WO2019160037A1 - Procédés de production de composés à l'aide d'halogénure d'acide - Google Patents

Procédés de production de composés à l'aide d'halogénure d'acide Download PDF

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WO2019160037A1
WO2019160037A1 PCT/JP2019/005345 JP2019005345W WO2019160037A1 WO 2019160037 A1 WO2019160037 A1 WO 2019160037A1 JP 2019005345 W JP2019005345 W JP 2019005345W WO 2019160037 A1 WO2019160037 A1 WO 2019160037A1
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acid
production method
stirred
amine
compound
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智彦 大和田
陸人 大塚
和夫 丸橋
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国立大学法人 東京大学
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    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/73—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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    • C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
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Definitions

  • 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.
  • hydrogen halide such as hydrogen chloride
  • the hydrogen halide and the raw material amine form a salt.
  • the reaction was saturated at about 50%, and the amide compound could not be obtained in high yield.
  • 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.
  • the amine is one or more selected from the group consisting of aliphatic amines, aromatic amines, zwitterionic molecules and derivatives thereof.
  • 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.
  • the urea solvent is selected from the group consisting of N, N′-dimethylpropyleneurea (DMPU), tetramethylurea (TMU) and 1,3-dimethyl-2-imidazolidinone (DMI) 1
  • DMPU N, N′-dimethylpropyleneurea
  • TNU tetramethylurea
  • DMI 1,3-dimethyl-2-imidazolidinone
  • 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.
  • 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).
  • 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.
  • halogen and halogen atom include chlorine (Cl), bromine (Br), fluorine (F), and iodine (I), with chlorine (Cl) being preferred.
  • the acid halide is an acid chloride (acid chloride).
  • “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 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.
  • 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.
  • 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 ⁇ electrons. Have.
  • the “aromatic ring group” may be an aromatic hydrocarbon group or an aromatic heterocyclic group.
  • 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.
  • the hydroxyl group represents —OH
  • the carboxyl group represents —COOH
  • the sulfonic acid group represents (—S ( ⁇ O) 2 OH)
  • the carbonyl group represents —CO — (— C ( ⁇ O) —
  • the thiocarbonyl group represents —CS — (— C ( ⁇ S) —).
  • ⁇ Raw material Amine>
  • 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 means an amine having an aliphatic hydrocarbon chain.
  • 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.
  • substituents 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).
  • the amino group may be further substituted with one or more substituents, and examples of the substituent include an alkyl group.
  • the alkoxy group, alkylcarbonyl group, alkoxycarbonyl group, and alkylcarbonyloxy group may be further substituted with one or more substituents.
  • 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.
  • the group —R 101 —R 102 may be further substituted with one or more substituents.
  • substituents include a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an alkyl group
  • substituents include carbonyl group, alkoxycarbonyl group, alkylcarbonyloxy group, carboxyl group, sulfonic acid group, amino group, nitro group and cyano group.
  • the substituents may be the same or different.
  • 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.
  • 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.
  • substituents include a halogen atom, a group —R 201 —R 202 (where R 201 represents a single group).
  • R 202 represents an aromatic ring group
  • R 202 represents an aromatic ring group
  • R 202 represents an aromatic ring group
  • substituent B the amino group may be further substituted with one or more substituents, and examples of the substituent include an alkyl group.
  • 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.
  • the group —R 201 —R 202 may be further substituted with one or more substituents.
  • substituents examples include a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an alkyl group
  • substituents 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 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.
  • a zwitterionic molecule in which a carboxyl group is esterified that is, an ester of a zwitterionic molecule
  • 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.
  • 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
  • the substituent A may be further substituted
  • 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.
  • a typical example of a zwitterionic molecule is an amino acid.
  • amino acids in the present invention include ⁇ -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 ⁇ carbon (for example, , ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid).
  • 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.
  • zwitterionic molecules include not only amino acids but also peptides formed by polymerizing a plurality of amino acids and compounds containing amino acids.
