₃ ): 7.765 (2H, d, J = 7.4 Hz), 7.587 (2H, d, J = 7.1 Hz), 7.405 (2H, d, d, J = 7.5, 7.4 Hz) ), 7.315 (2H, d, d, J = 7.4, 7.4 Hz), 7.242-7.174 (3H, m), 7.073 (2H, d, J = 7.0 Hz), 6.406 (1H, d, J = 7.6 Hz) , 5.132 (1H, d, J = 8.4 Hz), 4.846 (1H, d, d, J = 14.4, 6.5 Hz), 4.465-4.159 (4H, m), 3.716 (3H, s), 3.152 (1H, d , d, J = 13.9, 5.7 Hz), 4.068 (1H, d, d, J = 13.9, 5.9 Hz), 1.655-1.459 (3H, m), 0.916 (6H, d, J = 9.3 Hz). ¹³ C -NMR (100 MHz, CDCl ₃ ): 171.88, 171.79, 145.89, 141.45, 135.73, 129.38, 128.70, 127.88, 127.29, 127.23, 125.24, 125.16, 120.16, 120.13, 67.21, 53.31, 52.51, 47.27, 41.47, 37.97, 24.75, 23.00.
Analytical results: C ₃₁ H ₃₄ N ₂ O ₅ : C, 72.35; H, 6.66; N, 5.44, measured values: Found: C, 72.52; H, 6.81; N, 5.35. HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated value: C ₃₁ H ₃₄ N ₂ NaO ₅ ⁺ : 523.2360, measured value: 523.2373.

Example M7: Synthesis of dipeptide (Leu-Val)

Fmoc-Leu-OH (0.3556 g, 1.006 mmol) was placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). 1 mL of DMAC and thionyl chloride (0.08 mL, 1.102 mmol) were added with stirring. The whole was stirred at 23 ° C. for 1 hour. L-valine (0.1349 g, 1.152 mmol) was added. The whole was stirred at 23 ° C. for 4 hours. 30 mL of water was added. A white precipitate was formed. The solid was filtered off with suction and washed with 60 mL of water. Dry in vacuum. The crude product was dissolved in 10 mL of methanol and 40 mL of water was added. A white precipitate was formed. The solid was filtered off with suction and washed with 60 mL of water. Dry in vacuum. The crude product was purified by column chromatography (methanol: chloroform = 1: 6). 0.3628 g (yield: 80%) of the title compound (white solid) was obtained.

Melting point: 170-172 ° C (colorless powder)
¹ H-NMR (400 MHz, CDCl ₃ ): 7.739 (2H, d, J = 7.5 Hz), 7.555 (2H, d, J = 7.4 Hz), 7.375 (2H, d, d, J = 7.4, 7.3 Hz) ), 7.276 (2H, d, d, J = 7.4, 7.4 Hz), 6.879 (1H, d, J = 8.6 Hz), 5.740 (2H, d, J = 8.6 Hz), 4.452 (2H, d, d, J = 8.7, 4.8 Hz), 4.376-4.324 (3H, m), 4.186 (1H, t, J = 7.1 Hz), 2.246-2.166 (1H, m), 1.667-1.521 (3H, m), 0.929-0.890 ^{. (12H, m) 13 C} -NMR (100 MHz, CDCl 3): 172.96, 156.66, 143.76, 141.41, 127.89, 127.21, 125.18, 120.14, 120.11, 67.43, 57.29, 53.62, 47.17, 41.17, 31.21, 24.73, 22.94, 22.22, 19.07, 17.74.
HRMS (ESI-TOF, [N + Na] ⁺ ): Calculated: C ₂₆ H ₃₂ N ₂ NaO ₅ ⁺ : 475.2203, measured: 475.2223.

Example M8: Synthesis of dipeptide (Leu-Phe)

Fmoc-Leu-OH (0.3522 g, 0.997 mmol) was placed in a 30 mL round bottom flask equipped with a stir bar. The flask was immersed in an ice water bath (0 ° C.). 1 mL of DMAC and thionyl chloride (0.08 mL, 1.102 mmol) were added with stirring. The whole was stirred at 23 ° C. for 1 hour. L-phenylalanine (0.1910 g, 1.156 mmol) was added. The whole was stirred at 23 ° C. for 4 hours. 30 mL of water was added. A white precipitate was formed. The solid was filtered off with suction and washed with 60 mL of water. Dry in vacuum. The crude product was dissolved in 20 mL of methanol and 30 mL of 0.4 M hydrochloric acid was added. A white precipitate was formed. The solid was filtered off with suction and washed with 60 mL of water. Dry in vacuum. The crude product was purified by column chromatography (methanol: chloroform = 1: 6). 0.3873 g (yield: 78%) of the title compound (white solid) was obtained.

