Method for amidation of carboxylic acid compound

Abstract

The present invention relates to a method for preparing an amide compound and, more specifically, to a method for preparing an amide compound into which various types of functional groups are introduced through decarboxylation amidation between various carboxylic acid compounds and dioxazolone compounds. In addition, according to the present invention, a chiral carboxylic acid compound can be used as a starting material and reacted with a dioxazolone compound to synthesize various forms of chiral amines while maintaining three-dimensional information.

Description

Method for amidation of carboxylic acid compounds

[0001] The present invention relates to a method for amidating a carboxylic acid compound, and more particularly, to a method for producing an amide compound having various functional groups introduced therein by base-mediated decarboxylation amidation of a carboxylic acid compound using 1,4,2-dioxazol-5-one as an amidation reagent in the presence of a transition metal.

[0002] In recent decades, strategies involving transition metal-catalyzed carbon-carbon or carbon-heteroatom bond couplings have emerged as powerful synthetic tools for constructing complex molecular structures. Among these, decarboxylation of carbon-nitrogen bonds using abundant carboxylic acids or their derivatives has received significant attention for accessing alkyl or arylamines, key pharmacophores.

[0003] Despite remarkable progress, transition metal-catalyzed carbon-carbon or carbon-nitrogen bond formation reactions still suffer from the necessity of using prefunctionalized aryl (alkyl) halides (or similar halides) to initiate oxidative addition. To address this shortcoming, a decarboxylation cross-coupling strategy using carboxylic acids, which represent abundant and readily available sources of aryl (alkyl) compounds, has emerged as an alternative.

[0004] Indeed, although transition metal-catalyzed decarboxylation functionalizations have been developed, they have been limited primarily to aryl- or alkynylcarboxylic acid substrates under rather harsh reaction conditions (above 100°C) due to the thermodynamically demanding CO2 release. To overcome these limitations, redox-mediated one-electron processes for the decarboxylation of carboxylic acids or their derivatives (e.g., redox-active esters (RAEs)) have been actively studied, particularly to achieve milder cross-coupling procedures that enable decarboxylating C(sp3)-N bond formation by accessing one of the essential biorelevant motifs prevalent in natural products, agrochemicals, and pharmaceuticals.

[0005] In recent years, the use of redox-active esters derived from carboxylic acids has been reported to be effective in facilitating C(sp3)-N bond formation under reductive decarboxylation conditions. Examples include the intramolecular decarboxylative amidation of N-hydroxyphthalimide (NHP) esters using photocatalysis, intermolecular C(sp3)-N bond formation via metallaphotoredox catalysts, and the facile chemical reduction of RAE using Zn(0) or Bi(I) to induce the formation of a decarboxylating carboradical for subsequent trapping with a diazirine reagent or coupling with an N-nucleophile via radical-polar crossover. However, all of these reported methods involve the participation of a trigonal planar carboradical as an essential intermediate, which has the disadvantage of losing the stereochemical information of the starting material when using chiral carboxylic acid substrates.

[0006] Chiral compounds are compounds with specific optical activity, and are important compounds used in the pharmaceutical and fine chemical industries. They are very important compounds whose share in the global pharmaceutical market is increasing day by day.

[0007] Methods for synthesizing alpha-chiral amines, which are considered important functional groups in various bioactive molecules, are very limited. Alpha-chiral amines are typically synthesized via stereoselective reductive amination or reduction of ketimines, but these reactions require equivalent or excessive amounts of reducing agent and prevent the accessibility of alpha-tertiary amines. Furthermore, most previously reported decarboxylation functionalization reactions of carboxylic acids result in the formation of carboradical intermediates via one-electron transfer, thereby losing the inherent stereoinformation.

[0008] Therefore, there is an urgent need for the development of a method for efficiently preparing synthetically versatile N-substituted amide compounds in a stereoconservative manner that can preserve the stereochemical information of carboxylic acid compounds that are abundant in nature or are easy to synthesize, especially chiral carboxylic acids, thereby providing α-chiral amines that serve as very important key intermediates in the fields of medicine and chemistry.

[0009] Accordingly, the inventors of the present invention, while striving to solve the above-mentioned problems, discovered that a chiral amide compound accessible to an alpha-chiral amine can be produced by using a dioxazolone compound as an amidating reagent that is robust and highly reactive, and forming a decarboxylated stereospecific carbon-nitrogen bond using a carboxylic acid compound that is abundant in nature and can be easily prepared synthetically as a substrate in the presence of a base, thereby completing the present invention.

[0010] The present invention aims to provide a method for amidating a carboxylic acid compound.

[0011] The present invention aims to provide a method for producing amide compounds having various functional groups introduced therein by base-mediated decarboxylation amidation of all types of carboxylic acid compounds using a dioxazolone compound as an amidation reagent under transition metal-free conditions.

[0012] The present invention aims to provide a method for the stereospecific decarboxylation amidation of chiral carboxylic acids using a dioxazolone compound as a strong amidating reagent under mild and transition metal-free conditions.

[0013] The present invention provides a method for amidating a carboxylic acid compound, and includes a method for producing an amide compound having various functional groups introduced therein by subjecting all types of carboxylic acid compounds to base-mediated decarboxylation amidation using a dioxazolone compound as an amidation reagent under transition metal-free conditions.

[0014] One aspect of the present invention provides a method for preparing an amide compound represented by the following chemical formula 1 by decarboxylating amidation of a carboxylic acid compound represented by the following chemical formula 2 with a dioxazolone compound represented by the following chemical formula 3 in the presence of a base:

[0015] [Chemical Formula 1]

[0016]

[0017] [Chemical Formula 2]

[0018]

[0019] [Chemical Formula 3]

[0020]

[0021] In the above chemical formulas 1 to 3,

[0022] R and R' are each independently a substituted or unsubstituted C1-C30 hydrocarbyl, or a substituted or unsubstituted C1-C30 heterohydrocarbyl.

[0023] In one embodiment, R is C1-C30 alkyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C1-C30 alkoxyC1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C6-C30 aryl, C3-C30 heteroaryl, C6-C30 arylC1-C30 alkyl or C3-C30 heteroarylC1-C30 alkyl;

[0024] The above R's alkyl, cycloalkyl, heterocycloalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl is halogen, nitro, cyano, hydroxy, C1-C30 alkyl, haloC1-C30 alkyl, C1-C30 alkoxy, C6-C30 aryloxy, C1-C30 alkylthio, C6-C30 arylthio, C2-C30 alkenyl, C2-C30 alkynyl, C3-C30 heterocycloalkyl, C6-C30 aryl, C6-C30 arylC1-C30 alkyl, hydroxyC6-C30 cycloalkyl, C1-C30 alkylC3-C30 cycloalkyl, C3-C30 cycloalkylC1-C30 alkyl, C6-C30 arylC1-C30 alkyloxy, C1-C30 alkylcarbonyl, C6-C30 arylcarbonyl, haloC1-C30 alkylcarbonyl, C1-C30 alkoxycarbonyl, C6-C30 aryloxycarbonyl, haloC1-C30 alkoxycarbonyl, C1-C30 alkylcarbonyloxy, C6-C30 arylcarbonyloxy, haloC1-C30 alkylcarbonyloxy, C1-C30 alkoxycarbonylamino, C6-C30 aryloxycarbonylamino, C1-C30 alkylsulfinyl, C6-C30 arylsulfinyl, C1-C30 alkylsulfonyl, C6-C30 arylsulfonyl and -B(R a )(R b ) may be further substituted with one or more selected from the group consisting of;

[0025] R a and R b are each independently hydrogen, hydroxy, C1-C30 alkyl or C1-C30 alkoxy, or may be linked to each other to form a ring,

[0026] R' is C1-C10 alkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C20 aryl, C3-C20 heteroaryl or -L-R'';

[0027] L is C1-C10 alkylene, C3-C10 cycloalkylene, C2-C10 alkenylene or C2-C10 alkynylene;

[0028] R'' is C6-C20 aryl or C3-C20 heteroaryl; the aryl or heteroaryl of R'' may be further substituted with one or more selected from C1-C10 alkoxycarbonyl and C6-C20 aryl;

[0029] The alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl of the above R' is halogen, cyano, nitro, C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, C6-C20 aryl, C6-C20 arylC1-C10 alkyl, C6-C20 aryloxy, C6-C20 arylC1-C10 alkyloxy, C1-C10 alkylcarbonyloxy, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, haloC1-C10 alkylcarbonyloxy, haloC1-C10 alkylcarbonyl, haloC1-C10 alkoxycarbonyl, C6-C20 arylcarbonyl, C6-C20 aryloxycarbonyl, amino, mono C1-C10 alkylamino and It may be further substituted with one or more selected from the group consisting of diC1-C10 alkylamino;

[0030] The above heteroaryl and heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O and S.

[0031] In one embodiment, R is C2-C10 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C1-C10 alkoxyC1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C6-C20 aryl, C6-C20 arylC1-C10 alkyl or C3-C20 heteroarylC1-C10 alkyl;

[0032] The above R's alkyl, cycloalkyl, heterocycloalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, arylalkyl or heteroarylalkyl is halogen, C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 heterocycloalkyl, C6-C20 aryl, C6-C20 arylC1-C10 alkyl, hydroxyC6-C20 cycloalkyl, C1-C10 alkylC3-C20 cycloalkyl, C3-C20 cycloalkylC1-C10 alkyl, C1-C10 alkylcarbonyl, C6-C20 arylcarbonyl, haloC1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, HaloC1-C10alkoxycarbonyl, C1-C10alkoxycarbonylamino, C6-C20aryloxycarbonylamino, C1-C10alkylsulfinyl, C6-C20arylsulfinyl and -B(R a )(R b ) may be further substituted with one or more selected from the group consisting of;

[0033] R a and R b are each independently hydroxy, or may be linked to each other to form a ring,

[0034] R' is C1-C10 alkyl or -L-R'';

[0035] L is C1-C10 alkylene, C2-C10 alkenylene or C2-C10 alkynylene;

[0036] R'' is C6-C20 aryl or C3-C20 heteroaryl; the aryl or heteroaryl of R'' may be further substituted with one or more selected from C1-C10 alkoxycarbonyl and C6-C20 aryl.

[0037] In one embodiment, the dioxazolone compound of the above chemical formula 3 can be used in an amount of 1 to 5 moles per mole of the carboxylic acid compound of the above chemical formula 2.

[0038] In one embodiment, the base may be used in an amount of 0.1 to 3 moles per mole of the carboxylic acid compound of the chemical formula 2.

[0039] In one embodiment, the base is potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3), pyridine, triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 1,8-bis(tetramethylguanidino)naphthalene (TMGN), tert-butylimino-tris(dimethylamino)phosphorane, P1-t-Bu), tert-octylimino-tris(dimethylamino)phosphorene (P1-t-Oct), 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ 5 ,4λ 5 -Catenadi(phosphazene)(1-Ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ 5 ,4λ 5 -catenadi(phosphazene), P2-Et), 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ 5 ,4λ 5 -Catenadi(phosphazene)(1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ 5 ,4λ 5 -catenadi(phosphazene), P2-t-Bu), 1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)-phosphoranylideneamino]-2λ 5 ,4λ 5 -Cathenadi(phosphazene) (1-tert-Butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)-phosphoranylidenamino]-2λ 5,4λ 5 -catenadi(phosphazene, P4-t-Bu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), (tert-butylimino)tris(pyrrolidino)phosphorane (BTPP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), It may be one or more selected from the group consisting of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), and 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0040] In one embodiment, the reaction can be performed in the absence of a transition metal.

[0041] In one embodiment, the reaction can be carried out in an aprotic solvent.

[0042] In one embodiment, the aprotic solvent may be one or more selected from the group consisting of hexane, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), chloroform, dichloromethane (DCM), dichloroethane (DCE), benzene, chlorobenzene, toluene, and xylene.

[0043] In one embodiment, the reaction can be performed at 0 to 60°C.

[0044] According to the manufacturing method of the present invention, an amide compound having various functional groups introduced can be manufactured by base-mediated decarboxylation amidation of all types of carboxylic acid compounds using a dioxazolone compound as an amidation reagent under conditions without a transition metal.

[0045] According to the manufacturing method of the present invention, it can be easily applied to the synthesis of α-tertiary amide compounds that cannot be synthesized by conventional reductive amination methods.

[0046] In particular, the manufacturing method of the present invention allows for the efficient synthesis of amidation products in which the stereochemical information of the chiral carboxylic acid substrate is maintained. Using chiral carboxylic acid substrates, which are abundant in nature and readily available synthetically, primary, secondary, or tertiary chiral amines can be accessed under simple reaction conditions, making them expected to find wide-ranging applications.

[0047] According to the manufacturing method of the present invention, a chiral amidation product providing a target α-chiral amine, which serves as a very important key intermediate in the fields of medicine and chemistry, can be rapidly and efficiently synthesized, and thus can be applied to various industrial synthesis or pharmaceutical synthesis.

[0048] Hereinafter, the present invention will be described in more detail. Unless otherwise defined, the technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which this invention pertains. In the following description, descriptions of well-known functions and configurations that may unnecessarily obscure the gist of the present invention will be omitted. The terminology used in this specification is intended solely to effectively describe specific embodiments and is not intended to limit the present invention.

[0049] As used herein, the singular forms may be intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0050] Throughout this specification, the terms "comprises," "includes," "contains," or "has" a component, unless specifically stated to the contrary, do not exclude other components, but rather imply that the component may include other components, and do not exclude additional unrecited elements, materials, or processes.

[0051] The numerical ranges used herein include the lower and upper limits and all values ​​within that range, increments logically derived from the shape and width of the defined range, all doubly defined values, and all possible combinations of the upper and lower limits of numerical ranges defined in different shapes. Unless otherwise specified herein, values ​​outside the defined range that may arise due to experimental error or rounding of values ​​are also included in the defined numerical range.

[0052] In this specification, “substituent,” “radical,” “group,” “moiety,” and “fragment” can be used interchangeably.