  • amino acid and peptide derivatives for example, carboxyl groups formed esters.
  • ester forms and amide forms in which an amino group forms an amide are also included.
  • zwitterionic molecules include, but are not limited to, anthranilic acid, 3-carboxyaniline and 4-carboxyaniline.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 substituents may be the same or different.
  • R 6 represents — (N (—R 9 )) — and Q represents an oxygen atom
  • the compound of Formula 3 represents a urea compound
  • R 5 , R 7 , R 8, and R 9 further represent
  • the compound of formula 3 represents urea
  • R 5 , R 7 and R 8 further represent a hydrogen atom
  • the compound of formula 3 represents a semicarbazide.
  • R 7 , R 8 and R 9 preferably represent a hydrogen atom.
  • R 6 represents — (N (—R 9 )) — and Q represents a sulfur atom
  • the compound of Formula 3 represents a thiourea compound
  • R 5 , R 7 , R 8, and R 9 further represent
  • R 5 , R 7 , R 8 further represent a hydrogen atom
  • R 9 further represents an amino group
  • the compound of formula 3 represents a thiosemicarbazide.
  • R 7 , R 8 and R 9 preferably represent a hydrogen atom.
  • 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).
  • R 7 and R 8 preferably represent a hydrogen atom.
  • 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).
  • R 7 and R 8 preferably represent a hydrogen atom.
  • 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.
  • R 7 and R 8 preferably represent a hydrogen atom.
  • 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.
  • 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.
  • the substituents may be the same or different.
  • An aromatic alcohol means an alcohol having an aromatic ring.
  • 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.
  • the substituent B may be further substituted.
  • the aromatic alcohol is substituted with a plurality of substituents, the substituents may be the same or different.
  • Acid halide examples include carboxylic acid halides and sulfonic acid halides.
  • Carboxylic acid halides include aliphatic carboxylic acids and aromatic carboxylic acids.
  • 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 ⁇ -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.
  • the substituents may be the same or different.
  • 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.
  • 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 —
  • R 14 represents a hydrogen atom or an aliphatic hydrocarbon group.
  • the aliphatic carboxylic acid in Formula 7 may be substituted with a substituent.
  • the halide of an aliphatic carboxylic acid includes a halide of an ester of an aliphatic carboxylic acid.
  • 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).
  • a halogenating agent such as thionyl chloride or sulfuryl chloride.
  • 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.
  • typical examples of zwitterionic molecules include amino acids. That is, in the present invention, an amino acid halide obtained by halogenating an ⁇ -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 ⁇ -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.
  • 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.
  • the aromatic carboxylic acid is substituted with a plurality of substituents, the substituents may be the same or different.
  • 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.
  • R 16 represents an aromatic ring group
  • Hal represents a halogen atom
  • R 17 represents a single bond or —NR 18 —
  • R 18 represents a hydrogen atom or an aliphatic hydrocarbon group.
  • the aromatic carboxylic acid in Formula 9 may be substituted with a substituent.
  • the aromatic carboxylic acid halide includes an aromatic carboxylic acid ester halide.
  • 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)
  • R 16 represents a halogen atom or an aromatic ring group substituted by a halogen atom
  • R 19 represents an aliphatic hydrocarbon group
  • the halide of aromatic carboxylic acid can be prepared according to a known method.
  • it can be prepared by reacting aromatic carboxylic acid or its ester with a halogenating agent such as thionyl chloride or sulfuryl chloride.
  • a halogenating agent such as thionyl chloride or sulfuryl chloride.
  • 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 include aliphatic sulfonic acids and aromatic sulfonic acids.
  • 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.
  • the substituents may be the same or different.
  • 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).
  • R 20 represents an aliphatic hydrocarbon group and Hal represents a halogen atom.
  • R 20 represents an aliphatic hydrocarbon group and Hal represents a halogen atom.
  • 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.
  • 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.
