KR20230041631A - Method for producing pyrimidin-2-amine - Google Patents

Abstract

The present invention relates to a method for manufacturing pyrimidine-2-amine and, more specifically, to a method for manufacturing a pyrimidine-2-amine compound via a pyrimidine-2-iminium salt intermediate by using a nucleophilic imine-type reagent, in which various amino functional groups are selectively introduced at position No. 2 of pyrimidine.

Description

Method for producing pyrimidin-2-amine compound {METHOD FOR PRODUCING PYRIMIDIN-2-AMINE}

The present invention relates to a method for preparing a pyrimidine-2-amine compound, and more particularly, to a pyrimidine-2-iminium salt intermediate using a nucleophilic imine-type reagent. It relates to a method for preparing a pyrimidin-2-amine compound in which various amino functional groups are selectively introduced at position 2 of

N-heteroaryl amine is an important molecular skeleton present in many molecules exhibiting various physiological activities or medicinal effects. In particular, 2-aminopyrimidine is a key structural motif prevalent in bioactive molecules. However, it is difficult to introduce an amine functional group to carbon 2 of a pyrimidine through direct functionalization.

Since 29 of the 100 best-selling small molecule pharmaceuticals in 2020 are N-heteroaryl amines, the selective and efficient production of aminated N-heteroarenes can facilitate the discovery of biologically active molecules. A frequently used approach for the synthesis of N-heteroaryl amines is nucleophilic aromatic substitution and transition-metal-mediated cross-coupling. Direct carbon-hydrogen (C-H) functionalization presents an attractive alternative because it does not require prior pre-functionalized substrates, although it involves inherent problems in selectivity control due to the localization of C-H bonds in organic molecules. Regioselective heteroarene C-H amination reactions allow rapid access to synthetic intermediates. Strategies such as C-H metallization, N-radical substitution, nucleophilic functionalization, etc. have been implemented to synthesize a diverse array of aminated N-heteroarenes.

However, despite research efforts on direct N-heteroarene amination, the range of accessible C–H bonds in N-heteroaromatic substrates is still largely limited.

Indeed, the Chichibabin reaction and aromatic nitration are representative approaches for the C2- and C3-selective amination of pyridines, respectively, and a modern application of the Chichibabin reaction is a mild method for the C2-H amination of pyridines and quinolines. led to the development of Recently, C4-selective amination of pyridines and pyrimidines was demonstrated by McNally and co-workers through the mediation of heteroaryl phosphonium salts.

However, although 2-aminopyrimidines are an important backbone found in numerous commercially available pharmaceuticals and pesticides and are highly desirable structural motifs in discovery chemistry, no general strategy for C2-selective amination of pyrimidines has been developed to date. Not found.

Therefore, there is an urgent need to develop a method for efficiently producing pyrimidine-2-amine through C2-selective amination of pyrimidine, which serves as an important structural core motif in medicine, pesticide, and various chemical fields.

Adv. Heterocycl. Chem. 1988, 44, 1-79. Acta Chem. Scand. 1994, 48, 1001-1006. Adv. Synth. Catal. 2021, 363, 2-39. Org. Lett. 2018, 20, 2607-2610. Angew. Chem., Int. Ed. 2018, 57, 12514-12518. Synthesis 2018, 50, 193-210.

As a result of intensive research efforts to selectively aminate C2 of pyrimidine, the present inventors have found that all types of pyrimidines can be synthesized through a combination of an activated pyrimidine and a nucleophilic imine type reagent (electron-deficient pyridine compound or imidoyl chloride compound). A pyridinyl-2-iminium salt is synthesized that can serve as a branch point that can subsequently be converted to -2-amines (1°, 2°, and 3° amine forms), which can be amine derivatized It was confirmed that the pyrimidin-2-amine compound was synthesized.

It is an object of the present invention to provide a C2-selective nucleophilic functionalization platform that provides a synthetic handle for the divergent synthesis of 2-aminopyrimidines by converting pyrimidines to pyrimidine-2-iminium salts. .

An object of the present invention is to provide a method for preparing a pyrimidin-2-amine compound that can be usefully used as a core structure in various fields such as medicine and agricultural chemicals.

The present invention provides a method for preparing a pyrimidine-2-amine compound, wherein various amino functional groups are selectively formed at the 2-position of pyrimidine over a pyrimidine-2-iminium salt intermediate using a reagent in the form of a nucleophilic imine. It includes a method for producing a pyrimidin-2-amine compound introduced into.

One aspect of the present invention is 1) preparing a pyrimidine-N-oxide intermediate by catalytically oxidizing a pyrimidine compound of Formula 2 below; 2) Following step 1), the pyrimidine-N-oxide intermediate was activated in situ in the presence of trifluoromethanesulfonic anhydride (Tf ₂ O) and reacted with a pyridine reagent of Formula 3-1 to obtain pyrimidine Preparing a -2-pyridinium salt; and 3) preparing a pyrimidin-2-amine compound represented by the following Chemical Formula 1-1 by aminolysis of the pyrimidine-2-pyridinium salt following step 2), wherein 1) and 2) Provided is a method for preparing a pyrimidine-2-amine compound, wherein the steps are performed in an in-situ continuous process without a separation process:

[Formula 1-1]

[Formula 2]

[Formula 3-1]

In Formulas 1-1, 2 and 3-1,

R ₁ , R ₂ and R ₃ are each independently hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C1-C20 alkoxy, C2-C20 alkenyl, C3-C20 heteroaryl or -NR' C(=O)Ar ₁ , or R ₁ to R ₃ may be linked to adjacent substituents to form a ring;

R ₄ is haloC1-C20 alkyl, cyano, C1-C20 alkylcarbonyl or C6-C20 arylcarbonyl;

R' is hydrogen or C1-C20 alkyl;

Ar ₁ is C6-C20 aryl or C3-C20 heteroaryl;