[0053] In this specification, "C A -C B " means "the number of carbon atoms is greater than or equal to A and less than or equal to B".

[0054] In this specification, "substitution" means that a hydrogen atom bonded to a carbon or nitrogen atom of a compound is replaced with another substituent, and the position of substitution is not limited as long as it is a position where a hydrogen atom is replaced, i.e., a position where a substituent can be replaced, and when two or more are substituted, the two or more substituents may be the same or different from each other.

[0055] In the description "substituted or unsubstituted" described herein, "substituted" means that a hydrogen atom in a functional group is replaced by another atom or another functional group (i.e., a substituent).

[0056] The term "hydrocarbyl" as used herein means a radical having one bonding position derived from a hydrocarbon, and includes alkyl, alkenyl, alkynyl, cycloalkyl, aryl or a combination thereof.

[0057] The term "heterohydrocarbyl" as used herein means a radical having one bonding position derived from a heterohydrocarbon comprising at least one heteroatom selected from N, O and S.

[0058] The term "alkyl" as used herein includes a monovalent straight-chain or branched saturated hydrocarbon radical composed solely of carbon and hydrogen atoms, which may be further substituted by other substituents. The alkyl may have 1 to 30 carbon atoms. The alkyl may have 1 to 20 carbon atoms. The alkyl may have 1 to 10 carbon atoms. Examples of such alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, 1,2-dimethylpropyl, isopentyl, 1-ethylpropyl, neopentyl, t-pentyl, hexyl, heptyl, octyl, ethylhexyl, methylheptyl, nonyl, decyl, dodecyl, tetradecyl, and the like.

[0059] The term "alkoxy" as used herein refers to an -O-alkyl radical, where "alkyl" is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and the like.

[0060] The term "aryl" as used herein refers to a monovalent organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, which may include a single or fused ring system, suitably containing 4 to 7 ring atoms in each ring, preferably 5 or 6 ring atoms, and may include a form in which multiple aryls are linked, and may be further substituted by other substituents. The ring atoms may have 6 to 20 carbon atoms, preferably 6 to 12 carbon atoms. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, phenylnaphthyl, benzylidene-1H-indenyl, and the like.

[0061] The term "aryloxy" as used herein means an -O-aryl radical, where 'aryl' is as defined above. Examples of such aryloxy radicals include, but are not limited to, phenoxy, naphthoxy, and the like.

[0062] The term "heteroaryl" as used herein refers to a monovalent heteroaromatic ring radical which is an aryl group having at least one heteroatom selected from N, O, and S as an aromatic ring skeletal atom, and the remaining aromatic ring skeletal atoms are carbon. The heteroaryl is a 5 to 8-membered monocyclic heteroaryl, a polycyclic heteroaryl in which two or more monocyclic heteroaryls are fused, and a polycyclic heteroaryl condensed with one or more benzene rings, and may be partially saturated. The heteroaryl also includes a form in which one or more heteroaryls are linked. Specific examples include monocyclic heteroaromatic rings such as furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, triazine, pyridine, pyrazine, pyrimidine, and pyridazine; Polycyclic heteroaromatic rings such as benzofuran, benzothiophene, isobenzofuran, benzimidazole, benzothiazole, benzoisothiazole, benzoisoxazole, benzoxazole, isoindole, indole, indazole, tetrahydroindazole, benzo[d]oxazol-2(3H)-one, pyrazolopyrimidine, quinoline, isoquinoline, dibenzofuran, dibenzothiophene, carbazole, benzocarbazole, etc.; but are not limited thereto.

[0063] The term "halo" or "halogen" as used herein refers to a halogen group element, including, for example, fluoro, chloro, bromo, and iodo.

[0064] The term "cycloalkyl" as used herein refers to a non-aromatic carbocyclic monovalent radical composed of one or more rings, including saturated or unsaturated monocyclic, polycyclic or spirocyclic forms, which may be further substituted by other substituents. Here, polycyclic means a group in which cycloalkyl is directly connected to or condensed with another ring group. Here, the other ring group may be cycloalkyl, but may also be another type of ring group, such as a heterocycloalkyl, an aromatic ring, a heterocycle, etc. The carbon atoms in the cycloalkyl may be optionally oxidized. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxocyclopentyl, norbornyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, adamantly, decalinyl, cubyl, hexadecahydro-1H-cyclopenta[a]phenanthrenyl, Examples thereof include, but are not limited to, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, octahydronaphthalenyl, cyclohexenyl, and cycloheptenyl.

[0065] The term "heterocycloalkyl" as used herein refers to a saturated or partially unsaturated monocyclic or polycyclic ring having the indicated number of ring atoms, including at least one heteroatom selected from N, O and S, the remaining ring atoms being carbon, and which may be further substituted by other substituents. Here, polycyclic means a group in which heterocycloalkyl is directly connected to another ring group, or a group connected in a spiro form. Here, the other ring group may be heterocycloalkyl, but may also be another type of ring group, such as a cycloalkyl, an aromatic ring, a heterocycle, etc. A nitrogen, carbon or sulfur atom in said heterocycloalkyl may be optionally oxidized; a nitrogen atom may be optionally quaternized; and the heterocycloalkyl may be partially or fully saturated. In addition, a bond may be formed via a heteroatom or a carbon atom present in said heterocycloalkyl. Specific examples include oxetane, aziridine, pyrrolidine, azetidine, piperidine, tetrahydrofuran, tetrahydropyridine, tetrahydropyran, piperazine, morpholine, thiomorpholine, 10,11-dihydro-5H-dibenz[b,f]azepine, 10,11-dihydrodibenzo[b,f]thiepine, pyrrolidine-2-one, pyrrolidine-2,5-dione, dioxoisoindoline, 10-oxo-10,11-dihydrodibenzo[b,f]thiepine, 10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine, It may include a monovalent radical of a non-aromatic heterocycle such as imidazolidine-2,4-dione, thiazolidine-2,4-dione, pyrimidine-2,4(1H,3H)-dione, pyridazin-3(2H)-one, 3-azabicyclo[3.1.0]hexane, octahydropyrrolo[3,4-c]pyrrole, 2,7-diazaspiro[4.4]nonane, 2-azaspiro[4.4]nonane, etc.

[0066] The term "alkenyl" as used herein refers to a straight or branched unsaturated hydrocarbon monovalent radical containing one or more double bonds between two or more carbon atoms, which may be partially saturated and may be further substituted by other substituents. Specifically, it includes, but is not limited to, ethenyl, 1-propenyl, 2-propenyl, allyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, isoprenyl, geranyl, 5-tetradecenyl, and the like.

[0067] The term "alkynyl" as used herein refers to a straight or branched unsaturated hydrocarbon monovalent radical containing one or more triple bonds between two or more carbon atoms, which may be partially saturated and may be further substituted by other substituents. Specifically, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-butynyl, 1,3-butadiynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, Including but not limited to 2-noninyl, 8-noninyl, 1-decynyl, 2-decynyl, 9-decynyl, etc.

[0068] The term "arylalkyl" as used herein means an alkyl radical substituted with at least one aryl, wherein aryl and alkyl are as defined above. Examples of such arylalkyl radicals include, but are not limited to, benzyl, trityl, and the like.

[0069] As used herein, “alkylcarbonyl” means alkyl-C(=O)-, and “arylcarbonyl” means aryl-C(=O)-, wherein alkyl and aryl are as defined above.

[0070] As used herein, “alkoxycarbonyl” means alkoxy-C(=O)-, and “aryloxycarbonyl” means aryloxy-C(=O)-, wherein alkoxy and aryloxy are as defined above.

[0071] The term "alkoxycarbonylamino" in this specification means a -NHC(=O)-alkoxy radical, and "aryloxycarbonylamino" means -NHC(=O)-aryloxy, wherein alkoxy and aryloxy are as defined above.

[0072] The term "haloalkyl" or "haloalkoxy" as used herein means an alkyl or alkoxy group, respectively, in which one or more hydrogen atoms are replaced by a halogen atom, wherein alkyl and halogen are as defined above.

[0073] The term "alkylsulfinyl" as used herein means -SO-alkyl, "arylsulfinyl" means -SO-aryl, "alkylsulfonyl" means -SO2-alkyl, and "arylsulfonyl" means -SO2-aryl, where alkyl and aryl are as defined above.

[0074] The term "alkylene" as used herein means a divalent straight-chain or branched saturated hydrocarbon group composed solely of carbon and hydrogen atoms, specifically including, but not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, t-butylene, pentylene, hexylene, octylene, nonylene, and the like.

[0075] The term "alkenylene" as used herein refers to a divalent group obtained by removing two hydrogen atoms from an alkene, specifically including, but not limited to, ethenylene, propenylene, or butenylene.

[0076] The term "alkynylene" as used herein refers to a divalent group obtained by removing two hydrogen atoms from an alkyne, including but not limited to ethynylene, propynylene, or butynylene.

[0077] The term "heteroatom" as used herein means an atom other than carbon (C), and may specifically be a nitrogen (N), oxygen (O), or sulfur (S) atom. The above-mentioned heteroaryl and heterocycloalkyl may contain one or more heteroatoms, for example, 1, 1 to 2, 1 to 3, or 1 to 4 heteroatoms.

[0078] The present invention relates to a method for amidating a carboxylic acid compound, and more particularly, to a method for producing an amide compound having various functional groups introduced therein by subjecting primary, secondary, and tertiary carboxylic acid compounds to base-mediated decarboxylation amidation using 1,4,2-dioxazol-5-one as an amidation reagent in the presence of a transition metal.

[0079] According to one aspect of the present invention, a method for producing an amide compound represented by the following chemical formula 1 is provided by decarboxylating and amidating a carboxylic acid compound represented by the following chemical formula 2 with a dioxazolone compound represented by the following chemical formula 3 in the presence of a base.

[0080] [Chemical Formula 1]

[0081]

[0082] [Chemical Formula 2]

[0083]

[0084] [Chemical Formula 3]

[0085]

[0086] In the above chemical formulas 1 to 3,

[0087] R and R' are each independently a substituted or unsubstituted C1-C30 hydrocarbyl, or a substituted or unsubstituted C1-C30 heterohydrocarbyl.

[0088] According to the manufacturing method of the present invention, an amide compound having various functional groups introduced can be efficiently manufactured by base-mediated decarboxylation amidation of all types of carboxylic acid compounds using a dioxazolone compound as an amidation reagent under transition metal-free conditions.

[0089] According to the manufacturing method of the present invention, an amidation product can be manufactured in which the stereospecific information of the chiral carboxylic compound is maintained intact through a stereospecific decarboxylation amidation reaction with a dioxazolone compound as an amidation reagent, starting from a chiral carboxylic acid compound in the presence of a base. This reaction is initiated by the nucleophilic addition of a carboxylic acid to the carbonyl of dioxazolone, and includes a stereospecific decarboxylation amidation process through the subsequent rearrangement to form a carbon-nitrogen bond while releasing carbon dioxide. In the above-described decarboxylation amidation process, the carboradical intermediate that is essentially formed in the decarboxylation functionalization reaction of a conventional carboxylic acid is not formed at all, so that the stereospecific information of the chiral carboxylic acid compound is maintained intact in the final product, the amidation compound.

[0090] Accordingly, a chiral amide compound accessible to an alpha-chiral amine can be efficiently prepared by forming a decarboxylated stereospecific carbon-nitrogen bond using a dioxazolone compound as an amidation reagent in the presence of a base and a chiral carboxylic acid compound, which is abundant in nature and can be easily prepared synthetically, as a substrate.

[0091] In one embodiment, the dioxazolone compound of the above chemical formula 3 is not particularly limited, but may be used in an amount of 1 to 5 moles per mole of the carboxylic acid compound of the above chemical formula 2, and may be used in an amount of 2 to 3 moles in terms of reaction efficiency.

[0092] In one embodiment, the base is not particularly limited, but may be used in an amount of 0.1 to 3 moles per mole of the carboxylic acid compound of the above chemical formula 2, and in terms of reaction efficiency, may be used in an amount of 0.2 to 3 moles, or 0.25 to 3 moles. When the base is used within the above range, improved reactivity and yield may be exhibited.

[0093] In one embodiment, the base is potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3), pyridine, triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 1,8-bis(tetramethylguanidino)naphthalene (TMGN), tert-butylimino-tris(dimethylamino)phosphorane, P1-t-Bu), tert-octylimino-tris(dimethylamino)phosphorene (P1-t-Oct), 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ 5 ,4λ 5 -Catenadi(phosphazene)(1-Ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ 5 ,4λ 5 -catenadi(phosphazene), P2-Et), 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ 5 ,4λ 5 -Catenadi(phosphazene)(1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ 5 ,4λ 5-catenadi(phosphazene), P2-t-Bu), 1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)-phosphoranylideneamino]-2λ 5 ,4λ 5 -Cathenadi(phosphazene) (1-tert-Butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)-phosphoranylidenamino]-2λ 5 ,4λ 5-catenadi(phosphazene, P4-t-Bu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), (tert-butylimino)tris(pyrrolidino)phosphorane (BTPP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), It may be one or more selected from the group consisting of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and 1,4-diazabicyclo[2.2.2]octane (DABCO), specifically 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), tert-butylimino-tris(dimethylamino)phosphorane (P1-t-Bu), or It may be 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0094] In one embodiment, the reaction can be performed in the absence of a transition metal.

[0095] In one embodiment, the reaction may be carried out in the presence of an organic solvent, and there is no need to limit the organic solvent as long as it does not react with the reactants. In terms of reaction efficiency, the organic solvent may be an aprotic solvent. In one specific example, the aprotic solvent may be one or more selected from the group consisting of hexane, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), chloroform, dichloromethane (DCM), dichloroethane (DCE), benzene, chlorobenzene, toluene, and xylene, and more specifically, one or more selected from N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), and toluene may be used as the reaction solvent.

[0096] In one embodiment, the reaction can be carried out under mild conditions, and the reaction temperature can be any temperature commonly used in organic synthesis, but specifically, it can be carried out at 0 to 60°C or 20 to 60°C, and can be appropriately adjusted as needed. The reaction time can vary depending on the reactant, the amount of the reactant, the type of solvent, and the amount of the solvent, and is not particularly limited.