  • the aromatic sulfonic acid is substituted with a plurality of substituents, the substituents may be the same or different.
  • 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.
  • 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.
  • a halogenating agent such as thionyl chloride or sulfuryl chloride.
  • an amide solvent and a urea solvent can be used as the reaction solvent.
  • 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.
  • the amide solvent and the urea solvent may be used alone or in combination.
  • 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
  • An amide solvent and / or a urea solvent may be added.
  • 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.
  • amide solvents examples 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).
  • DMAC N-dimethylacetamide
  • DEA N, N-diethylacetamide
  • DMF N-dimethylformamide
  • DEF N-diethylformamide
  • NMP N-methyl-2-pyrrolidone
  • NEP N-ethyl-2-pyrrolidone
  • urea solvents examples include organic solvents having a urea structure (—NHCONH—), such as N, N′-dimethylpropyleneurea (DMPU), tetramethylurea (TMU) and 1,3. -Dimethyl-2-imidazolidinone (DMI).
  • DMPU N, N′-dimethylpropyleneurea
  • TNU tetramethylurea
  • DI 1,3. -Dimethyl-2-imidazolidinone
  • 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 are suppressed.
  • the formation of salts (precipitates) of raw materials such as amines and hydrogen halides and the formation of precipitates of reaction products are suppressed.
  • 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.
  • 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.
  • a stoichiometric amount is used.
  • either one of the raw materials may be excessive.
  • 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.
  • 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.
  • 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.
  • hydrogen halide gas for example, hydrogen chloride gas
  • the reaction of the acid halide with the amine, amide compound or alcohol can be continued by subsequently stirring the mixed solution.
  • the reaction temperature can be ⁇ 15 ° C. to 35 ° C. (preferably 0 ° C. to 20 ° C.).
  • 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.
  • the reaction product is subjected to silica gel chromatography, column chromatography, filtration, crystallization. It can be separated and purified by known methods such as
  • 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).
  • a poor solvent eg, 1 to 5 times the amount of the reaction solution
  • 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.
  • 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).
  • an extraction method can be used when it is difficult to recover the reaction product by the precipitation method.
  • 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.
  • a carboxylic acid amide compound comprising a step of reacting in the presence of a urea-based solvent.
  • the carboxylic acid amide compound of the reaction product includes a urea compound and a carbamate compound
  • the urea compound and the carbamate compound can be produced by appropriately selecting the carboxylic acid halide and amine to be reacted.
  • 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.
  • 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.
  • a carboxylic acid halide for example, a compound of formula 7 or 9
  • an amide compound for example, a compound of formula 3
  • 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.
  • the carboxylic acid amide compound of the reaction product contains a urea compound
  • the urea compound can be produced by appropriately selecting the carboxylic acid halide and amine to be reacted.
  • 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.
  • 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.
  • raw materials, solvents, reaction conditions and procedures can be determined according to the description in this specification.
  • a carboxylic acid halide for example, a compound of formula 7 or 9
  • an alcohol for example, a compound of formula 4 or 5
  • a method for producing a carboxylic acid ester compound comprising a step of reacting in the presence of
  • raw materials, solvents, reaction conditions and procedures can be determined according to the description in this specification.
  • a sulfonic acid halide for example, a compound of formula 11 or formula 13
  • an alcohol for example, a compound of formula 4 or formula 5
  • a sulfonate compound comprising a step of reacting.
  • raw materials, solvents, reaction conditions and procedures can be determined according to the description in this specification.
  • 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.
  • raw materials, solvents, reaction conditions and procedures can be determined according to the description of the present specification.
  • peptide is not limited by the chain length of amino acid residues, but is meant to include oligopeptides, polypeptides, and proteins.
  • an amino acid halide having an ⁇ -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).
  • a protecting group for example, a fluorenylmethoxycarbonyl group (Fmoc).
  • Fmoc fluorenylmethoxycarbonyl group
  • Benzyloxycarbonyl group and tert-butoxycarbonyl group for example, a fluorenylmethoxycarbonyl group (Fmoc).