Alkyl, cycloalkyl, aryl, alkoxy, alkenyl and heteroaryl of R ₁ to R ₃ are C1-C20 alkyl, halogen, C1-C20 alkoxy hydroxy, C6-C20 aryl, haloC6-C20 aryl, -OSiR _a1 may be further substituted with one or more selected from R _a2 R _a3 , -L ₁ -NR _b1 -L ₂ -R _b2 and -CHR _c1 R _c2 ;

R _a1 , R _a2 and R _a3 are each independently C1-C20 alkyl, C3-C20 cycloalkyl or C6-C20 aryl;

L ₁ is C6-C20 arylene or haloC6-C20 arylene, L ₂ is SO ₂ or C=O;

R _b1 is hydrogen or C1-C20 alkyl;

R _b2 is C1-C20 alkoxy, C6-C20 aryl or halo C6-C20 aryl;

R _c1 is C3-C20 cycloalkyl;

R _c2 is -L ₃ -R _d1 , L ₃ is C1-C20 alkylene and R _d1 is cyano, halogen or nitro.

Another aspect of the present invention is 1) preparing a pyrimidine-N-oxide intermediate by catalytically oxidizing a pyrimidine compound of Formula 2 below; 2) Following step 1), the pyrimidine-N-oxide intermediate was activated in situ in the presence of trifluoromethanesulfonic anhydride (Tf ₂ O) and reacted with a pyridine reagent of Formula 3-2 to obtain pyrimidine Preparing a -2-pyridinium salt; and 3) following step 2), partially reducing the pyrimidine-2-pyridinium salt to prepare a cyclic (2-enamino)pyrimidine compound represented by the following Chemical Formula 1-2; And 2) provides a method for preparing a cyclic (2-enamino) pyrimidine compound in which step is performed as an in-situ continuous process without a separation process:

[Formula 1-2]

[Formula 2]

[Formula 3-2]

In Formulas 1-2, 2 and 3-2,

R ₁ , R ₂ and R ₃ are each independently hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C1-C20 alkoxy, C2-C20 alkenyl, C3-C20 heteroaryl or -NR' C(=O)Ar ₁ , or R ₁ to R ₃ may be linked to adjacent substituents to form a ring;

R ₅ is haloC1-C20 alkyl, cyano, C1-C20 alkylcarbonyl or C6-C20 arylcarbonyl;

R' is hydrogen or C1-C20 alkyl;

Ar ₁ is C6-C20 aryl or C3-C20 heteroaryl;

Alkyl, cycloalkyl, aryl, alkoxy, alkenyl and heteroaryl of R ₁ to R ₃ are C1-C20 alkyl, halogen, C1-C20 alkoxy hydroxy, C6-C20 aryl, haloC6-C20 aryl, -OSiR _a1 may be further substituted with one or more selected from R _a2 R _a3 , -L ₁ -NR _b1 -L ₂ -R _b2 and -CHR _c1 R _c2 ;

R _a1 , R _a2 and R _a3 are each independently C1-C20 alkyl, C3-C20 cycloalkyl or C6-C20 aryl;

L ₁ is C6-C20 arylene or haloC6-C20 arylene, L ₂ is SO ₂ or C=O;

R _b1 is hydrogen or C1-C20 alkyl;

R _b2 is C1-C20 alkoxy, C6-C20 aryl or halo C6-C20 aryl;

R _c1 is C3-C20 cycloalkyl;

R _c2 is -L ₃ -R _d1 , L ₃ is C1-C20 alkylene and R _d1 is cyano, halogen or nitro.

Another aspect of the present invention is 1) preparing a pyrimidine-N-oxide intermediate by catalytically oxidizing a pyrimidine compound of Formula 2 below; 2) Following step 1), the pyrimidine-N-oxide intermediate is reacted with an imidoyl chloride compound of Formula 4-1 in the presence of trifluoromethanesulfonic anhydride (Tf ₂ O) to obtain pyrimidine-2- preparing an iminium salt; and 3) following step 2), preparing a pyrimidine-2-substituted amine compound of Formula 1-3 by treating, reducing or hydrolyzing the pyrimidine-2-iminium salt with sodium bicarbonate. It provides a method for preparing a pyrimidine-2-substituted amine compound, wherein steps 1) and 2) are performed as an in-situ continuous process without a separation process:

[Formula 1-3]

[Formula 2]

[Formula 4-1]

In Formulas 1-3, 2 and 4-1,

R ₁ , R ₂ and R ₃ are each independently hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C1-C20 alkoxy, C2-C20 alkenyl, C3-C20 heteroaryl or -NR' C(=O)Ar ₁ , or R ₁ to R ₃ may be linked to adjacent substituents to form a ring;

R″ is hydrogen, -C(=0)R ₁₂ or -CH ₂ R ₁₂ ;

R ₁₁ is C1-C20 alkyl, C6-C20 aryl, allyl, haloC1-C20 alkyl, C6-C20 arylC1-C20 alkyl or C3-C20 cycloalkyl, wherein said cycloalkyl is halogen, haloC1-C20 alkyl and halo may be further substituted with one or more selected from C6-C20 aryl;

R ₁₂ is C1-C20 alkyl or C6-C20 aryl;

R ₄ is haloC1-C20 alkyl, C1-C20 alkylcarbonyl or C6-C20 arylcarbonyl;

R' is hydrogen or C1-C20 alkyl;

Ar ₁ is C6-C20 aryl or C3-C20 heteroaryl;

Alkyl, cycloalkyl, aryl, alkoxy, alkenyl and heteroaryl of R ₁ to R ₃ are C1-C20 alkyl, halogen, C1-C20 alkoxy hydroxy, C6-C20 aryl, haloC6-C20 aryl, -OSiR _a1 may be further substituted with one or more selected from R _a2 R _a3 , -L ₁ -NR _b1 -L ₂ -R _b2 and -CHR _c1 R _c2 ;

R _a1 , R _a2 and R _a3 are each independently C1-C20 alkyl, C3-C20 cycloalkyl or C6-C20 aryl;

L ₁ is C6-C20 arylene or haloC6-C20 arylene, L ₂ is SO ₂ or C=O;

R _b1 is hydrogen or C1-C20 alkyl;

R _b2 is C1-C20 alkoxy, C6-C20 aryl or halo C6-C20 aryl;

R _c1 is C3-C20 cycloalkyl;

R _c2 is -L ₃ -R _d1 , L ₃ is C1-C20 alkylene and R _d1 is cyano, halogen or nitro.