[0097] In one embodiment, R is C1-C30 alkyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C1-C30 alkoxyC1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C6-C30 aryl, C3-C30 heteroaryl, C6-C30 arylC1-C30 alkyl or C3-C30 heteroarylC1-C30 alkyl;

[0098] The above R's alkyl, cycloalkyl, heterocycloalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl is halogen, nitro, cyano, hydroxy, C1-C30 alkyl, haloC1-C30 alkyl, C1-C30 alkoxy, C6-C30 aryloxy, C1-C30 alkylthio, C6-C30 arylthio, C2-C30 alkenyl, C2-C30 alkynyl, C3-C30 heterocycloalkyl, C6-C30 aryl, C6-C30 arylC1-C30 alkyl, hydroxyC6-C30 cycloalkyl, C1-C30 alkylC3-C30 cycloalkyl, C3-C30 cycloalkylC1-C30 alkyl, C6-C30 arylC1-C30 alkyloxy, C1-C30 alkylcarbonyl, C6-C30 arylcarbonyl, haloC1-C30 alkylcarbonyl, C1-C30 alkoxycarbonyl, C6-C30 aryloxycarbonyl, haloC1-C30 alkoxycarbonyl, C1-C30 alkylcarbonyloxy, C6-C30 arylcarbonyloxy, haloC1-C30 alkylcarbonyloxy, C1-C30 alkoxycarbonylamino, C6-C30 aryloxycarbonylamino, C1-C30 alkylsulfinyl, C6-C30 arylsulfinyl, C1-C30 alkylsulfonyl, C6-C30 arylsulfonyl and -B(R a )(R b ) may be further substituted with one or more selected from the group consisting of;

[0099] R a and R b are each independently hydrogen, hydroxy, C1-C30 alkyl or C1-C30 alkoxy, or may be linked to each other to form a ring,

[0100] R' is C1-C10 alkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C20 aryl, C3-C20 heteroaryl or -L-R'';

[0101] L is C1-C10 alkylene, C3-C10 cycloalkylene, C2-C10 alkenylene or C2-C10 alkynylene;

[0102] R'' is C6-C20 aryl or C3-C20 heteroaryl; the aryl or heteroaryl of R'' may be further substituted with one or more selected from C1-C10 alkoxycarbonyl and C6-C20 aryl;

[0103] The alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl of the above R' is halogen, cyano, nitro, C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, C6-C20 aryl, C6-C20 arylC1-C10 alkyl, C6-C20 aryloxy, C6-C20 arylC1-C10 alkyloxy, C1-C10 alkylcarbonyloxy, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, haloC1-C10 alkylcarbonyloxy, haloC1-C10 alkylcarbonyl, haloC1-C10 alkoxycarbonyl, C6-C20 arylcarbonyl, C6-C20 aryloxycarbonyl, amino, mono C1-C10 alkylamino and It may be further substituted with one or more selected from the group consisting of diC1-C10 alkylamino;

[0104] The above heteroaryl and heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O and S.

[0105] In one embodiment, R is C2-C10 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C1-C10 alkoxyC1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C6-C20 aryl, C6-C20 arylC1-C10 alkyl or C3-C20 heteroarylC1-C10 alkyl;

[0106] The above R's alkyl, cycloalkyl, heterocycloalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, arylalkyl or heteroarylalkyl is halogen, C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 heterocycloalkyl, C6-C20 aryl, C6-C20 arylC1-C10 alkyl, hydroxyC6-C20 cycloalkyl, C1-C10 alkylC3-C20 cycloalkyl, C3-C20 cycloalkylC1-C10 alkyl, C1-C10 alkylcarbonyl, C6-C20 arylcarbonyl, haloC1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, HaloC1-C10alkoxycarbonyl, C1-C10alkoxycarbonylamino, C6-C20aryloxycarbonylamino, C1-C10alkylsulfinyl, C6-C20arylsulfinyl and -B(R a )(R b ) may be further substituted with one or more selected from the group consisting of;

[0107] R a and R b are each independently hydroxy, or may be linked to each other to form a ring,

[0108] R' is C1-C10 alkyl or -L-R'';

[0109] L is C1-C10 alkylene, C2-C10 alkenylene or C2-C10 alkynylene;

[0110] R'' is C6-C20 aryl or C3-C20 heteroaryl; the aryl or heteroaryl of R'' may be further substituted with one or more selected from C1-C10 alkoxycarbonyl and C6-C20 aryl.

[0111] In one embodiment, R' is C1-C5 alkyl or -L-R''; L is C2-C3 alkylene, C3-C5 alkenylene or C3-C5 alkynylene; R'' is C6-C12 aryl or C3-C12 heteroaryl, and the aryl or heteroaryl of R'' may be further substituted with one or more selected from C1-C5 alkoxycarbonyl and C6-C12 aryl.

[0112] In one specific example, R may be selected from the following structures.

[0113]

[0114] In one specific example, R' can be methyl, ethyl, propyl, butyl or pentyl.

[0115] In one specific example, R' is -L-R''; L is ethylene, propylene, vinylene, butenylene or butynylene; R'' is phenyl or oxazole, and the phenyl or oxazole of R'' may be further substituted with one or more selected from methoxycarbonyl and phenyl.

[0116] The present invention provides an effective method for efficiently synthesizing chiral amide compounds that provide target alpha-chiral amines, which serve as crucial key intermediates in the fields of medicine and chemistry. According to the present invention, amidation products can be efficiently synthesized while retaining the stereochemical information of the chiral carboxylic acid substrate.

[0117] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0118] Unless otherwise specified, all commercially available reagents and solvents were used without further purification. All reactions that were not sensitive to air and moisture were performed under ambient atmosphere. Thin layer chromatography (TLC) was performed using pre-coated silica gel 60 F254 plates and visualized by UV light (254 nm) or potassium permanganate (KMnO4) staining. Flash chromatography was performed on a RediSep using the indicated eluent system. ® R fCombiFlash equipped with silica column (230 to 400 mesh) ® R f + It was performed in the system. 1 H NMR spectra were obtained using an Agilent Technologies DD2 (600 MHz), Bruker Avance Neo (500 MHz), or AVANCE NEONanobay (400 MHz). Chemical shifts are reported in ppm relative to the residual solvent peak (CHCl3 in CDCl3: 7.26 ppm, (CD3)SO(CD2H) in DMSO-d6: 2.50 ppm). 13 C NMR spectra were acquired using a Bruker AVANCE III HD (100 MHz), AVANCE NEO (125 MHz) or Agilent Technologies DD2 (150 MHz) and were fully separated by broad-band proton decoupling. 19 F NMR spectra were obtained using an Agilent Technologies DD2 (564 MHz), Bruker Avance 500 (471 MHz), or AVANCE III HD (376 MHz). Infrared (IR) spectra were obtained using a Bruker Alpha FT-IR Spectrometer equipped with an iD5 ATR accessory, and frequencies are in wavenumber (cm -1) were expressed as . Melting points (mp) were measured using a Buchi Melting Point M-565. High-resolution mass spectra (HRMS) were obtained using electron ionization (EI) or fast atom bombardment (FAB) methods at the Korea Basic Science Institute (Daegu). X-ray diffraction (XRD) data were collected on a Bruker SMART APEX II coated with paraton-N oil under a flow of N2(g) at 120 K. High-pressure liquid chromatography (HPLC) analysis was performed using a Shimadzu Prominence HPLC system consisting of an LC20A pump and an SPD-M20A photodiode array detector. Optical rotation was determined using a Jasco P-2000 Polarimeter equipped with a temperature controller. 3-Methyl-1,4,2-dioxazole-5-one was synthesized according to a previously reported method [Nat. It was synthesized and used according to [Chem.13, 378-385 (2021).].

[0119] Example I: Decarboxylation amidation using an achiral carboxylic acid

[0120]

[0121] In a 4 mL vial equipped with a stirrer, a carboxylic acid compound (formula 1, 0.200 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.00 equiv., 0.400 mmol, 60.9 mg) and anhydrous dimethyl sulfoxide (DMSO, 1.00 mL, 0.200 M) were added, followed by the addition of 3-methyl-1,4,2-dioxazol-5-one (2.00 equiv., 0.400 mmol, 40.4 mg), and the mixture was stirred at room temperature for 4 h. After completion of the reaction, the crude reaction mixture was diluted with dichloromethane (DCM, 5.0 mL), 1 N HCl aqueous solution (10 mL) was added, and the mixture was extracted with DCM (5 mL × 3 times). The collected organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone, 100:0 to 50:50) to obtain the desired product, an amide compound (chemical formula 1).

[0122] The following amide compounds were prepared through the decarboxylation amidation described above using various achiral carboxylic acids as starting materials.

[0123] [Example 1] Preparation of N-Cyclohexylacetamide (1)

[0124]

[0125] Eluent DCM / Acetone = 85:15; colorless solid (22.6 mg, 80%); 1 H NMR (600 MHz, CDCl3)δ 5.40 (s, 1H), 3.79-3.71 (m, 1H), 1.96 (s, 3H), 1.94-1.88 (m, 2H), 1.73-1.66 (m, 2H), 1.64-1.58 (m, 1H), 1.40-1.32 (m, 2H), 1.21-1.06 (m, 3H); 13 C NMR (150 MHz, CDCl3)δ 169.2, 48.4, 33.4, 25.7, 25.0, 23.8.

[0126] [Example 2] Preparation of N-Cyclobutylacetamide (2)

[0127]

[0128] Eluent DCM / Acetone = 60:40; Colorless solid (11.6 mg, 51%); mp= 50-52℃; 1 H NMR (600 MHz, CDCl3) δ 5.63 (s, 1H), 4.44-4.34 (m, 1H), 2.39-2.29 (m, 2H), 1.94 (s, 3H), 1.88-1.79 (m, 2H), 1.74-1.66 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 169.2, 44.9, 31.5, 23.5, 15.2; IR (cm -1 ) 3250, 3062, 2973, 1624, 1544, 1293; HRMS (EI) m / z calcd. For C6H 11 NO [M] + : 113.0841, found: 113.0842.

[0129] [Example 3] Preparation of N-Cyclopentylacetamide (3)

[0130]

[0131] Eluent DCM / Acetone = 80:20; Colorless solid (16.2 mg, 64%); 1 H NMR (600 MHz, CDCl3) δ 5.45 (s, 1H), 4.19 (h,J= 7.0 Hz, 1H), 2.02-1.96 (m, 2H), 1.95 (s, 3H), 1.66 (tdd,J= 10.3, 8.6, 5.2 Hz, 2H), 1.59 (ddddd,J= 11.3, 9.8, 8.7, 5.6, 4.0 Hz, 2H), 1.39-1.31 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 169.7, 51.4, 33.3, 23.8, 23.6.

[0132] [Example 4] Preparation of N-Cycloheptylacetamide (4)

[0133]

[0134] Eluent DCM / Acetone = 85:15; Colorless solid (27.4 mg, 88%); 1 H NMR (600 MHz, CDCl3) δ 5.46 (s, 1H), 3.93 (ddq,J= 13.3, 8.9, 4.4 Hz, 1H), 1.93 (s, 3H), 1.90 (dt,J= 7.9, 5.6 Hz, 2H), 1.64-1.56 (m, 4H), 1.54-1.46 (m, 4H), 1.43-1.35 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 168.9, 50.6, 35.3, 28.2, 24.2, 23.8.

[0135] [Example 5] Preparation of N-(Bicyclo[2.2.1]heptan-2-yl)acetamide (5)

[0136]

[0137] Eluent DCM / Acetone = 80:20; Colorless solid (9.4 mg, 31%); 1 H NMR (600 MHz, CDCl3) δ 5.46 (s, 1H), 4.12 (dddd,J= 11.6, 8.8, 5.2, 3.0 Hz, 1H), 2.43 (d,J= 4.1 Hz, 1H), 2.21 (t,J= 4.5 Hz, 1H), 2.09 (dddd,J= 13.0, 11.4, 4.7, 3.2 Hz, 1H), 1.98 (s, 3H), 1.62-1.55 (m, 1H), 1.51-1.40 (m, 3H), 1.32 (ddt,J= 10.0, 3.3, 1.7 Hz, 1H), 1.21 (dddd,J=11.5, 8.5, 4.7, 2.3 Hz, 1H), 0.69 (ddd,J= 12.9, 4.7, 3.1 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 170.0, 50.9, 40.2, 38.2, 37.8, 36.6, 29.9, 23.5, 21.5.

[0138] [Example 6] Preparation of N-(4,4-Difluorocyclohexyl)acetamide (6)

[0139]

[0140] Eluent DCM / Acetone = 75:25; Colorless solid (20.6 mg, 58%); mp= 153-155℃; 1 H NMR (600 MHz, CDCl3) δ 5.35 (s, 1H), 3.94-3.84 (m, 1H), 2.14-2.04 (m, 2H), 2.03-1.95 (m, 5H), 1.85 (dtt,J= 31.3, 13.5, 4.4 Hz, 2H), 1.50 (qd,J= 12.8, 4.0 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 169.6, 122.6 (dd,J= 242.8, 239.9 Hz), 46.4, 32.4 (t,J= 25.1 Hz), 28.8 (d,J= 9.6 Hz), 23.6; 19 F NMR (471MHz, CDCl3) δ -94.78 (d,J= 237.5 Hz), -101.54 (d,J= 237.9 Hz); IR (cm -1 ) 3300, 2944, 1638, 1552, 1123; HRMS (EI) m / z calcd. For C8H 13 F2NO [M] + : 177.0965, found: 177.0968.