Melting point: 177-178 ° C (colorless powder)
¹ H-NMR (400 MHz, CDCl ₃ ): 7.763 (2H, d, J = 7.4 Hz), 7.571 (2H, d, d, J = 6.5, 6.4 Hz), 7.396 (2H, d, d, J = 7.2, 7.0 Hz), 7.297 (2H, d, d, J = 7.4, 7.2 Hz), 7.185-7.089 (5H, m), 6.727 (1H, d, J = 6.5 Hz), 5.374 (1H, d, J = 7.6 Hz), 4.816 (1H, t, d, J = 6.4, 6.5 Hz), 4.457-4.173 (4H, m), 3.184 (1H, d, d, J = 13.9, 5.2 Hz), 2.992 (1H, d, d, J = 13.8, 6.5 Hz), 1.593-1.434 (3H, m), 0.880 (3H, d, J = 6.3 Hz), 0.864 (3H, d, J = 6.6 Hz). ¹³ C-NMR ( 100 MHz, CDCl ₃ ): 156.35, 143.66, 141.31, 135.63, 134.76, 129.36, 128.52, 127.82, 127.12, 125.11, 125.00, 120.06, 120.04, 67.28, 53.24, 47.07, 41.05, 37.38, 29.71, 24.59, 22.79, 22.00 .
Analytical results: C ₃₀ H ₃₂ N ₂ O ₅ ⁺ 0.5H ₂ O: C, 70.71; H, 6.53; N, 5.50, measured values: Found: C, 70.77; H, 6.56; N, 5.13. HRMS (ESI- TOF, [N + Na] ⁺ ): Calculated value: C ₃₀ H ₃₂ N ₂ NaO ₅ ⁺ : 523.2203, measured value: 523.2198.

Claims

A step of reacting an acid halide with an amine, an amide compound and / or an alcohol in the presence of one or more solvents selected from the group consisting of an amide solvent and a urea solvent. A method for producing an acid amide compound, a sulfonic acid amide compound or an ester compound.
The production method according to claim 1, wherein the amine is one or more selected from the group consisting of aliphatic amines, aromatic amines, zwitterionic molecules and derivatives thereof.
The production method according to claim 2, wherein the zwitterionic molecule is an amino acid, anthranilic acid, 3-carboxyaniline or 4-carboxyaniline.
The production method according to any one of claims 1 to 3, wherein the amine is an amine having a pKBH + value of 2 or less.
The production method according to claim 1, wherein the amide compound is a urea compound, carbamic acid, carbamate, thiourea compound, thiocarbamic acid and / or thiocarbamate.
The production method according to claim 1, wherein the alcohol is an aliphatic alcohol or an aromatic alcohol.
The production method according to any one of claims 1 to 6, wherein the acid halide is a carboxylic acid halide or a sulfonic acid halide.
The production method according to any one of claims 1 to 6, wherein the acid halide is a halide of an amino acid or a halide of a peptide.
The production method according to any one of claims 1 to 8, wherein the acid halide is an acid chloride.
The production method according to any one of claims 1 to 9, wherein the solvent is an amide solvent.
The amide solvents are N, N-dimethylacetamide (DMAC), N, N-diethylacetamide (DEA), N, N-dimethylformamide (DMF), N, N-diethylformamide (DEF), N-methyl- The production method according to any one of claims 1 to 10, which is one or more solvents selected from the group consisting of 2-pyrrolidone (NMP) and N-ethyl-2-pyrrolidone (NEP). .
The production method according to any one of claims 1 to 9, wherein the solvent is a urea solvent.
The urea solvent is one or two selected from the group consisting of N, N′-dimethylpropyleneurea (DMPU), tetramethylurea (TMU) and 1,3-dimethyl-2-imidazolidinone (DMI) The production method according to any one of claims 1 to 9 and 12, which is a solvent of at least one species.
The production method according to any one of claims 1 to 13, wherein the solvent is used as a reaction solvent.
The production method according to any one of claims 1 to 14, further comprising a step of mixing the acid halide and the amine, amide compound and / or alcohol at -15 ° C to 35 ° C.
The method according to claim 15, further comprising a step of stirring the mixture at -15 ° C to 35 ° C after the mixing step.
The production method according to any one of claims 1 to 16, wherein the step is carried out in a reaction system substantially free of a base catalyst that captures hydrogen halide generated by the reaction.
The production method according to any one of claims 1 to 17, wherein a carboxylic acid amide compound is produced by reacting a carboxylic acid halide with an amine as an acid halide.
The production method according to any one of claims 1 to 17, wherein a carboxylic acid amide compound is produced by reacting a carboxylic acid halide with an amide compound as an acid halide.
The production method according to any one of claims 1 to 17, wherein a sulfonic acid amide compound is produced by reacting a sulfonic acid halide with an amine as an acid halide.
The production method according to any one of claims 1 to 17, wherein an ester compound is produced by reacting a carboxylic acid halide with an alcohol as the acid halide.
The production method according to any one of claims 1 to 17, wherein an ester compound is produced by reacting a sulfonic acid halide with an alcohol as an acid halide.
The acid halide according to any one of claims 1 to 17, wherein the acid halide is an amino acid halide or a peptide halide, the amine is an amino acid or a peptide, and the produced carboxylic acid amide compound is a peptide. The manufacturing method as described.
The acid halide is a carboxylic acid halide, the amine is an amino acid having optical activity, and the produced carboxylic acid amide compound is a carboxylic acid amide compound having optical activity. The manufacturing method as described in any one of these.
An acid halide and two or more kinds of amines and / or amide compounds having different basicities are reacted to selectively produce any one of two or more kinds of carboxylic acid amide compounds or sulfonic acid amide compounds. The production method according to any one of claims 1 to 19, characterized in that:
An acid halide is reacted with an amine or an amide compound having two or more amino groups having different basicities to selectively form an amide bond with respect to any one of the amino groups. The production method according to any one of claims 1 to 20.