According to the production method of the present invention, a pyrimidine compound or an imidoyl chloride compound deficient in electrons is reacted with a pyrimidine activated by a nucleophilic imine type reagent over a pyrimidine-2-iminium salt intermediate. A pyrimidin-2-amine compound in which various amine functional groups ranging from primary to tertiary amines are selectively introduced at position 2 can be efficiently prepared.

According to the preparation method of the present invention, a C2-selective nucleophilic functionalization platform that converts pyrimidines to pyrimidine-2-iminium salts to provide a synthetic handle for the divergent synthesis of 2-aminopyrimidines can provide.

In addition, according to the production method of the present invention, the electron-deficient pyridine compound used in the reaction can be recovered and recycled, and the mass production of pyrimidine-2-amine compound from pyrimidine is possible, so commercial applicability is high.

In addition, the pyrimidin-2-amine compound prepared according to the production method of the present invention can be very usefully applied as an intermediate and synthetic unit in various fields such as various natural products and pharmaceuticals.

Hereinafter, the present invention will be described in more detail. If there is no other definition in the technical terms and scientific terms used at this time, they have meanings commonly understood by those of ordinary skill in the art to which this invention belongs, and will unnecessarily obscure the gist of the present invention in the following description. Descriptions of possible known functions and configurations are omitted.

Throughout this specification, unless the context requires otherwise, the terms "comprise" and "comprising" include a given step or component, or group of steps or components, but any other step or component, or It is to be understood that steps or groups of components are not excluded.

In this specification, “substituent”, “radical”, “group”, “moiety”, and “fragment” may be used interchangeably.

In the present specification, “C _A -C _B ” means “a number of carbon atoms greater than or equal to A and less than or equal to B”.

In the present specification, "substitution" means that a hydrogen atom bonded to a carbon atom of a compound is replaced with another substituent, and the position to be substituted is not limited as long as the hydrogen atom is substituted, that is, a position where the substituent can be substituted, and two or more substitutions In this case, two or more substituents may be the same as or different from each other.

The term “alkyl” in this specification means a monovalent straight-chain or branched saturated hydrocarbon radical composed only of carbon and hydrogen atoms. The alkyl may have 1 to 20 carbon atoms. The alkyl may have 1 to 10 carbon atoms. The alkyl may have 1 to 7 carbon atoms. Examples of such alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, tetradecyl, and the like.

The term "alkoxy" in this specification 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.

As used herein, the term "aryl" means an aromatic ring monovalent organic radical derived from an aromatic hydrocarbon by removing one hydrogen, and each ring has preferably 4 to 7, preferably 5 or 6 ring atoms. It may include a single or fused ring system including, and may include a form in which a plurality of aryls are connected by single bonds. It may have 6 to 20 carbon atoms, preferably 6 to 12 carbon atoms as ring atoms. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like.

The term "heteroaryl" used herein refers to a heteroaromatic ring monovalent radical which is an aryl group containing 1 to 4 heteroatoms selected from N, O and S as aromatic ring skeletal atoms, and the remaining aromatic ring skeletal atoms are carbon. It is a 5- to 6-membered monocyclic heteroaryl, and a polycyclic heteroaryl condensed with one or more benzene rings, which may be partially saturated. In addition, the heteroaryl in the present invention includes a form in which one or more heteroaryls are connected by a single bond. Examples of such heteroaryl groups are pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, imidazolyl, benzoimidazolyl, iso oxazolyl, benzoisoxazolyl, thiophenyl, benzothiophenyl, furyl, benzofuryl, and the like.

The term “halo” or “halogen” in this specification refers to a halogen group element and includes, for example, fluoro, chloro, bromo and iodo.

The term "haloalkyl" used herein refers to an alkyl radical substituted with at least one halogen, where 'alkyl' is as defined above. Examples of such haloalkyl radicals include, but are not limited to, fluoromethyl, trifluoromethyl, bromomethyl, perfluoroethyl, and the like.

The term "cycloalkyl" in this specification is a non-aromatic carbocyclic monovalent radical composed of one or more rings, and may include saturated or unsaturated monocyclic, polycyclic or spirocyclic forms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl (bicyclo[ 3.1.0]hexyl), bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, adamantly, decalinyl and the like, but are not limited thereto.

The term "alkenyl" as used herein refers to a linear or branched unsaturated hydrocarbon monovalent radical containing one or more double bonds between two or more carbon atoms, which may be partially saturated. Specifically, ethenyl, 1-propenyl, 2-propenyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, isoprenyl, geranyl, 5-tetradecenyl, and the like.

As used herein, the term "alkylene" refers to a divalent straight-chain or branched saturated hydrocarbon divalent group composed only of carbon and hydrogen atoms, specifically methylene, ethylene, propylene, isopropylene, butylene, isobutylene, t-butyl but is not limited to, ene, pentylene, hexylene, octylene, nonylene, and the like.

As used herein, the term "arylene" is an aromatic ring divalent organic radical derived from an aromatic hydrocarbon, and is a single or fused ring system containing preferably 4 to 7, preferably 5 or 6, ring atoms in each ring. Including, including a form in which a plurality of aryls are connected by single bonds. For example, naphthylene, biphenylene, terphenylene, anthrylene, indenylene, fluorenylene, pyrene, phenanthrylene, triphenylenylene, pyrenylene, perylenenylene, chrysenylene, naphthacenyl but is not limited to rene and fluoranthenylene and the like or combinations thereof.