  • peptide halide a peptide in which the C-terminal ⁇ -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).
  • a protecting group for example, a fluorenylmethoxycarbonyl group (Fmoc), Benzyloxycarbonyl group and tert-butoxycarbonyl group.
  • 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).
  • a peptide in which the N-terminal ⁇ -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).
  • 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.
  • 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.
  • the target peptide can be produced in a high yield without protecting the C-terminal amino acid or the carboxyl group of the peptide.
  • 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.
  • 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.
  • 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.
  • raw materials, solvents, reaction conditions and procedures can be determined according to the description of the present specification.
  • 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.
  • “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.
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • “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).
  • 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.
  • amino groups constituting an amide structure, thioamide structure, urea structure, thiourea structure, semicarbazide structure, thiosemicarbazide structure, and the like are included.
  • 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.
  • an acid pKa 5 or less; for example, 1.5 to 5 equivalents with respect to the total amino groups
  • the additive as an acid can use the same thing as the above.
  • a base pK BH + 10 or more; for example, 1.5 to 5 equivalents relative to the total of amino groups
  • the ratio of the amide bond of the amino group having the smallest basicity can be reduced.
  • 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)
  • R 5 -R 6- (C Q) (-NR 7 R 8 ) (wherein R 5 , R 6 ,
  • the substituent A or the optionally substituted group A or A substituent B 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.
  • 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 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.
  • Example A Synthesis of carboxylic acid amide compound (1)
  • a carboxylic acid amide compound was synthesized by reacting an aliphatic amine and an acid chloride in various organic solvents.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example B Synthesis of Carboxamide Compound (2)
  • a carboxylic acid amide compound was synthesized by reacting an aliphatic amine with an acid chloride in various organic solvents.
  • 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 C Synthesis of carboxylic acid amide compound (3)
  • a carboxylic acid amide compound was synthesized by reacting an aromatic amine and an acid chloride in various organic solvents.
  • an amide solvent and a urea solvent were used.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example D Synthesis of carboxamide compound (4)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)
  • various zwitterionic molecules and acid chlorides were reacted in an amide solvent to synthesize a carboxylic acid amide compound.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • L-phenylalanine (1.7408 g, 10.538 mmol)
  • 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: 5
  • 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.
  • D-phenylalanine (1.7035 g, 10.1212 mmol)
  • 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 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.
  • 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.
  • 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.
  • 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.
  • Example G Synthesis of amide compound (7)
  • 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.
  • 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.
  • Example H Synthesis of Carbamate Compound
  • a carbamate compound was synthesized by reacting various amines with a carboxylic acid ester chloride in an amide solvent.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example J Synthesis of sulfonamide compound
  • various amines and sulfonic acid chlorides were reacted in an amide solvent to synthesize a sulfonamide compound.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example L Synthesis of amide compound (8)
  • 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.
  • 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.
  • Example L3 Selective synthesis of an aromatic amide (N- (4-aminomethyl-phenyl) -2-chloroacetamide) in the presence of an aliphatic amine
  • Example M Synthesis of amide compound (9)
  • a dipeptide was synthesized by reacting two amino acids in an amide solvent.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

Abstract

Le but de la présente invention est de fournir des procédés de production d'un composé carboxamide, d'un composé de sulfonamide et d'un composé ester à l'aide d'un halogénure d'acide. Les procédés de production d'un composé carboxamide, d'un composé de sulfonamide et d'un composé ester comprennent chacun une étape consistant à faire réagir un halogénure d'acide avec une amine, un composé amide, ou un alcool en présence d'un solvant à base d'amide et/ou d'un solvant à base d'urée. L'amine peut être choisie parmi des amines aliphatiques, des amines aromatiques et des molécules zwittérioniques et leurs dérivés. L'halogénure d'acide peut être choisi parmi des halogénures de carbonyle et des halogénures de sulfonyle.
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