[0141] [Example 7] Preparation of N-(1,2,3,4-Tetrahydronaphthalen-2-yl)acetamide (7)

[0142]

[0143] Eluent DCM / Acetone = 80:20; colorless solid (27.8 mg, 73%); 1 H NMR (600 MHz, CDCl3) δ 7.16-7.08 (m, 3H), 7.08-7.04 (m, 1H), 5.55 (s, 1H), 4.34-4.26 (m, 1H), 3.12 (dd,J= 16.3, 5.2 Hz, 1H), 2.88 (tdt,J= 17.2, 12.1, 6.6 Hz, 2H), 2.65 (dd,J= 16.3, 7.9 Hz, 1H), 2.09-2.01 (m, 1H), 1.98 (d,J= 0.9 Hz, 3H), 1.79 (tdd,J= 10.3, 8.4, 4.3 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 169.7, 135.7, 134.2, 130.1, 129.0, 126.8, 126.1, 43.3, 36.8, 29.6, 26.7, 23.7.

[0144] [Example 8] Preparation of N-(2,3-Dihydro-1H-inden-2-yl)acetamide (8)

[0145]

[0146] Eluent DCM / Acetone = 80:20; colorless solid (20.3 mg, 58%); 1 H NMR (600 MHz, CDCl3) δ 7.26-7.21 (m. 2H), 7.20-7.16 (m, 2H), 5.72 (s, 1H), 4.73 (tq,J= 7.4, 4.2, 3.8 Hz, 1H), 3.30 (dd,J= 16.1, 7.0 Hz, 2H), 2.80 (dd,J= 16.1, 4.2 Hz, 2H), 1.94 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 169.8, 141.0, 126.9, 125.0, 50.8, 40.3, 23.6.

[0147] [Example 9] Preparation of tert-Butyl 4-acetamidopiperidine-1-carboxylate (9)

[0148]

[0149] Eluent DCM / Acetone = 60:40; Colorless solid (37.1 mg, 77%); 1 H NMR (600 MHz, CDCl3) δ 5.48 (d,J= 8.0 Hz, 1H), 4.18-3.94 (m, 2H), 3.90 (tdt,J= 11.6, 8.2, 4.1 Hz, 1H), 2.90-2.73 (m, 2H), 1.96 (s, 3H), 1.92-1.86 (m, 2H), 1.44 (s, 9H), 1.32-1.21 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 169.5, 154.8, 79.8, 46.9, 42.9, 32.2, 28.6, 23.6.

[0150] [Example 10] Preparation of N-(1,4-Diphenylbutan-2-yl)acetamide (10)

[0151]

[0152] Eluent DCM / Acetone = 90:10; Colorless solid (47.8 mg, 89%); 1 H NMR (600 MHz, CDCl3) δ 7.31-7.25 (m, 4H), 7.24-7.21 (m, 1H), 7.20-7.13 (m, 5H), 5.16 (d, J = 8.4 Hz, 1H), 4.27 (dddd, J = 15.3, 9.0, 6.3, 4.6 Hz, 1H), 2.87-2.79 (m, 2H), 2.66 (ddd, J = 9.4, 6.6, 3.0 Hz, 2H), 1.91 (s, 3H), 1.89-1.82 (m, 1H), 1.70-1.62 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 169.7, 141.8, 137.9, 129.6, 128.5(9), 128.5(7), 128.4(5), 126.7, 126.1, 50.2, 41.0, 35.8, 32.7, 23.6; IR (cm -1 ) 3318, 3022, 2939, 1630, 1531; HRMS (EI) m / z calcd. For C 18 H 21 NO [M] + : 267.1623, found: 267.1620.

[0153] [Example 11] Preparation of N-(Pentan-3-yl)acetamide (11)

[0154]

[0155] Eluent DCM / Acetone = 80:20; Colorless solid (19.7 mg, 76%); 1 H NMR (600 MHz, CDCl3) δ 5.23 (s, 1H), 3.77 (dddd,J= 13.1, 9.1, 7.8, 5.4 Hz, 1H), 1.98 (s, 3H), 1.53 (dddd,J= 14.9, 12.9, 7.4, 5.3 Hz, 2H), 1.35 (dt,J= 13.8, 7.5 Hz, 2H), 0.88 (t,J= 7.5 Hz, 6H); 13 C NMR (150 MHz, CDCl3) δ 169.9, 52.1, 27.5, 23.7, 10.3.

[0156] [Example 12] Preparation of N-(dec-1-yn-4-yl)acetamide (12)

[0157]

[0158] Eluent DCM / Acetone = 85:15; Colorless solid (30.3 mg, 78%); 1H NMR (600 MHz, CDCl3) δ 5.52 (d,J= 9.0 Hz, 1H), 4.04 (ddddd,J= 9.1, 8.2, 6.4, 5.2, 4.1 Hz, 1H), 2.49 (ddd,J= 16.9, 5.2, 2.7 Hz, 1H), 2.36 (ddd,J= 16.8, 4.1, 2.6 Hz, 1H), 2.01-1.97 (m, 4H), 1.63-1.48 (m, 2H), 1.35-1.23 (m, 8H), 0.90-0.85 (m, 3H); 13 C NMR (150 MHz, CDCl3) δ 169.7, 80.5, 70.9, 47.2, 33.5, 31.8, 29.2, 26.1, 24.2, 23.6, 22.7, 14.2; IR (cm -1 ) 3287, 3263, 2950, ​​2921, 2852, 1644, 1555; HRMS (EI) m / z calcd. For C 12 H 21 NO [M] + : 195.1623, found: 195.1622.

[0159] [Example 13] Preparation of N-Benzylacetamide (13)

[0160]

[0161] Eluent DCM / Acetone = 80:20; Colorless solid (22.1 mg, 74%); 1 H NMR (600 MHz, CDCl3) δ 7.35-7.31 (m, 2H), 7.30-7.25 (m, 3H), 5.84 (s, 1H), 4.42 (d, J= 5.7 Hz, 2H), 2.01 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 170.0, 138.4, 128.9, 128.0, 127.7, 43.9, 23.4.

[0162] [Example 14] Preparation of N-Phenethylacetamide (14)

[0163]

[0164] Eluent DCM / Acetone = 80:20; Colorless solid (20.9 mg, 64%); 1 H NMR (600 MHz, CDCl3) δ 7.33-7.30 (m, 2H), 7.25-7.22 (m, 1H), 7.21-7.18 (m, 2H), 5.48 (s, 1H), 3.52 (q,J= 6.8 Hz, 2H) 2.82 (t,J= 7.0 Hz, 2H), 1.94 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 170.2, 139.0, 128.9, 128.8, 126.7, 40.8, 35.8, 23.5.

[0165] [Example 15] Preparation of N-(3-Phenylpropyl)acetamide (15)

[0166]

[0167] Eluent DCM / Acetone = 80:20; colorless liquid (22.8 mg, 64%); 1 H NMR (600 MHz, CDCl3) δ 7.31-7.25 (m, 2H), 7.21-7.16 (m, 3H), 5.45 (s, 1H), 3.31-3.26 (m, 2H), 2.65 (t,J= 7.7 Hz, 2H), 1.93 (s, 3H), 1.84 (p,J= 7.3 Hz, 2H); 13 C NMR (150 MHz, CDCl3) δ 170.2, 141.6, 128.6, 128.5, 126.2, 39.5, 33.5, 31.3, 23.5.

[0168] [Example 16] Preparation of N-Neopentylacetamide (16)

[0169]

[0170] Eluent DCM / Acetone = 75:25; Colorless solid (18.5 mg, 72%); mp= 63-65℃; 1H NMR(600 MHz, CDCl3) δ 5.51 (s, 1H), 3.06 (d,J= 6.3 Hz, 2H), 2.00 (s, 3H), 0.90 (s, 9H); 13 C NMR (150 MHz, CDCl3) δ 170.2, 50.8, 31.9, 27.3, 23.6; IR (cm -1 ) 3261, 3086, 2957, 2864, 1636, 1583; HRMS(EI) m / z calcd. For C7H 15 NO [M] + : 129.1154, found: 129.1150.

[0171] [실시예 17] Preparation of N-(5-Chloropentyl)acetamide (17).

[0172]

[0173] DCM / Acetone = 70:30; colorless liquid (22.0 mg, 67%); 1 H NMR(600 MHz, CDCl3) δ 5.49 (s, 1H), 3.54 (t,J= 6.6 Hz, 2H), 3.28-3.23 (m, 2H), 1.97 (s, 3H), 1.82-1.76 (m, 2H), 1.57-1.50 (m, 2H), 1.50-1.44 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 170.2, 45.0, 39.5, 32.2, 29.1, 24.3, 23.5; IR (cm -1 ) 3282, 3086, 2933, 2863, 1647, 1553; HRMS(EI) m / z calcd. For C7H 14 ClNO [M] + : 163.0764, found: 163.0763.

[0174] [실시예 18]Preparation of N-(Cyclopropylmethyl)acetamide (18).

[0175]

[0176] Eluent DCM / Acetone = 75:25; colorless liquid (36.2 mg, 64%); 1 H NMR (600 MHz, CDCl3) δ 5.66 (s, 1H), 3.09 (dd, J = 7.2, 5.4 Hz, 2H), 1.98 (s, 3H), 0.97-0.90 (m, 1H), 0.51-0.47 (m, 2H), 0.20-0.17 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 170.1, 44.6, 23.5, 10.8, 3.5.

[0177] [Example 19] Preparation of N,N'-(Pentane-1,5-diyl)diacetamide (19)

[0178]

[0179] The reaction was carried out in DMF solvent. After completion of the reaction, the crude mixture was purified by silica column chromatography (eluent: DCM:MeOH, 90:10) to obtain the product.

[0180] Colorless solid (27.7 mg, 74%); 1 H NMR (600 MHz, CDCl3) δ 5.73 (s, 2H), 3.24 (td,J= 6.9, 5.8 Hz, 4H), 1.98 (s, 6H), 1.52 (p,J= 7.1 Hz, 4H), 1.38-1.31 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 170.5, 39.3, 29.1, 23.8, 23.4.

[0181] [Example 20] Preparation of (E)-N-(Hept-2-en-1-yl)acetamide (20)

[0182]

[0183] Eluent DCM / Acetone = 80:20; colorless liquid (17.3 mg, 56%); 1H NMR (600 MHz, CDCl3) δ 5.61 (dtt,J= 14.9, 6.7, 1.4 Hz, 1H), 5.53-5.36 (m, 2H), 3.82-3.78 (m, 2H), 2.03-1.99 (m, 2H), 1.98 (s, 3H), 1.37-1.26 (m, 4H), 0.89 (t,J= 7.1 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 169.9, 134.2, 125.6, 41.8, 32.0, 31.4, 23.5, 22.3, 14.0; IR (cm -1 ) 3280, 3077, 2956, 2924, 2856, 1648, 1546; HRMS (EI) m / z calcd. For C9H 17 NO [M] + : 155.1310, found: 155.1309.

[0184] [Example 21] Preparation of N-(Thiophen-3-ylmethyl)acetamide (21)

[0185]

[0186] Eluent DCM / Acetone = 80:20; Colorless solid (20.2 mg, 65%); 1 H NMR (600 MHz, CDCl3) δ 7.30 (dd,J= 5.0, 3.0 Hz, 1H), 7.17-7.13 (m, 1H), 7.03 (dd,J= 5.0, 1.3 Hz, 1H), 5.72 (s, 1H), 4.44 (d,J= 5.6 Hz, 2H), 2.01 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 169.9, 139.1, 127.5, 126.6, 122.5, 39.0, 23.4.

[0187] [Example 22] Preparation of N-(3-(Benzyloxy)propyl)acetamide (22)

[0188]

[0189] DCM / Acetone = 65:35; colorless liquid (27.4mg, 66%); 1 H NMR(600 MHz, CDCl3) δ 7.38-7.28 (m, 5H), 6.01 (s, 1H), 4.50 (s, 2H), 3.59 (t,J= 5.7 Hz, 2H), 3.37 (q,J= 6.0 Hz, 2H), 1.88 (s, 3H), 1.83-1.78 (m, 2H); 13 C NMR(150 MHz, CDCl3) δ 170.1, 138.3, 128.6, 127.9, 127.8, 73.3, 69.5, 38.4, 29.1, 23.4; IR (cm -1 ) 3286, 3086, 2928, 2859, 1646, 1549, 1098; HRMS (FAB) m / z calcd. For C 12 H 18 NO2[M+H] + : 208.1338, found: 208.1335.

[0190] Preparation of [실시예 23]N-{3-(1,3-Dioxoisoindolin-2-yl)propyl}acetamide (23)

[0191]

[0192] DCM / Acetone = 80:20; colorless 고체 (25.9mg, 53%); mp= 130-132℃; 1 H NMR(600 MHz, CDCl3) δ 7.85 (dd,J= 5.4, 3.1 Hz, 2H), 7.73 (dd,J= 5.5, 3.0 Hz, 2H), 6.20 (s, 1H), 3.76 (t,J= 6.4 Hz, 2H), 3.23 (q,J= 6.3 Hz, 2H), 2.02 (s, 3H), 1.89-1.83 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 170.3, 168.9, 134.3, 132.1, 123.5, 36.2, 35.0, 28.4, 23.6; IR (cm -1) 3313, 1767, 1694, 1634, 1552; HRMS (EI) m / z calcd. For C 13 H 14 N2O3[M] + : 246.1004, found: 246.1006.

[0193] [Example 24] Preparation of N-(2-Phenylpropan-2-yl)acetamide (24)

[0194]

[0195] The reaction was carried out for 12 hours. Eluent DCM / Acetone = 80:20; colorless solid (12.8 mg, 36%); 1 H NMR (500 MHz, CDCl3) δ 7.42-7.35 (m, 2H), 7.37-7.29 (m, 2H), 7.25-7.20 (m, 1H), 5.74 (s, 1H), 1.97 (s, 3H), 1.70 (s, 6H); 13 C NMR (125 MHz, CDCl3) δ 169.2, 147.0, 128.5, 126.8, 124.9, 56.1, 29.2, 24.5.