The present invention relates to a method for preparing a pyrimidin-2-amine compound, and more particularly, by reacting a pyridine compound or an imidoyl chloride compound deficient in electrons with activated pyrimidine as a reagent in the form of a nucleophilic imine. A method for efficiently producing pyrimidine-2-amine compounds in which various amine functional groups ranging from primary to tertiary amines are selectively introduced at position 2 of pyrimidine over a pyrimidine-2-iminium salt intermediate will be.

According to one aspect of the present invention, 1) preparing a pyrimidine-N-oxide intermediate by catalytically oxidizing a pyrimidine compound represented by Formula 2 below; 2) Following step 1), the pyrimidine-N-oxide intermediate was activated in situ in the presence of trifluoromethanesulfonic anhydride (Tf ₂ O) and reacted with a pyridine reagent of Formula 3-1 to obtain pyrimidine Preparing a -2-pyridinium salt; and 3) preparing a pyrimidin-2-amine compound represented by the following Chemical Formula 1-1 by aminolysis of the pyrimidine-2-pyridinium salt following step 2), wherein 1) and 2) Provided is a method for producing a pyrimidine-2-amine compound in which the steps are performed as an in-situ continuous process without a separation process.

[Formula 1-1]

[Formula 2]

[Formula 3-1]

In Formulas 1-1, 2 and 3-1,

R ₁ , R ₂ and R ₃ are each independently hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C1-C20 alkoxy, C2-C20 alkenyl, C3-C20 heteroaryl or -NR' C(=O)Ar ₁ , or R ₁ to R ₃ may be linked to adjacent substituents to form a ring;

R ₄ is haloC1-C20 alkyl, cyano, C1-C20 alkylcarbonyl or C6-C20 arylcarbonyl;

R' is hydrogen or C1-C20 alkyl;

Ar ₁ is C6-C20 aryl or C3-C20 heteroaryl;

Alkyl, cycloalkyl, aryl, alkoxy, alkenyl and heteroaryl of R ₁ to R ₃ are C1-C20 alkyl, halogen, C1-C20 alkoxy hydroxy, C6-C20 aryl, haloC6-C20 aryl, -SiR _a1 may be further substituted with one or more selected from R _a2 R _a3 , -L ₁ -NR _b1 -L ₂ -R _b2 and -CHR _c1 R _c2 ;

R _a1 , R _a2 and R _a3 are each independently C1-C20 alkyl, C3-C20 cycloalkyl or C6-C20 aryl;

L ₁ is C6-C20 arylene or haloC6-C20 arylene, L ₂ is SO ₂ or C=O;

R _b1 is hydrogen or C1-C20 alkyl;

R _b2 is C1-C20 alkoxy, C6-C20 aryl or halo C6-C20 aryl;

R _c1 is C3-C20 cycloalkyl;

R _c2 is -L ₃ -R _d1 , L ₃ is C1-C20 alkylene and R _d1 is cyano, halogen or nitro.

The method for preparing the pyrimidin-2-amine compound represented by Chemical Formula 1-1 according to the present invention comprises catalytic oxidation and activation of a pyrimidine compound represented by Chemical Formula 2 as a starting material, followed by nucleophilic imine-type reagent, a pyridine compound deficient in electrons. A pyrimidine-2-amine compound in which an amine functional group is selectively introduced at position 2 of pyrimidine can be efficiently prepared through reaction with and aminolysis. According to the present invention, a wide variety of substrates with various substituents can be introduced as starting materials.

The catalytic oxidation in step 1) may be performed in the presence of an oxidizing agent and methyltrioxorenium (MeReO ₃ ), and the amount of methyltrioxorenium used is not particularly limited, but is 1.0 to 1.0 to pyrimidine compound of formula (2). 30.0 mol%, or 2.0 to 25.0 mol%, or 5.0 to 20.0 mol%.

The oxidizing agent may be hydrogen peroxide or a hydrogen peroxide adduct, and the hydrogen peroxide adduct may be urea-hydrogen peroxide or sodium percarbonate, preferably hydrogen peroxide, and more specifically, a 50% hydrogen peroxide aqueous solution.

The amount of the oxidizing agent used is not particularly limited, but may be used in the range of 1 to 5 equivalents, 1.5 to 5 equivalents, or 2 to 5 equivalents relative to the pyrimidine compound of Formula 2.

Trifluoromethanesulfonic acid may be additionally added during the catalytic oxidation in step 1), and added in an amount of 1 equivalent or more, specifically 1 to 3 equivalents, or 1 to 2 equivalents relative to the pyrimidine compound of Formula 2 It can be.

In step 2), the amount of trifluoromethanesulfonic anhydride (Tf ₂ O) used is not particularly limited, but is 1 equivalent or more, specifically 1 to 3 equivalents, or 1 to 2 equivalents, relative to the pyrimidine compound of Formula 2. A range of equivalents can be used.

In step 2), the pyridine reagent of Chemical Formula 3-1 may be used in an excess amount, specifically in the range of 1.5 to 5 equivalents or 2 to 3 equivalents relative to the pyrimidine compound of Chemical Formula 2.

The pyrimidine-2-pyridinium salt intermediate prepared through steps 1) and 2) is a C2-selective nucleophilic functionalization platform that provides a synthetic handle for divergent synthesis of 2-aminopyrimidine. can work

Aminolysis in step 3) may be performed in the presence of aqueous ammonia. Upon amine derivatization of pyrimidine-2-pyridinium salts, a primary amine product (formula 1-1) can be obtained by using ammonia as an amino source.

In one embodiment, the reaction of all the steps can be carried out under mild conditions, and the reaction temperature can be any normal temperature used in organic synthesis, but specifically, the catalytic oxidation of step 1) is 20 to 30 It is carried out at ℃, the step 2) is carried out at 0 to 30 ℃, the step 3) can be carried out at 60 to 90 ℃, it can be appropriately adjusted as needed. The reaction time may vary depending on the reactant, the amount of the reactant, the type and amount of the solvent, and is not particularly limited.

In one embodiment, the reaction of all the steps may be performed in an organic solvent, and there is no need to limit the organic solvent as long as it does not react with the reactants. For example, as the organic solvent, dichloromethane (DCM), dichloroethane, tetrachloroethane, acetonitrile (MeCN, acetonitrile), nitromethane, toluene, Benzene, ethanol (EtOH), etc. may be used alone or in combination of two or more. Specifically, at least one selected from dichloromethane, acetonitrile, and ethanol may be used as the reaction solvent.

A process for preparing the pyrimidin-2-amine compound of Chemical Formula 1-1 through steps 1) to 3) is shown in Scheme 1 below. As shown in Reaction Scheme 1, the pyrimidine-N-oxide intermediate formed by catalytic oxidation of the pyrimidine compound of Formula 2 is activated in situ in the presence of trifluoromethanesulfonic anhydride, and at the same time pyridine of Formula 3-1 A pyrimidin-2-amine compound of Chemical Formula 1-1 may be prepared by reacting with a reagent to form a pyrimidine-2-pyridinium salt of Chemical Formula A-1 as a key intermediate and immediately aminolysis without separation and purification.

[Scheme 1]

In Scheme 1, R ₁ to R ₄ are as described above.

로 연결되어 고리를 형성할 수 있으며; a는 1 내지 10의 정수이고; R_a1, R_a2 및 R_a3는 각각 독립적으로 C1-C10알킬이고; Ar은 C6-C12아릴 또는 할로C6-C12아릴이고; Ar₁은 C6-C12아릴이고; 상기 R₁ 내지 R₃의 헤테로아릴은 C1-C10알킬, -L₁-NH-L₂-R_b2 및 -CHR_c1R_c2부터 선택되는 어느 하나 이상으로 더 치환될 수 있으며; L₁은 C6-C12아릴렌 또는 할로C6-C12아릴렌이고, L₂는 SO₂ 또는 C=O이고; R_b2는 C1-C10알콕시, C6-C12아릴 또는 할로C6-C12아릴이고; R_c1은 C3-C10시클로알킬이고; R_c2는 -(CH₂)_b-CN이고, b는 1 내지 10의 정수일 수 있고; 상기 화학식 3-1의 R₄은 할로C1-C10알킬 또는 C6-C20아릴카보닐일 수 있다.In one embodiment, R ₁ , R ₂ and R ₃ in Formulas 1-1 and 2 are each independently hydrogen, C1-C10 alkyl, hydroxyC1-C10 alkyl, -(CH ₂ ) _a -OSiR _a1 R _a2 R _a3 , C3-C10 cycloalkyl, C6-C12 aryl, haloC6-C12 aryl, C1-C10 alkoxy, -CH=CH-Ar, C3-C10 heteroaryl or -NHC(=O)Ar ₁ or R ₂ and R ₃ are

Can be linked to form a ring; a is an integer from 1 to 10; R _a1 , R _a2 and R _a3 are each independently C1-C10 alkyl; Ar is C6-C12 aryl or haloC6-C12 aryl; Ar ₁ is C6-C12 aryl; The heteroaryl of R ₁ to R ₃ may be further substituted with one or more selected from C1-C10 alkyl, -L ₁ -NH-L ₂ -R _b2 and -CHR _c1 R _c2 ; L ₁ is C6-C12 arylene or haloC6-C12 arylene, L ₂ is SO ₂ or C=O; R _b2 is C1-C10 alkoxy, C6-C12 aryl or haloC6-C12 aryl; R _c1 is C3-C10 cycloalkyl; R _c2 is -(CH ₂ ) _b -CN, b may be an integer from 1 to 10; R ₄ in Formula 3-1 may be haloC1-C10 alkyl or C6-C20 arylcarbonyl.

According to another aspect of the present invention, 1) preparing a pyrimidine-N-oxide intermediate by catalytically oxidizing a pyrimidine compound represented by Formula 2 below; 2) Following step 1), the pyrimidine-N-oxide intermediate was activated in situ in the presence of trifluoromethanesulfonic anhydride and reacted with a pyridine reagent of Formula 3-2 to obtain pyrimidine-2-pyridinium preparing a salt; and 3) following step 2), partially reducing the pyrimidine-2-pyridinium salt to prepare a cyclic (2-enamino)pyrimidine compound represented by the following Chemical Formula 1-2; and 2) is performed as an in-situ continuous process without a separation process, providing a method for producing a cyclic (2-enamino)pyrimidine compound.

[Formula 1-2]

[Formula 2]

[Formula 3-2]

In Formulas 1-2, 2 and 3-2,

R ₁ , R ₂ and R ₃ are each independently hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C1-C20 alkoxy, C2-C20 alkenyl, C3-C20 heteroaryl or -NR' C(=O)Ar ₁ , or R ₁ to R ₃ may be linked to adjacent substituents to form a ring;

R ₅ is haloC1-C20 alkyl, cyano, C1-C20 alkylcarbonyl or C6-C20 arylcarbonyl;

R' is hydrogen or C1-C20 alkyl;

Ar ₁ is C6-C20 aryl or C3-C20 heteroaryl;

Alkyl, cycloalkyl, aryl, alkoxy, alkenyl and heteroaryl of R ₁ to R ₃ are C1-C20 alkyl, halogen, C1-C20 alkoxy hydroxy, C6-C20 aryl, haloC6-C20 aryl, -SiR _a1 may be further substituted with one or more selected from R _a2 R _a3 , -L ₁ -NR _b1 -L ₂ -R _b2 and -CHR _c1 R _c2 ;

R _a1 , R _a2 and R _a3 are each independently C1-C20 alkyl, C3-C20 cycloalkyl or C6-C20 aryl;

L ₁ is C6-C20 arylene or haloC6-C20 arylene, L ₂ is SO ₂ or C=O;

R _b1 is hydrogen or C1-C20 alkyl;

R _b2 is C1-C20 alkoxy, C6-C20 aryl or halo C6-C20 aryl;

R _c1 is C3-C20 cycloalkyl;

R _c2 is -L ₃ -R _d1 , L ₃ is C1-C20 alkylene and R _d1 is cyano, halogen or nitro.