[0196] [Example 25] Preparation of N-(1-Phenylcyclopentyl)acetamide (25)

[0197]

[0198] The reaction was carried out for 12 hours. Eluent DCM / Acetone = 90:10; Colorless solid (18.7 mg, 46%); mp= 109-111℃; 1 H NMR (500 MHz, CDCl3) δ 7.43-7.39 (m, 2H), 7.32 (t,J= 7.8 Hz, 2H), 7.24-7.19 (m, 1H), 5.86 (s, 1H), 2.42-2.33 (m, 2H), 2.14-2.03 (m, 2H), 1.96 (s, 3H), 1.88-1.77 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 169.5, 145.0, 128.1, 126.5, 125.7, 66.7, 39.2, 24.1, 23.2; IR (cm -1 ) 3312, 2964, 1735, 1646, 1539, 1492, 1294, 757, 696, 593, 529; HRMS (EI) m / z calcd. For C 13 H 17 NO [M] + : 203.1310, found: 203.1308.

[0199] [Example 26] Preparation of N-(1-Phenylcyclobutyl)acetamide (26)

[0200]

[0201] The reaction was carried out for 12 hours. Eluent DCM / Acetone = 85:15; colorless liquid (30.8 mg, 81%); mp= 161-163℃; 1 H NMR (500 MHz, CDCl3) δ 7.47-7.41 (m, 2H), 7.37-7.29 (m, 2H), 7.25-7.18 (m, 1H), 6.09 (s, 1H), 2.64-2.55 (m, 4H), 2.15-2.01 (m, 1H), 1.92 (s. 3H), 1.90-1.79 (m, 1H); 13 C NMR (125 MHz, CDCl3) δ 169.2, 145.5, 128.3, 126.8, 125.7, 59.9, 34.2, 24.0, 15.6; IR (cm -1 ) 3278, 2945, 1642, 1539, 1294, 1032, 754, 698, 599, 536; HRMS (EI) m / z calcd. For C 12 H 15 NO [M] + : 189.1154, found: 189.1152.

[0202] [Example 27] Preparation of Methyl (1r,5r)-5-acetamidobicyclo[3.1.1]heptane-1-carboxylate (27)

[0203]

[0204] The reaction was carried out for 12 hours. Eluent DCM / Acetone = 85:15; Colorless solid (33.1 mg, 78%); mp= 114-116℃; 1 H NMR (500 MHz, CDCl3) δ 5.78 (s, 1H), 3.65 (s, 3H), 2.39 (dt, J = 7.3, 3.6 Hz, 2H), 2.04-1.99 (m, 2H), 1.99-1.94 (m, 2H), 1.92-1.82 (m, 7H); 13 C NMR (125 MHz, CDCl3) δ 175.4, 169.5, 52.5, 51.9, 42.4, 41.1, 33.1, 29.2, 23.9, 16.7; IR (cm -1 ) 3274, 3081, 2919, 2862, 1727, 1555, 1436, 1290, 1166, 1065, 731, 606, 526; HRMS (EI) m / z calcd. For C 11 H 17 NO3[M] + : 211.1208, found: 211.1207.

[0205] [Example 28] Preparation of N-(Bicyclo[1.1.1]pentan-1-yl)acetamide (28)

[0206]

[0207] The reaction was carried out for 12 hours. Eluent DCM / Acetone = 90:10; Colorless solid (15.8 mg, 66%); mp= 103-105℃; 1 H NMR (500 MHz, CDCl3) δ 5.95 (s, 1H), 2.42 (s, 1H), 2.07 (s, 6H), 1.91 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.5, 52.8, 48.9, 24.9, 23.7; IR (cm -1 ) 3242, 2994, 2913, 2876, 1636, 1548, 1373, 1297, 1194, 1022, 796, 749; HRMS (FAB) m / z calcd. For C7H 12 NO [M+H] + : 126.0919, found: 126.0917.

[0208] [Example 29] Preparation of Methyl (2r,3R,4s,5S)-4-acetamidocubane-1-carboxylate (29)

[0209]

[0210] The reaction was carried out for 12 hours. Eluent DCM / Acetone = 90:10; Colorless solid (25.1 mg, 57%); mp= 148-150℃; 1 H NMR (500 MHz, CDCl3) δ 6.29 (s, 1H), 4.14 (tdd, J = 8.2, 3.8, 1.9 Hz, 6H), 3.71 (s, 3H), 2.01 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 172.7, 169.6, 66.6, 55.8, 51.6, 50.2, 45.0, 23.1; IR (cm -1 ) 3247, 2992, 1715, 1634, 1525, 1313, 1214, 1092, 842, 603, 442; HRMS (FAB) m / z calcd. For C9H 18 NO [M+H] + : 220.0974, found: 220.0973.

[0211] [Example 30] Preparation of N-[{1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}methyl]acetamide (30)

[0212]

[0213] Eluent DCM / Acetone = 80:20; Colorless solid (55.3 mg, 75%); mp= 155-157℃; 1 H NMR (600 MHz, CDCl3) δ 7.67-7.63 (m, 2H), 7.49-7.45 (m, 2H), 7.00 (d,J= 2.6 Hz, 1H), 6.82 (d,J= 9.0 Hz, 1H), 6.67 (dd,J= 9.0, 2.5 Hz, 1H), 5.60 (s, 1H), 4.53 (d,J= 5.1 Hz, 2H), 3.82 (s, 3H), 2.41 (s, 3H), 2.00 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 170.1, 168.5, 156.3, 139.7, 136.4, 133.8, 131.3, 131.0, 130.1, 129.3, 115.9, 115.2, 112.2, 101.2, 55.9, 33.7, 23.4, 13.2; IR (cm -1 ) 3298, 1679, 1606, 1540, 1356, 1321; HRMS (EI) m / z calcd. For C 20 H 19 ClN2O3[M] + : 370.1084, found: 370.1086.

[0214] [Example 31] Preparation of N-(1-[4-{(2-Oxocyclopentyl)methyl}phenyl]ethyl)acetamide (31)

[0215]

[0216] Eluent DCM / Acetone = 80:20; colorless liquid (41.2 mg, 79%); 1H NMR (600 MHz, CDCl3) δ 7.24-7.21 (m, 2H), 7.15-7.11 (m, 2H), 5.72 (d,J= 8.1 Hz, 1H), 5.10 (p,J= 7.2 Hz, 1H), 3.11 (dd,J= 14.0, 4.2 Hz, 1H), 2.52 (dd,J= 14.0, 9.4 Hz, 1H), 2.37-2.29 (m, 2H), 2.14-2.05 (m, 2H), 2.01-1.92 (m, 4H), 1.78-1.68 (m, 1H), 1.58-1.51 (m, 1H), 1.47 (d,J= 6.9 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 220.2, 169.1, 141.2, 139.3, 129.3, 126.4, 51.1, 48.6, 38.3, 35.3, 29.3, 23.6, 21.8, 20.7; IR (cm -1 ) 3284, 2967, 1734, 1643, 1539; HRMS (EI) m / z calcd. For C 16 H 21 NO2[M] + : 259.1572, found: 259.1574.

[0217] [Example 32] Preparation of N-{1-(10-Oxo-10,11-dihydrodibenzo[b,f]thiepin-2-yl)ethyl}acetamide (32)

[0218]

[0219] Eluent DCM / Acetone = 80:20; Colorless solid (22.6 mg, 36%); mp= 179-181℃; 1H NMR(600 MHz, CDCl3) δ 8.19 (dd,J= 8.0, 1.6 Hz, 1H), 7.60 (dd,J= 7.9, 1.2 Hz, 2H), 7.43 (ddd,J= 7.8, 7.2, 1.6 Hz, 1H), 7.38 (d,J= 2.0). Hz, 1H), 7.31 (ddd,J= 8.3, 7.3, 1.2 Hz, 1H), 7.15 (dd,J= 8.0, 2.0 Hz, 1H), 5.68 (d,J= 7.8 Hz, 1H), 5.10 (p,J= 7.1 Hz, 1H), 4.40-4.32 (m,2H), 1.99(s,3H), 1.45(d,J=7.0Hz,3H); 13 C NMR(150 MHz, CDCl3) δ 191.6, 169.3, 145.7, 140.4, 138.1, 136.3, 133.5, 132.7, 131.7, 131.7; 51.3, 48.6, 23.6, 22.0; IR (cm -1 ) 3246, 1670, 1632, 1548, 1284; HRMS (EI) m / z calcd. For C 18 H 17 NO2S [M] + : 311.0980, found:

[0220] [Figure 33](Z)-N-([5-Fluoro-2-methyl-1-{4-(methylsulfinyl)benzylidene}-1H-indene-3-yl]methyl)acetamide (33) was synthesized

[0221]

[0222] Dilution DCM / Acetone = 60:40; 황색 고체 (41.5mg, 56%); mp= 177-179°C; 1H NMR(600 MHz, CDCl3) δ 7.71–7.68 (m, 2H), 7.65–7.62 (m, 2H), 7.17 (s, 1H), 7.15 (dd,J= 8.4, 5.1 Hz, 1H), 6.92 (dd,J= 8.8, 2.5 Hz, 1H), 6.57 (td,J= 8.8, 2.5 Hz, 1H), 5.69 (s, 1H), 4.39 (d,J= 5.3 Hz, 2H), 2.79 (s, 3H), 2.23 (s, 3H), 2.01 (s, 3H); 13 C NMR(150 MHz, CDCl3) δ 170.2, 163.6 (d,J= 247.2 Hz), 146.2, 146.1, 145.8, 141.9, 139.6, 138.6, 135.1, 130.3, 129.7, 124.0, 111.1 (d,J= 22.6 Hz), 106.4 (d,J= 24.1 Hz), 44.1, 34.5, 23.3, 10.5; 19 F NMR (471 MHz, CDCl3) δ-112.21; IR (cm -1 ) 3254, 1659, 1546, 1463; HRMS (EI) m / z calcd. For C 21 H 20 FNO2S [M] + : 369.1199, found:

[0223] [System 34]N-[(R)-3-{(3R,5R,8R,9S,10S,13R,14S,17R)-3-Hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl}butyl]acetamide (34) was obtained 제조

[0224]

[0225] Dilution DCM / Acetone = 60:40; 무색 고체(42.3mg, 54%); mp= 226-228°C; 1H NMR (600 MHz, CDCl3) δ 5.40 (s, 1H), 3.62 (tt,J= 11.1, 4.6 Hz, 1H), 3.36-3.28 (m, 1H), 3.20-3.11 (m, 1H), 1.99-1.92 (m, 4H), 1.88-1.71 (m, 4H), 1.70-1.53 ​​(m, 5H), 1.53-1.47 (m, 1H), 1.46-1.34 (m, 5H), 1.35-1.27 (m, 1H), 1.27-1.17 (m, 4H), 1.16-0.96 (m, 6H), 0.94 (d,J= 6.6 Hz, 3H), 0.91 (s, 3H), 0.64 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 170.1, 72.0, 56.6, 56.3, 42.9, 42.2, 40.6, 40.3, 37.5, 36.6, 36.0, 35.9, 35.5, 34.7, 34.2, 30.7, 28.5, 27.3, 26.6, 24.3, 23.5, 23.5, 21.0, 18.8, 12.1; IR (cm -1 ) 3436, 3320, 2927, 2880, 2861, 1656, 1550; HRMS (EI) m / z calcd. For C 25 H 43 NO2[M] + : 389.3294, found: 389.3292.

[0226] [Example 35] Preparation of (E)-N-(1-Phenylprop-1-en-2-yl)acetamide (35)

[0227]

[0228] Eluent DCM / Acetone = 90:10; Colorless solid (21.3 mg, 61%); mp= 80-82℃; 1H NMR (600 MHz, CDCl3) δ 7.31 (t,J= 7.6 Hz, 2H), 7.22 (d,J= 7.7 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H), 7.01 (s, 1H),6.68 (s, 1H),2.10 (s, 3H), 2.09 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 168.7, 137.2, 132.9, 129.1, 128.2, 126.2, 116.3, 24.9, 18.1; IR (cm -1 ) 3278, 3182, 3080, 1662, 1544, 1280, 856, 744, 697, 608, 506; HRMS (EI) m / z calcd. For C 11 H 13 NO [M] + : 175.0997, found: 175.0998.

[0229] Example II: Decarboxylation amidation using aryl carboxylic acid

[0230]

[0231] In a 4 mL vial equipped with a stirrer, an aryl carboxylic acid compound (formula 1, 0.200 mmol), DBU (2.00 equiv., 0.400 mmol, 60.9 mg), and DMSO (1.00 mL, 0.200 M) were added, followed by the addition of 3-methyl-1,4,2-dioxazol-5-one (3.00 equiv., 0.600 mmol, 60.6 mg), and the mixture was stirred at 60 °C for 4 h. After completion of the reaction, the crude reaction mixture was diluted with DCM (5.0 mL), 1 N HCl aqueous solution (10 mL) was added, and extracted with DCM (5 mL × 3 times). The combined organic layers were washed with KHSO4 aqueous solution (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone, 95:5 to 90:10) to obtain the desired product, an amide compound (chemical formula 1).

[0232] The following amide compounds were prepared through the decarboxylation amidation described above using various aryl carboxylic acids as starting materials.

[0233] [Example 36] Preparation of N-Phenylacetamide (36)

[0234]

[0235] Eluent DCM / Acetone = 90:10; Colorless solid (12.1 mg, 45%); 1 H NMR (500 MHz, CDCl3) δ 7.53-7.47 (m, 2H), 7.42 (s, 1H), 7.31 (t, J= 8.0 Hz, 2H), 7.13-7.07 (m, 1H), 2.17 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 168.6, 138.0, 129.1, 124.4, 120.0, 24.7.

[0236] [Example 37] Preparation of N-(p-Tolyl)acetamide (37)

[0237]

[0238] Eluent DCM / Acetone = 90:10; Colorless solid (14.9 mg, 50%); 1 H NMR (500 MHz, CDCl3) δ 7.42-7.36 (m, 2H), 7.28 (s, 1H), 7.13 (d, J = 8.1 Hz, 2H), 2.33 (s, 3H), 2.18 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 168.4, 135.4, 134.1, 129.6, 120.2, 24.7, 21.0.