The method for preparing the cyclic (2-enamino)pyrimidine compound represented by Chemical Formula 1-2 according to the present invention includes catalytic oxidation and activation of the pyrimidine compound represented by Chemical Formula 2 as a starting material, followed by deficient electrons as a reagent in the form of a nucleophilic imine. A cyclic (2-enamino)pyrimidine compound in which a partially reduced cyclic amine functional group is selectively introduced at the 2-position of pyrimidine can be efficiently prepared through a reaction with a pyridine compound and a partial reduction process. . According to the present invention, a wide variety of substrates with various substituents can be introduced as starting materials.

Steps 1) and 2) are the same as described above, but in step 2), the pyridine reagent of Formula 3-2 is used in an excess amount, specifically 1.5 to 5 equivalents, relative to the pyrimidine compound of Formula 2, or It can be used in the range of 2 to 3 equivalents.

The pyrimidine-2-pyridinium salt intermediate prepared through steps 1) and 2) is a C2-selective nucleophilic functionalization platform that provides a synthetic handle for divergent synthesis of 2-aminopyrimidine. can work

The partial reduction in step 3) may be performed in the presence of hydrogen gas and a platinum group metal catalyst including platinum, palladium, rhodium and/or ruthenium, specifically hydrogen gas and PtO ₂ It may be carried out in the presence of there is. The metal catalyst, specifically PtO ₂ , may be used in an amount of 1.0 to 20.0 mol%, or 1 to 15 mol%, or 3 to 10 mol%, based on the pyrimidine compound of Formula 2.

In one embodiment, the reaction of all the steps can be carried out under mild conditions, and the reaction temperature can be any normal temperature used in organic synthesis, but specifically, the catalytic oxidation of step 1) is 20 to 30 It is carried out at ℃, the step 2) is carried out at 0 to 30 ℃, the step 3) can be carried out at 20 to 30 ℃, it can be appropriately adjusted as needed. The reaction time may vary depending on the reactant, the amount of the reactant, the type and amount of the solvent, and is not particularly limited.

In one embodiment, the reaction of all the steps may be performed in an organic solvent, and there is no need to limit the organic solvent as long as it does not react with the reactants. For example, as the organic solvent, dichloromethane (DCM), dichloroethane, tetrachloroethane, acetonitrile (MeCN, acetonitrile), nitromethane, toluene, Benzene, ethanol (EtOH), etc. may be used alone or in combination of two or more. Specifically, at least one selected from dichloromethane, acetonitrile, and ethanol may be used as the reaction solvent.

A process for preparing the cyclic (2-enamino)pyrimidine compound of Chemical Formula 1-2 through steps 1) to 3) is shown in Scheme 2 below. As shown in Reaction Scheme 2, the pyrimidine-N-oxide intermediate formed by catalytic oxidation of the pyrimidine compound of Formula 2 is activated in situ in the presence of trifluoromethanesulfonic anhydride, and at the same time pyridine of Formula 3-2 A pyrimidine-2-pyridinium salt of Formula A-2 is formed as a key intermediate by reaction with a reagent, and a cyclic (2-enamino)pyrimidine compound of Formula 1-2 is prepared by partial reduction directly without separation and purification. can

[Scheme 2]

In Scheme 1, R ₁ to R ₃ and R ₅ are the same as described above.

로 연결되어 고리를 형성할 수 있으며; a는 1 내지 10의 정수이고; R_a1, R_a2 및 R_a3는 각각 독립적으로 C1-C10알킬이고; Ar은 C6-C12아릴 또는 할로C6-C12아릴이고; Ar₁은 C6-C12아릴이고; 상기 R₁ 내지 R₃의 헤테로아릴은 C1-C10알킬, -L₁-NH-L₂-R_b2 및 -CHR_c1R_c2부터 선택되는 어느 하나 이상으로 더 치환될 수 있으며; L₁은 C6-C12아릴렌 또는 할로C6-C12아릴렌이고, L₂는 SO₂ 또는 C=O이고; R_b2는 C1-C10알콕시, C6-C12아릴 또는 할로C6-C12아릴이고; R_c1은 C3-C10시클로알킬이고; R_c2는 -(CH₂)_b-CN이고, b는 1 내지 10의 정수일 수 있고; 상기 화학식 3-2의 R₅은 할로C1-C10알킬일 수 있다.In one embodiment, R ₁ , R ₂ and R ₃ in Formulas 1-2 and 2 are each independently hydrogen, C1-C10 alkyl, hydroxyC1-C10 alkyl, -(CH ₂ ) _a -OSiR _a1 R _a2 R _a3 , C3-C10 cycloalkyl, C6-C12 aryl, haloC6-C12 aryl, C1-C10 alkoxy, -CH=CH-Ar, C3-C10 heteroaryl or -NHC(=O)Ar ₁ or R ₂ and R ₃ are

Can be linked to form a ring; a is an integer from 1 to 10; R _a1 , R _a2 and R _a3 are each independently C1-C10 alkyl; Ar is C6-C12 aryl or haloC6-C12 aryl; Ar ₁ is C6-C12 aryl; The heteroaryl of R ₁ to R ₃ may be further substituted with one or more selected from C1-C10 alkyl, -L ₁ -NH-L ₂ -R _b2 and -CHR _c1 R _c2 ; L ₁ is C6-C12 arylene or haloC6-C12 arylene, L ₂ is SO ₂ or C=O; R _b2 is C1-C10 alkoxy, C6-C12 aryl or haloC6-C12 aryl; R _c1 is C3-C10 cycloalkyl; R _c2 is -(CH ₂ ) _b -CN, b may be an integer from 1 to 10; R ₅ in Formula 3-2 may be haloC1-C10 alkyl.

According to another aspect of the present invention, 1) preparing a pyrimidine-N-oxide intermediate by catalytically oxidizing a pyrimidine compound represented by Formula 2 below; 2) Following step 1), the pyrimidine-N-oxide intermediate was reacted with an imidoyl chloride compound of Formula 4-1 in the presence of trifluoromethanesulfonic anhydride to prepare a pyrimidine-2-iminium salt doing; and 3) following step 2), preparing a pyrimidine-2-substituted amine compound of Formula 1-3 by treating, reducing or hydrolyzing the pyrimidine-2-iminium salt with sodium bicarbonate. Including, it provides a method for preparing a pyrimidine-2-substituted amine compound, wherein steps 1) and 2) are performed as an in-situ continuous process without a separation process.

[Formula 1-3]

[Formula 2]

[Formula 4-1]

In Formulas 1-3, 2 and 4-1,

R ₁ , R ₂ and R ₃ are each independently hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C1-C20 alkoxy, C2-C20 alkenyl, C3-C20 heteroaryl or -NR' C(=O)Ar ₁ , or R ₁ to R ₃ may be linked to adjacent substituents to form a ring;

R″ is hydrogen, -C(=0)R ₁₂ or -CH ₂ R ₁₂ ;

R ₁₁ is C1-C20 alkyl, C6-C20 aryl, allyl, haloC1-C20 alkyl, C6-C20 arylC1-C20 alkyl or C3-C20 cycloalkyl, wherein said cycloalkyl is halogen, haloC1-C20 alkyl and halo may be further substituted with one or more selected from C6-C20 aryl;

R ₁₂ is C1-C20 alkyl or C6-C20 aryl;

R ₄ is haloC1-C20 alkyl, C1-C20 alkylcarbonyl or C6-C20 arylcarbonyl;

R' is hydrogen or C1-C20 alkyl;

Ar ₁ is C6-C20 aryl or C3-C20 heteroaryl;

Alkyl, cycloalkyl, aryl, alkoxy, alkenyl and heteroaryl of R ₁ to R ₃ are C1-C20 alkyl, halogen, C1-C20 alkoxy hydroxy, C6-C20 aryl, haloC6-C20 aryl, -OSiR _a1 may be further substituted with one or more selected from R _a2 R _a3 , -L ₁ -NR _b1 -L ₂ -R _b2 and -CHR _c1 R _c2 ;

R _a1 , R _a2 and R _a3 are each independently C1-C20 alkyl, C3-C20 cycloalkyl or C6-C20 aryl;

L ₁ is C6-C20 arylene or haloC6-C20 arylene, L ₂ is SO ₂ or C=O;

R _b1 is hydrogen or C1-C20 alkyl;

R _b2 is C1-C20 alkoxy, C6-C20 aryl or halo C6-C20 aryl;

R _c1 is C3-C20 cycloalkyl;

R _c2 is -L ₃ -R _d1 , L ₃ is C1-C20 alkylene and R _d1 is cyano, halogen or nitro.

The method for preparing the pyrimidine-2-substituted amine compound represented by Chemical Formula 1-3 according to the present invention comprises catalytic oxidation of the pyrimidine compound represented by Chemical Formula 2 as a starting material, subsequent activation, and a nucleophilic imine-type reagent, imidoyl chloride compound. A pyrimidine-2-substituted amine compound in which a substituted amine functional group is selectively introduced at the 2-position of pyrimidine can be efficiently prepared through reaction with and post-treatment. According to the present invention, a wide variety of substrates with various substituents can be introduced as starting materials.

Step 1) is the same as described above.

The imidoyl chloride compound of Chemical Formula 4-1 in step 2) may be prepared by reacting an amide compound of Chemical Formula 4 with oxalyl chloride in the presence of an organic base, which is prepared immediately before use and immediately without separation and purification. The pyrimidine-N-oxide intermediate formed in step 1) may be reacted in the presence of trifluoromethanesulfonic anhydride.

[Formula 4]

In Formula 4, R ₁₁ and R ₁₂ are the same as described above.

The imidoyl chloride compound of Formula 4-1 is 1 to 5 equivalents, or 2 to 3 equivalents of the amide compound of Formula 4, or 1 to 5 equivalents, or 2 to 3 equivalents of oxalyl chloride, relative to the pyrimidine compound of Formula 2, and It is prepared by reacting 1 to 5 equivalents or 2 to 3 equivalents of an organic base, and can be used directly in the next reaction in situ without a separate purification process. The organic base used may be selected from pyridine, triethylamine, diisopropylamine, N,N-diisopropylethylamine, 2,6-lutidine or mixtures thereof, specifically 2,6-lutidine It could be Dean.

The amount of trifluoromethanesulfonic anhydride (Tf ₂ O) used in step 2) is not particularly limited, but is 1 equivalent or more, specifically 1 to 3 equivalents, or 1 to 2 equivalents, relative to the pyrimidine compound of Formula 2. A range of equivalents can be used.

In step 2), the imidoyl chloride reagent of Chemical Formula 4-1 may be used in an excess amount, specifically in the range of 1.5 to 5 equivalents or 2 to 3 equivalents relative to the pyrimidine compound of Chemical Formula 2.

The pyrimidine-2-iminium salt intermediate prepared through steps 1) and 2) is a C2-selective nucleophilic functionalization platform that provides a synthetic handle for divergent synthesis of 2-aminopyrimidine. can work

Step 3) may be a step of preparing a pyrimidine-2-amide compound of Formula 1-3A by treating with sodium bicarbonate.

[Formula 1-3A]

In Formula 1-3A, R ₁ to R ₃ , R ₁₁ and R ₁₂ have the same definitions as above.