[0239] [Example 38] Preparation of N-(3-Methoxyphenyl)acetamide (38)

[0240]

[0241] Eluent DCM / Acetone = 95:5 (without work-up); colorless solid (21.6 mg, 65%); 1 H NMR (500 MHz, CDCl3) δ 8.35 (dd,J= 8.1, 1.6 Hz, 1H), 7.76 (s, 1H), 7.03 (td,J= 7.8, 1.7 Hz, 1H), 6.95 (td,J= 7.7, 1.4 Hz, 1H), 6.87 (dd,J= 8.1, 1.4 Hz, 1H), 3.88 (s, 3H), 2.20 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 168.3, 147.8, 127.8, 123.7, 121.2, 119.9, 110.0, 55.8, 25.1.

[0242] [Example 39] Preparation of N-{4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}acetamide (39)

[0243]

[0244] Eluent DCM / Acetone = 90:10; Colorless solid (20.8 mg, 40%); 1 H NMR (500 MHz, CDCl3) δ 7.76 (d,J= 8.1 Hz, 2H), 7.51 (d,J= 8.0 Hz, 2H), 7.35 (s, 1H), 2.17 (d,J= 1.7 Hz, 3H), 1.33 (s, 12H); 13 C NMR (125 MHz, CDCl3, one carbon peak is missing due to boron coupling) δ 168.6, 140.6, 135.9, 118.7, 83.9, 25.0, 24.9.

[0245] [Example 40] Preparation of N-[6-{3-(Adamantan-1-yl)-4-methoxyphenyl}naphthalen-2-yl]acetamide (40)

[0246]

[0247] Eluent DCM / Acetone = 95:5; Colorless solid (44.3 mg, 52%); mp= 225-227℃; 1 H NMR (500 MHz, THF-d8) δ 9.14 (s, 1H), 8.32 (d,J= 2.2 Hz, 1H), 7.93 (d,J= 1.8 Hz, 1H), 7.79 (s, 1H), 7.77 (s, 1H), 7.68 (dd,J= 8.5, 1.8 Hz, 1H), 7.58 (d,J= 2.3 Hz, 1H), 7.54 (dd,J= 8.8, 2.1 Hz, 1H), 7.51 (dd,J= 8.4, 2.3 Hz, 1H), 7.02 (d,J= 8.4 Hz, 1H), 3.87 (s, 3H), 2.22 (d,J= 2.9 Hz, 6H), 2.12-2.04 (m, 6H), 1.89-1.77 (m, 6H); 13C NMR (125 MHz, THF-d8) δ 168.4, 159.4, 139.2, 138.4, 138.1, 134.2, 134.0, 131.6, 129.1, 128.6, 126.6, 126.2, 126.2, 125.2, 120.7, 115.8, 112.9, 55.4, 41.6, 38.1, 38.0, 30.4, 24.2; IR (cm -1 ) 3307, 2901, 2850, 1683, 1543, 1503, 1394, 1235, 1025, 874, 803, 730, 591, 464; HRMS (EI) m / z calcd. For C 29 H 31 NO2[M] + : 425.2355, found: 425.2357.

[0248] Example III: Decarboxylation amidation using a chiral carboxylic acid

[0249]

[0250] A 4 mL vial equipped with a stirrer was added with a chiral carboxylic acid compound (formula 1, 0.200 mmol), DBU (2.00 equiv., 0.400 mmol, 60.9 mg), and anhydrous DMSO (1.00 mL, 0.200 M), followed by the addition of 3-methyl-1,4,2-dioxazol-5-one (2.00 equiv., 0.400 mmol, 40.4 mg), and the mixture was stirred at room temperature for 4 h. After completion of the reaction, the crude reaction mixture was diluted with DCM (5.0 mL), 1 N HCl aqueous solution (10 mL) was added, and extracted with DCM (5 mL × 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetone, 100:0 to 50:50) to obtain the desired product, an amide compound (chemical formula 1). The enantiomeric ratio (er) was determined by HPLC analysis.

[0251] The following amide compounds were prepared through the decarboxylation amidation described above using various chiral carboxylic acids as starting materials.

[0252] [Example 41] Preparation of (S)-N-(1-Phenylethyl)acetamide (41)

[0253]

[0254] Eluent DCM / Acetone = 85:15; colorless solid (26.7 mg, 83%); 1 H NMR (600 MHz, CDCl3) δ 7.37-7.30 (m, 4H), 7.29-7.24 (m, 1H), 5.73 (s, 1H), 5.13 (p,J= 7.1 Hz, 1H), 1.98 (s, 3H), 1.49 (d,J= 6.9 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 169.2, 143.3, 128.8, 127.6, 126.3, 48.9, 23.6, 21.8; Specific Rotation[α] D 29 = -149.1° (c0.51, CH2Cl2); HPLC Analysis. CHIRALPAK OD-H, 27℃;n-hexane:i-PrOH = 90:10, 0.5 mL / min, 210 nm, t R1 (major) = 20.2 min, t R2 (minor) = 21.6 min, >99:1 er

[0255] [Example 42] Preparation of (S)-N-(1,2,3,4-Tetrahydronaphthalen-1-yl)acetamide (42)

[0256]

[0257] Eluent DCM / Acetone = 80:20; Colorless powder (30.5 mg, 81%); 1H NMR(600 MHz, CDCl3) δ 7.29-7.26 (m, 1H), 7.20-7.14 (m, 2H), 7.12-7.08 (m, 1H), 5.67 (s, 1H), 5.22-5.14 (m, 1H), 2.78 (qt,J= 17.1, 5.8 Hz, 2H), 2.08-2.03 (m, 1H), 2.02 (s, 3H), 1.87-1.78 (m, 3H); 13 C NMR(150 MHz, CDCl3) δ 168.8, 139.1, 136.8, 129.3, 128.8, 127.4, 126.4, 47.6, 30.8, 29.3, 24.0, 20.4; Specific Rotation[α] D 29 = 90.8° (c0.47, CH2Cl2); HPLC Analysis. CHIRALPAK AD-H, 32℃;n-hexane:i-PrOH = 80:20, 0.5 mL / min, 210 nm, t R1 (major) = 7.8 min, t R2 (minor) = 8.9 min, >99:1 e.r.

[0258] [실시예 43] (S)-N-(Cyclohex-3-en-1-yl)acetamide (43)의 제조

[0259]

[0260] 용리액 DCM / Acetone = 70:30; 무색 고체 (20.1 mg, 72%); m.p.= 74-76℃; 1 H NMR(600 MHz, CDCl3) δ 5.72-5.66 (m, 1H), 5.63-5.58 (m, 1H), 5.47 (s, 1H), 4.11 (dddd,J= 12.6, 8.2, 6.7, 3.0 Hz, 1H), 2.43-2.35 (m, 1H), 2.21-2.07 (m, 2H), 1.97 (s, 3H), 1.90-1.82 (m, 2H), 1.57 (dddd,J= 12.7, 9.5, 8.0, 5.9 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 169.5, 127.2, 124.5, 44.6, 31.8, 28.0, 23.8, 23.5; IR (cm -1 ) 3290, 3032, 2917, 2839, 1635, 1549, 1360, 1281, 651, 604, 511; Specific Rotation[α] D 29 = -14.4° (c0.46, CH2Cl2); HRMS (FAB) m / z calcd. For C8H 14 NO [M+H] + : 140.1075, found: 140.1078; HPLC analysis. CHIRALPAK AS-H, 32℃; n-hexane:i-PrOH = 95:5, 0.5 mL / min, 210 nm, t R1 (minor) = 145.5 min, t R2 (major) = 150.2 min, 99:1 er

[0261] [실시예 44] Preparation of (R)-N-{Methoxy(phenyl)methyl}acetamide (44)

[0262]

[0263] Wash with 1N HCl instead of brine. DCM / Acetone = 90:10; colorless gome (17.0 mg, 47%); 1 H NMR(600 MHz, CDCl3) δ 7.44-7.40 (m, 2H), 7.40-7.36 (m, 2H), 7.35-7.32 (m, 1H), 6.12 (d,J= 9.5 Hz, 1H), 5.93 (d,J= 9.2 Hz, 1H), 3.46 (s, 3H), 2.05 (s, 3H); 13 C NMR (150 MHz, CDCl3) δ 170.2, 139.4, 128.8, 128.7, 126.0, 81.6, 56.2, 23.6; Specific Rotation[α] D26=6.1° (c0.07, CH2Cl2); HPLC Analysis. CHIRALPAK AD-H, 28℃;n-hexane:i-PrOH = 90:10, 0.5 mL / min, 210 nm, t R1 (minor) = 11.5 min, t R2 (major) = 12.5 min, 98:2 er

[0264] [Example 45] Preparation of (S)-N-(Tetrahydrofuran-2-yl)acetamide (45)

[0265]

[0266] Eluent DCM / Acetone 50:50 (without work-up); colorless liquid (19.1 mg, 74%); 1 H NMR (600 MHz, CDCl3) δ 5.91 (s, 1H), 5.70 (ddd,J= 8.3, 6.4, 4.8 Hz, 1H), 3.93 (dt,J= 8.5, 6.7 Hz, 1H), 3.80 (dt,J= 8.5, 6.9 Hz, 1H), 2.18 (ddt,J= 13.2, 8.3, 6.7 Hz, 1H), 1.98 (s, 3H), 1.94 (dtd,J= 13.3, 6.7, 1.7 Hz, 2H), 1.71 (dddd,J= 12.8, 7.9, 6.6, 4.7 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δ 170.1, 81.2, 67.6, 32.2, 24.8, 23.6; IR (cm -1 ) 3291, 2969, 1655, 1537, 1367, 1290, 1189, 1137, 1040, 922, 599, 515; HRMS (FAB) m / z calcd. For C6H 12 NO2[M+H] + : 130.0868, found: 130.0866; Specific Rotation[α] D 29= 75.4° (c0.41, CH2Cl2); HPLC Analysis. CHIRALPAK AD-H, 32°C; n-hexane:i-PrOH = 90:10, 0.5 mL / min, 210 nm, t R1 (major) = 12.8 min, t R2 (minor) = 13.6 min, 99:1 er

[0267] [Example 46] Preparation of tert-Butyl (S)-2-acetamidopyrrolidine-1-carboxylate (46)

[0268]

[0269] Washing with brine instead of 1N HCl. Eluent DCM / Acetone = 70:30; colorless solid (29.7 mg, 65%); 1 H NMR (600 MHz, CDCl3) δ 5.77 (s, 1H), 5.69 - 5.40 (m, 1H), 3.50-3.39 (m, 1H), 3.34-3.20 (m, 1H), 2.11-1.79 (m, 7H), 1.43 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 168.9, 154.2, 80.3, 64.2, 46.1, 33.9, 28.5, 23.5, 22.5; Specific Rotation[α] D 29 = 29.6° (c0.44, CH2Cl2); HPLC Analysis. CHIRALCEL OD-H, 28℃;n-hexane:i-PrOH = 80:20, 0.5 mL / min, 210 nm, t R1 (minor) = 7.5 min, t R2 (major) = 8.8 min, >99:1 er

[0270] [Example 47] Preparation of tert-Butyl {(1R,3S)-3-acetamidocyclohexyl}carbamate (47)

[0271]

[0272] Dilution DCM / Acetone = 60:40; 무색 고체 (36.9mg, 72%); mp= 185-187°C; 1 H NMR(600 MHz, CDCl3) δ 5.37 (d,J= 8.1 Hz, 1H), 4.43 (s, 1H), 3.80 (tdt,J= 11.9, 8.0, 4.0 Hz, 1H), 3.48 (s, 1H), 2.30-2.21 (m, 1H), 2.01–1.91 (m, 5H), 1.81–1.72 (m, 1H), 1.49–1.34 (m, 10H), 1.04–0.90 (m, 3H); 13 C NMR(100 MHz, CDCl3) δ 169.2, 155.1, 79.4, 48.8, 47.6, 40.2, 32.8, 32.5, 28.5, 23.6, 23.0; IR (cm -1 ) 3330, 3270, 2973, 2933, 2858, 1684, 1655, 1536; HRMS (EI) m / z calcd. For C 13 H 24 N2O3[M] + : 256.1787, found: 256.1785; Specific Rotation [ α ] . D 29 = -10.6° (c0.59, CH2Cl2); HPLC Analysis. CHIRALPAK AD-H, 28°C;n-hexane:i-PrOH=90:10, 0.5 mL / min, 210 nm, t R1 (major) = 12.6 min, t R2 (minor) = 18.6 min, >99:1

[0273] [Figure 48] (S)-N-{1-(6-Methoxynaphthalen-2-yl)ethyl}acetamide (48) was used

[0274]

[0275] Dilution DCM / Acetone = 85:15; 무색 고체 (42.1 mg, 87%); mp= 145-147°C; 1 H NMR(600 MHz, CDCl3) δ 7.71 (dd,J= 8.7, 4.7 Hz, 2H), 7.69–7.67 (m, 1H), 7.40 (dd,J= 8.5, 1.8 Hz, 1H), 7.15 (dd,J= 8.9, 2.5 Hz, 1H), 7.12 - 7.10 (m, 1H), 5.75 (d,J= 7.5 Hz, 1H), 5.27 (p,J= 7.1 Hz, 1H), 3.92 (s, 3H), 2.00 (s, 3H), 1.57 (d,J= 6.9 Hz, 3H); 13 C NMR(150 MHz, CDCl3) δ 169.2, 157.9, 138.3, 134.0, 129.5, 128.9, 127.5, 125.5, 124.6, 119.2, 105.8, 55.5, 48.9, 23.7,000; 21.7; IR (cm -1 ) 3272, 3061, 2971, 2928, 1630, 1604, 1542; HRMS (EI) m / z calcd. For C 15 H 17 NO2[M] + : 243.1259 , found : 243.1260 ; Specific Rotation [ α ] . D 29 = -147.4° (c0.47, CH2Cl2); HPLC Analysis. CHIRALPAK AD-H, 28°C;n-hexane:i-PrOH = 80:20, 0.5 mL / min, 210 nm, t R1 (major) = 9.1 min, t R2 (minor) = 10.8 min, >99:1e.r.

[0276] [Figure 49] (S)-N-{1-(5-Bromo-6-methoxynaphthalen-2-yl)ethyl}acetamide (49) was used

[0277]

[0278] DCM / Acetone = 85:15; colorless 고체 (54.1mg, 84%); mp= 183-185℃; 1 H NMR(500 MHz, CDCl3) δ 8.17 (d,J= 8.8 Hz, 1H), 7.76 (d,J= 9.0 Hz, 1H), 7.69-7.66 (m, 1H), 7.50 (dd,J= 8.8, 1.8 Hz, 1H), 7.25 (d,J= 9.0 Hz, 1H), 5.90 (d,J= 7.8 Hz, 1H), 5.27 (p,J= 7.1 Hz, 1H), 4.01 (s, 3H), 1.99 (s, 3H), 1.55 (d,J= 6.9 Hz, 3H); 13 C NMR(125 MHz, CDCl3) δ 169.3, 153.9, 139.2, 132.6, 129.8, 129.0, 127.0, 126.6, 125.0, 114.1, 108.6, 57.2, 48.6, 23.6, 21.7; IR (cm -1 ) 3283, 1636, 1601, 1539, 1275, 1068, 820, 802, 603; HRMS(EI) m / z calcd. For C 15 H 16 BrNO2[M] + : 321.0364, found: 321.0367; Specific Rotation[α] D 29 = -115.8° (c0.47, CH2Cl2); HPLC analysis. CHIRALPAK AD-H, 32℃; n-hexane:i-PrOH = 80:20, 0.5 mL / min, 230 nm, t R1 (major) = 11.2 min, t R2 (minor) = 9.5 min, 98:2 er

[0279] [실시예 50] Preparation of (S)-N-{1-(4-Isobutylphenyl)ethyl}acetamide (50)

[0280]

[0281] DCM / Acetone = 85:15; colorless liquid (36.5 mg, 83%); 1 H NMR(600 MHz, CDCl3) δ 7.22 (dd,J= 6.1, 1.7 Hz, 2H), 7.11 (dd,J= 6.3, 1.8 Hz, 2H), 5.74 (d,J= 7.8 Hz, 1H), 5.10 (p,J= 7.1 Hz, 1H), 2.45 (d,J= 7.2 Hz, 2H), 1.97 (s, 3H), 1.89-1.80 (m, 1H), 1.47 (d,J= 6.9 Hz, 3H), 0.89 (d,J= 6.6 Hz, 6H); 13 C NMR(150 MHz, CDCl3) δ 169.1, 141.0, 140.5, 129.5, 126.1, 48.6, 45.2, 30.3, 23.6, 22.5, 21.7; IR (cm -1 ) 3273, 2954, 1639, 1544, 1450, 1370; HRMS(EI) m / z calcd. For C 14 H 21 NO [M] + : 219.1623, found: 219.1620; Specific Rotation[α] D 29 = -101.9° (c0.22, CH2Cl2); HPLC analysis. CHIRALPAK AD-H, 28℃; n-hexane:i-PrOH = 90:10, 0.5mL / min, 210nm, t R1 (major) = 9.0 min, t R2 (minor) = 10.3 min, >99:1 er

[0282] [실시예 51]tert-Butyl [(2S,4S)-1-{(1,1'-biphenyl)-4-yl}-4-acetamidopentan-2-yl]carbamate (51)

[0283]

[0284] Dilution DCM / Acetone = 60:40; 무색 고체 (66.1mg, 83%); mp= 170-172°C; 1 H NMR(600 MHz, CDCl3) δ 7.59-7.55 (m, 2H), 7.53 (d,J= 7.9 Hz, 2H), 7.43 (t,J= 7.6 Hz, 2H), 7.33 (t,J= 7.4 Hz, 1H), 7.28-7.24 (m, 2H), 5.60 (s, 1H), 4.62 (d,J= 8.9 Hz, 1H), 4.09 (p,J= 6.9 Hz, 1H), 3.86 (s, 1H), 2.94-2.76 (m, 2H), 1.93 (s, 3H), 1.70-1.58 (m, 2H), 1.39 (s, 9H), 1.16 (d,J= 6.7Hz, 3H); 13 C NMR(150 MHz, CDCl3) δ 169.7, 155.6, 141.0, 139.5, 137.3, 130.0, 128.9, 127.3, 127.3, 127.1, 79.4, 49.0, 42.5, 41.2,000. 40.1, 28.5, 23.7, 20.6; IR (cm -1 ) 3336, 2975, 1678, 1647, 1518, 1166, 755, 691, 593; HRMS (FAB) m / z calcd. For C 24 H 33 N2O3[M+H] + : 397.2491, found: 397.2516; Specific Rotation [ α ] . D 29 = 27.2° (c0.45, CH2Cl2).

[0285] [Product 52]N-[(R)-1-{(1R,4R,4aS,8aR)-4,7-Dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-1-yl}ethyl]acetamide (52) was obtained

[0286]

[0287] Eluent DCM / Acetone = 80:20; Colorless solid (36.8 mg, 74%); mp= 166-168℃; 1 H NMR (400 MHz, CDCl3) δ 5.29-5.16 (m, 2H), 4.02 (tq,J= 9.5, 6.5 Hz, 1H), 2.51-2.45 (m, 1H), 1.98 (s, 3H), 1.96-1.84 (m, 1H), 1.84-1.74 (m, 1H), 1.68-1.36 (m, 8H), 1.23-1.01 (m, 6H), 0.90-0.77 (m, 4H); 13 C NMR (100 MHz, CDCl3) δ 169.6, 136.0, 119.8, 48.1, 47.4, 42.0, 37.8, 35.5, 27.8, 26.7, 25.8, 25.7, 23.8(4), 23.7(6), 19.9, 19.4; IR (cm -1 ) 2905, 1730, 1550, 1434, 1370, 732, 608, 470, 432; HRMS (EI) m / z calcd. For C 16 H 27 NO [M] + : 249.2093, found: 249.2094; Specific Rotation[α] D 29 = -11.2° (c0.61, CH2Cl2).

[0288] Example IV: Decarboxylation amidation using various oxazolone compounds

[0289]

[0290] Preparation of 3-substituted-1,4,2-dioxazol-5-one compounds

[0291] 3-(3-Phenylpropyl)-1,4,2-dioxazol-5-one, (E)-3-(4-phenylbut-3-en-1-yl)-1,4,2-dioxazol-5-one, methyl 4-{4-(5-oxo-1,4,2-dioxazol-3-yl)but-1-yn-1-yl}benzoate, (E)-3-styryl-1,4,2-dioxazol-5-one, and 3-{2-(4,5-diphenyloxazol-2-yl)ethyl}-1,4,2-dioxazol-5-one were prepared using a previously reported method [Science359, 1016-1021 (2018);J. Am. Chem. Soc.2021, 143, 10, 3993-4004;J. Am. Chem. Soc.2022, 144, 22, 10064-10074;Nat. Commun.13, 6445 (2022);J. Am. Chem. Soc.2024, 146, 1, 1001-1008].

[0292] Preparation of amide compounds through decarboxylation amidation

[0293] (S)-Naproxen (0.200 mmol, 46.1 mg), DBU (2.00 equiv., 0.400 mmol, 60.9 mg), and anhydrous DMF (1.00 mL, 0.200 M) were added to a 4 mL vial equipped with a stirrer, followed by the addition of 3-substituted-1,4,2-dioxazol-5-one (2.00 equiv., 0.400 mmol), and the mixture was stirred at 0 °C for 12 h. After completion of the reaction, the crude reaction mixture was diluted with DCM (5.0 mL), 1 N HCl aqueous solution (10 mL) was added, and the mixture was extracted with DCM (5 mL × 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane / acetonitrile, 95:5 to 90:10) to obtain the desired product, an amide compound (chemical formula 1-2). The enantiomeric ratio (er) was determined by HPLC analysis.

[0294] [Example 53] Preparation of (S)-N-{1-(6-Methoxynaphthalen-2-yl)ethyl}-4-phenylbutanamide (53)

[0295]

[0296] Eluent DCM / Acetonitrile = 90:10; Colorless solid (50.4 mg, 73%); mp= 109-111℃; 1H NMR(500 MHz, CDCl3) δ 7.77-7.67 (m, 3H), 7.42 (dd,J= 8.5, 1.9 Hz, 1H), 7.29 (dd,J= 8.2, 6.8 Hz, 2H), 7.25-7.12 (m, 5H), 5.83 (d,J= 8.1 Hz, 1H), 5.31 (p,J= 7.0 Hz, 1H), 3.94 (s, 3H), 2.66 (dd,J= 8.4, 6.7 Hz, 2H), 2.21 (td,J= 7.3, 2.7 Hz, 2H), 2.01 (p,J= 7.5 Hz, 2H), 1.58 (d,J= 6.9 Hz, 3H); 13 C NMR(125 MHz, CDCl3) δ 171.8, 157.8, 141.6, 138.4, 134.0, 129.5, 128.9, 128.6, 128.5, 127.4, 126.1, 125.4, 124.5, 119.2, 105.7, 55.4, 48.6, 36.1, 35.2, 27.2, 21.6; IR (cm -1 ) 3300, 1638, 1534, 1261, 1029, 888, 697, 675, 473; HRMS (EI) m / z calcd. For C 23 H 25 NO2[M] + : 347.1885, found: 347.1883; Specific Rotation[α] D 29 = -78.4° (c0.63, CH2Cl2); HPLC Analysis. CHIRALPAK AD-H, 32℃;n-hexane:i-PrOH= 90:10, 0.5 mL / min, 232 nm, t R1 (major) = 32.2 min, t R2 (minor) = 23.0 min, >99:1 e.r.

[0297] [실시예 54] (S,E)-N-{1-(6-Methoxynaphthalen-2-yl)ethyl}-5-phenylpent-4-enamide (54)의 제조

[0298]

[0299] 용리액 DCM / Acetonitrile = 90:10; 무색 고체 (60.4mg, 84%); m.p.= 144-146℃; 1 H NMR(400 MHz, CDCl3) δ 7.67-7.58 (m, 3H), 7.32-7.24 (m, 4H), 7.23-7.17 (m, 2H), 7.15 -7.04 (m, 2H), 6.42 (dt,J= 15.8, 1.5 Hz, 1H), 6.19 (dt,J= 15.8, 6.9 Hz, 1H), 5.78 (d,J= 8.1 Hz, 1H), 5.29 (dt,J= 14.0, 7.0 Hz, 1H), 3.91 (s, 3H), 2.62-2.52 (m, 2H), 2.44-2.28 (m, 2H), 1.56 (d,J= 6.9 Hz, 3H); 13 C NMR(100 MHz, CDCl3) δ 171.3, 157.8, 138.3, 137.4, 134.0, 131.3, 129.5, 128.9, 128.8, 128.7, 127.5, 127.3, 126.2, 125.5, 124.5, 119.2, 105.7, 55.5, 48.7, 36.7, 29.2, 21.7; IR (cm -1 ) 3303, 2926, 1635, 1607, 1504, 1262, 1178, 1029, 962, 855, 812, 689; HRMS (EI) m / z calcd. For C 24 H 25 NO2[M] + : 359.1885, found: 359.1882; Specific Rotation[α] D 29 = -42.6° (c0.29, CH2Cl2); HPLC Analysis. CHIRALPAK AD-H, 32℃;n-hexane:i-PrOH = 80:20, 0.5 mL / min, 250nm, t R1 (major) = 15.2 min, t R2(minor) = 12.2 min, 98:2

[0300] [Figure 55] Methyl(S)-4-(5-[{1-(6-methoxynaphthalen-2-yl)ethyl}amino]-5-oxopent-1-yn-1-yl)benzoate (55) was synthesized

[0301]

[0302] Solubility DCM / Acetonitrile = 95:5; 무색 고체 (67.4mg, 81%); mp= 146-148°C; 1 H NMR(600 MHz, CDCl3) δ 7.84–7.79 (m, 2H), 7.69–7.66 (m, 1H), 7.62 (d,J= 8.7 Hz, 2H), 7.39 (dd,J= 8.5, 1.9 Hz, 1H), 7.24 (d,J= 1.7 Hz, 1H), 7.23 (d,J= 1.7 Hz, 1H), 7.11 (dd,J= 8.9, 2.6 Hz, 1H), 7.07 (d,J= 2.6 Hz, 1H), 6.01 (d,J= 8.0 Hz, 1H), 5.35 -5.27 (m, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 2.84-2.73 (m, 2H), 2.58 -2.42 (m, 2H), 1.58 (d,J= 6.9 Hz, 3H); 13 C NMR(150 MHz, CDCl3) δ 170.2, 166.7, 157.9, 138.1, 134.0, 131.5, 129.5, 129.3, 128.9, 128.2, 127.5, 125.4, 124.6, 119.2, 134.0, 134.0, 131.5, 105.7, 91.8, 81.3, 55.4, 52.3, 49.0, 35.8, 21.7, 16.3; IR (cm -1 ) 3182, 1715, 1664, 1435, 1276, 1110, 829, 768; HRMS (EI) m / z calcd. For C 26 H 25 NO4[M] +: 415.1784, found: 415.1780; Specific Rotation[α] D 29 = -1.4° (c0.66, CH2Cl2); HPLC Analysis. CHIRALPAK AD-H, 32℃;n-hexane:i-PrOH = 80:20, 0.5 mL / min, 232 nm, t R1 (major) = 17.8 min, t R2 (minor) = 14.5 min, 94:6 e.r.

[0303] [실시예 56] (S)-N-{1-(6-methoxynaphthalen-2-yl)ethyl}cinnamamide (56)의 제조

[0304]

[0305] 용리액 DCM / Acetonitrile = 90:10; 무색 고체 (41.7mg, 63%); m.p.= 176-178℃; 1 H NMR(500 MHz, CDCl3) δ 7.73-7.66 (m, 3H), 7.64 (d,J= 15.6 Hz, 1H), 7.44 (td,J= 8.2, 7.7, 2.3 Hz, 3H), 7.37-7.28 (m, 3H), 7.13 (dd,J= 8.9, 2.6 Hz, 1H), 7.10 (d,J= 2.5 Hz, 1H), 6.43 (d,J= 15.6 Hz, 1H), 6.19 (d,J= 8.1 Hz, 1H), 5.40 (p,J= 7.1 Hz, 1H), 3.90 (s, 3H), 1.62 (d,J= 7.0 Hz, 3H); 13 C NMR(125 MHz, CDCl3,one carbon peak overlaps with others) δ 165.2, 157.8, 141.3, 138.3, 135.0, 134.0, 129.7, 129.5, 128.9, 127.9, 127.5, 125.5, 124.6, 120.9, 119.1, 105.7, 55.4, 49.0, 21.6; IR (cm-1 ) 3299, 2974, 1650, 1533, 1448, 1163, 851, 672, 492; HRMS (EI) m / z calcd. For C 22 H 21 NO2[M] + : 331.1572, found: 331.1576; Specific Rotation[α] D 29 = -3.8° (c0.55, CH2Cl2); HPLC Analysis. CHIRALPAK AD-H, 32℃;n-hexane:i-PrOH = 80:20, 0.5 mL / min, 280nm, t R1 (major) = 36.3 min, t R2 (minor) = 16.7 min, 96:4 e.r.

[0306] [실시예 57] (S)-3-(4,5-Diphenyloxazol-2-yl)-N-{1-(6-methoxynaphthalen-2-yl)ethyl}propanamide (57)의 제조

[0307]

[0308] 용리액 DCM / Acetonitrile = 90:10; 무색 고체 (51.4 mg, 54%); m.p.= 122-124℃; 1 H NMR(600 MHz, CDCl3) δ 7.63 (s, 1H), 7.59 (t,J= 8.2 Hz, 2H), 7.54 (dd,J= 7.5, 2.1 Hz, 4H), 7.37-7.26 (m, 7H), 7.10 (dd,J= 8.9, 2.5 Hz, 1H), 7.05 (d,J= 2.5 Hz, 1H), 6.55 (d,J= 8.0 Hz, 1H), 5.32-5.23 (m, 1H), 3.90 (s, 3H), 3.21 (t,J= 7.0 Hz, 2H), 2.85-2.75 (m, 2H), 1.54 (d,J= 6.9 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 170.6, 162.6, 157.8, 145.7, 138.4, 135.0, 134.0, 132.4, 129.5, 129.0, 128.9, 128.8, 128.6(9), 128.6(6), 128.2, 128.0, 127.5, 126.6, 125.4, 124.5, 119.1, 105.8, 55.4, 49.0, 33.4, 24.3, 21.9; IR (cm -1 ) 3360, 2964, 1641, 1529, 1195, 969, 858, 675, 483; HRMS (EI) m / z calcd. For C 31 H 28 N2O3[M] + : 476.2100, found: 476.2102; Specific Rotation[α] D 29 = -31.1° (c0.46, CH2Cl2); HPLC Analysis. CHIRALPAK AD-H, 32℃;n-hexane:i-PrOH = 80:20, 0.5 mL / min, 230 nm, t R1 (major) = 13.9 min, t R2 (minor) = 11.1 min, 99:1 er

[0309] [Example 58 and Comparative Examples 1 to 4] Decarboxylation amidation reaction according to the type of amination reagent

[0310] An experiment was conducted to determine whether a decarboxylation amidation reaction occurred through the reaction of cyclohexanecarboxylic acid and various amination reagents.

[0311]

[0312] In a 4 mL vial equipped with a stirrer, cyclohexanecarboxylic acid (A, 0.100 mmol), K2CO3 (2.00 equiv., 0.200 mmol, 27.6 mg) and anhydrous DMF (0.500 mL, 0.200 M) were added, followed by addition of the amination reagent (2.00 equiv.) in Table 1 below, and stirring was performed at room temperature for 4 hours. The yield of the product was determined by quantifying the crude product using 1,3,5-trimethoxybenzene as an internal standard (in DMSO-d6). 1 It was measured by H NMR analysis. The results according to the type of amination reagent are shown in Table 1 below.

[0313] Amination reagent Expected product Actual production of the product Comparison example 1 X Comparison Example 2 X Comparison Example 3 X Comparison Example 4 X Example 58 O [17% yield]

[0314] Chloramine T (B1), organic azides (B2, B3) and hydroxamates (B4), known as amination reagents, did not produce the desired amidation product, whereas only dioxazolone B5 produced the corresponding alkylamide product C3 in 17% yield.

[0315] From the above results, it can be seen that the dioxazolone compound produces the desired amidation product through decarboxylation amidation with a carboxylic acid compound.

[0316] [Examples 59 to 64 and Comparative Example 5] Decarboxylation amidation reaction depending on the type of base and solvent

[0317] To determine whether a decarboxylation amidation reaction occurred depending on the type of base and solvent, an experiment was conducted as described in Table 2 below.

[0318]

[0319] In a 4 mL vial equipped with a stirrer, cyclohexanecarboxylic acid (0.100 mmol, 12.8 mg), base and solvent (0.500 mL, 0.200 M) were added, followed by the addition of 3-methyl-1,4,2-dioxazol-5-one (2.00 equiv., 0.200 mmol, 20.2 mg), and the mixture was stirred at room temperature for 4 hours. The yield of the product was determined by quantifying the crude product using 1,3,5-trimethoxybenzene as an internal standard (in DMSO-d6). 1 It was measured by H NMR analysis. The results according to the type of base and solvent are shown in Table 2 below.

[0320] Base Solvent Yield (%)Example 59BTMG (2 equiv.)DMF35Example 60P1-t-Bu (2 equiv.)DMF66Example 61DBU (2 equiv.)DMF69Example 62TEA (2 equiv.)DMSO26Example 63BTMG (2 equiv.)DMSO51Example 64P1-t-Bu (2 equiv.)DMSO75Example 65DBU (2 equiv.)DMSO83Example 66DBU (0.25 equiv.)DMSO56Example 67DBU (2 equiv.)DCM62Example 68DBU (2 equiv.)Toluene30Comparative Example 5-DMSO<5BTMG: 2-tert-Butyl-1,1,3,3-tetramethylguanidineP1-t-Bu: tert-butylimino-tris(dimethylamino)phosphoraneDBU: 1,8-diazabicyclo[5.4.0]undec-7-eneTEA: triethylamineDIPEA: N,N-diisopropylethylamine

[0321] As shown in Table 2 above, the desired amidation product was obtained in the presence of various bases and solvents, but in the case of Comparative Example 5 without a base additive, no reactivity was observed, indicating that the base additive plays an important role in the decarboxylation amidation reaction of the present invention.

[0322] As described above, the method for producing an amidated compound of the present invention by carboxylating a carboxylic acid compound and a dioxazolone compound in the presence of a base can efficiently produce an amidated compound that is very usefully applicable as an intermediate and synthetic unit in various fields such as various natural products and pharmaceuticals.

[0323] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. A method for producing an amide compound represented by the following chemical formula 1 by decarboxylating and amidating a carboxylic acid compound represented by the following chemical formula 2 with a dioxazolone compound represented by the following chemical formula 3 in the presence of a base: [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] In the above chemical formulas 1 to 3, R and R' are each independently a substituted or unsubstituted C1-C30 hydrocarbyl, or a substituted or unsubstituted C1-C30 heterohydrocarbyl.

2. In paragraph 1, wherein R is C1-C30 alkyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C1-C30 alkoxyC1-C30 alkyl, C2-C30 alkenyl, C2-C30 alkynyl, C6-C30 aryl, C3-C30 heteroaryl, C6-C30 arylC1-C30 alkyl or C3-C30 heteroarylC1-C30 alkyl; The above R's alkyl, cycloalkyl, heterocycloalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl is halogen, nitro, cyano, hydroxy, C1-C30 alkyl, haloC1-C30 alkyl, C1-C30 alkoxy, C6-C30 aryloxy, C1-C30 alkylthio, C6-C30 arylthio, C2-C30 alkenyl, C2-C30 alkynyl, C3-C30 heterocycloalkyl, C6-C30 aryl, C6-C30 arylC1-C30 alkyl, hydroxyC6-C30 cycloalkyl, C1-C30 alkylC3-C30 cycloalkyl, C3-C30 cycloalkylC1-C30 alkyl, C6-C30 arylC1-C30 alkyloxy, C1-C30 alkylcarbonyl, C6-C30 arylcarbonyl, haloC1-C30 alkylcarbonyl, C1-C30 alkoxycarbonyl, C6-C30 aryloxycarbonyl, haloC1-C30 alkoxycarbonyl, C1-C30 alkylcarbonyloxy, C6-C30 arylcarbonyloxy, haloC1-C30 alkylcarbonyloxy, C1-C30 alkoxycarbonylamino, C6-C30 aryloxycarbonylamino, C1-C30 alkylsulfinyl, C6-C30 arylsulfinyl, C1-C30 alkylsulfonyl, C6-C30 arylsulfonyl and -B(R a )(R b ) may be further substituted with one or more selected from the group consisting of; R a and R b are each independently hydrogen, hydroxy, C1-C30 alkyl or C1-C30 alkoxy, or may be linked to each other to form a ring, R' is C1-C10 alkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C6-C20 aryl, C3-C20 heteroaryl or -L-R''; L is C1-C10 alkylene, C3-C10 cycloalkylene, C2-C10 alkenylene or C2-C10 alkynylene; R'' is C6-C20 aryl or C3-C20 heteroaryl; the aryl or heteroaryl of R'' may be further substituted with one or more selected from C1-C10 alkoxycarbonyl and C6-C20 aryl; The alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl of the above R' is halogen, cyano, nitro, C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, C6-C20 aryl, C6-C20 arylC1-C10 alkyl, C6-C20 aryloxy, C6-C20 arylC1-C10 alkyloxy, C1-C10 alkylcarbonyloxy, C1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, haloC1-C10 alkylcarbonyloxy, haloC1-C10 alkylcarbonyl, haloC1-C10 alkoxycarbonyl, C6-C20 arylcarbonyl, C6-C20 aryloxycarbonyl, amino, mono C1-C10 alkylamino and It may be further substituted with one or more selected from the group consisting of diC1-C10 alkylamino; A method for producing a compound, wherein the heteroaryl and heterocycloalkyl comprise 1 to 4 heteroatoms selected from N, O and S.

3. In paragraph 2, wherein R is C2-C10 alkyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl, C1-C10 alkoxyC1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C6-C20 aryl, C6-C20 arylC1-C10 alkyl or C3-C20 heteroarylC1-C10 alkyl; The above R's alkyl, cycloalkyl, heterocycloalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, arylalkyl or heteroarylalkyl is halogen, C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 heterocycloalkyl, C6-C20 aryl, C6-C20 arylC1-C10 alkyl, hydroxyC6-C20 cycloalkyl, C1-C10 alkylC3-C20 cycloalkyl, C3-C20 cycloalkylC1-C10 alkyl, C1-C10 alkylcarbonyl, C6-C20 arylcarbonyl, haloC1-C10 alkylcarbonyl, C1-C10 alkoxycarbonyl, HaloC1-C10alkoxycarbonyl, C1-C10alkoxycarbonylamino, C6-C20aryloxycarbonylamino, C1-C10alkylsulfinyl, C6-C20arylsulfinyl and -B(R a )(R b ) may be further substituted with one or more selected from the group consisting of; R a and R b are each independently hydroxy, or may be linked to each other to form a ring, R' is C1-C10 alkyl or -L-R''; L is C1-C10 alkylene, C2-C10 alkenylene or C2-C10 alkynylene; A manufacturing method, wherein R'' is C6-C20 aryl or C3-C20 heteroaryl; and the aryl or heteroaryl of R'' may be further substituted with one or more selected from C1-C10 alkoxycarbonyl and C6-C20 aryl.

4. In paragraph 1, A manufacturing method wherein the dioxazolone compound of the above chemical formula 3 is used in an amount of 1 to 5 moles per mole of the carboxylic acid compound of the above chemical formula 2.

5. In paragraph 1, A manufacturing method wherein the base is used in an amount of 0.1 to 3 moles per mole of the carboxylic acid compound of the chemical formula 2.

6. In paragraph 5, The above bases are potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), sodium carbonate (Na2CO3), pyridine, triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 1,8-bis(tetramethylguanidino)naphthalene (TMGN), tert-butylimino-tris(dimethylamino)phosphorane (P1-t-Bu), tert-octylimino-tris(dimethylamino)phosphorene (P1-t-Oct), 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ 5 ,4λ 5 -Catenadi(phosphazene)(P2-Et),tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ 5 ,4λ 5 -Catenadi(phosphazene)(P2-t-Bu), 1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)-phosphoranylideneamino]-2λ 5 ,4λ 5 - One or more selected from the group consisting of catenadi(phosphazene)(P4-t-Bu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), (tert-butylimino)tris(pyrrolidino)phosphorane (BTPP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 7-methyl-1,5,7-triazabicyclo[4.4.0]deca-5-ene (MTBD), 1,5,7-triazabicyclo[4.4.0]deca-5-ene (TBD) and 1,4-diazabicyclo[2.2.2]octane (DABCO), Manufacturing method.

7. In paragraph 1, A manufacturing method wherein the above reaction is performed in the absence of a transition metal.

8. In paragraph 1, A manufacturing method wherein the above reaction is carried out in an aprotic solvent.

9. In paragraph 8, A manufacturing method wherein the aprotic solvent is one or more selected from the group consisting of hexane, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), chloroform, dichloromethane (DCM), dichloroethane (DCE), benzene, chlorobenzene, toluene, and xylene.

10. In paragraph 1, A manufacturing method wherein the above reaction is performed at 0 to 60°C.

Images