Step 3) may be a step of hydrogenating the iminium ion by reaction with a reducing agent to form a product in the form of a tertiary amine, specifically sodium triacetoxyborohydride (Na(CH ₃ COO) ₃ BH ), sodium borohydride (NaBH ₄ ), sodium cyanoborohydride (NaBH ₃ CN), zinc borohydride (Zn(BH ₄ ) ₂ ), lithium aluminum hydride (LiAlH ₄ ) and lithium cyanoborohydride It may be a step of preparing a pyrimidine-2-disubstituted amine compound of Formula 1-3B by reduction with a reducing agent selected from lide (LiBH ₃ CN).

[Formula 1-3B]

In Formula 1-3B, R ₁ to R ₃ , R ₁₁ and R ₁₂ are the same as defined above.

Step 3) may be a step of forming a secondary amine product through hydrolysis, and specifically, preparing a pyrimidin-2-monosubstituted amine compound of Formula 1-3C by treating with methanol and sodium hydroxide can be

[Formula 1-3C]

In Formula 1-3C, R ₁ to R ₃ and R ₁₁ are the same as defined above.

In one embodiment, the reaction of all the steps can be carried out under mild conditions, and the reaction temperature can be any normal temperature used in organic synthesis, but specifically, the catalytic oxidation of step 1) is 20 to 30 It is carried out at ℃, the step 2) is carried out at 0 to 30 ℃, the step 3) can be carried out at 20 to 70 ℃, it can be appropriately adjusted as needed. The reaction time may vary depending on the reactant, the amount of the reactant, the type and amount of the solvent, and is not particularly limited.

In one embodiment, the reaction of all the steps may be performed in an organic solvent, and there is no need to limit the organic solvent as long as it does not react with the reactants. For example, as the organic solvent, dichloromethane (DCM), dichloroethane, tetrachloroethane, acetonitrile (MeCN, acetonitrile), nitromethane, toluene, Benzene, ethanol (EtOH), etc. may be used alone or in combination of two or more. Specifically, at least one selected from dichloromethane, acetonitrile, and ethanol may be used as the reaction solvent.

A process for preparing the pyrimidine-2-substituted amine compound of Chemical Formula 1-3 through steps 1) to 3) is shown in Scheme 3 below. As shown in Scheme 3, the pyrimidine-N-oxide intermediate of formula A-0 formed by catalytic oxidation of the pyrimidine compound of formula 2 is activated in situ in the presence of trifluoromethanesulfonic anhydride, and at the same time formula The pyrimidine-2-iminium salt of Formula A-3 is formed as a key intermediate by reacting with the imidoyl chloride reagent of 4-1, which is directly treated with sodium bicarbonate without separation or purification, or reduced or hydrolyzed to obtain Formula 1-3 A pyrimidine-2-substituted amine compound (R″ is hydrogen, -C(=O)R ₁₂ or -CH ₂ R ₁₂ ) can be prepared.

[Scheme 3]

In Scheme 3, R ₁ to R ₃ , R ₁₁ and R ₁₂ are as described above.

로 연결되어 고리를 형성할 수 있으며; a는 1 내지 10의 정수이고; R_a1, R_a2 및 R_a3는 각각 독립적으로 C1-C10알킬이고; Ar은 C6-C12아릴 또는 할로C6-C12아릴이고; Ar₁은 C6-C12아릴이고; 상기 R₁ 내지 R₃의 헤테로아릴은 C1-C10알킬, -L₁-NH-L₂-R_b2 및 -CHR_c1R_c2부터 선택되는 어느 하나 이상으로 더 치환될 수 있으며; L₁은 C6-C12아릴렌 또는 할로C6-C12아릴렌이고, L₂는 SO₂ 또는 C=O이고; R_b2는 C1-C10알콕시, C6-C12아릴 또는 할로C6-C12아릴이고; R_c1은 C3-C10시클로알킬이고; R_c2는 -(CH₂)_b-CN이고, b는 1 내지 10의 정수일 수 있고; In one embodiment, R ₁ , R ₂ and R ₃ in Formulas 1-3A, 1-3B, 1-3C and 2 are each independently hydrogen, C1-C10 alkyl, hydroxyC1-C10 alkyl, -( CH ₂ ) _a -OSiR _a1 R _a2 R _a3 , C3-C10 Cycloalkyl, C6-C12 Aryl, HaloC6-C12 Aryl, C1-C10 Alkoxy, -CH=CH-Ar, C3-C10 Heteroaryl or -NHC( =O)Ar ₁ or, wherein R ₂ and R ₃ are

Can be linked to form a ring; a is an integer from 1 to 10; R _a1 , R _a2 and R _a3 are each independently C1-C10 alkyl; Ar is C6-C12 aryl or haloC6-C12 aryl; Ar ₁ is C6-C12 aryl; The heteroaryl of R ₁ to R ₃ may be further substituted with one or more selected from C1-C10 alkyl, -L ₁ -NH-L ₂ -R _b2 and -CHR _c1 R _c2 ; L ₁ is C6-C12 arylene or haloC6-C12 arylene, L ₂ is SO ₂ or C=O; R _b2 is C1-C10 alkoxy, C6-C12 aryl or haloC6-C12 aryl; R _c1 is C3-C10 cycloalkyl; R _c2 is -(CH ₂ ) _b -CN, b may be an integer from 1 to 10;

R ₁₁ in Formulas 1-3A, 1-3B, 1-3C and 4 is C1-C10 alkyl, C6-C12 aryl, allyl, haloC1-C10 alkyl, C6-C12 arylC1-C10 alkyl or C3-C10 cyclo alkyl, wherein the cycloalkyl may be further substituted with one or more selected from halogen, haloC1-C10 alkyl and haloC6-C12 aryl; R ₁₂ can be C1-C10 alkyl or C6-C12 aryl.

The present invention is a very effective method for efficiently synthesizing pyrimidine-2-amine in one step through C2-selective amination of pyrimidine, which serves as an important structural key motif in medicine, pesticide, and various chemical fields. According to the present invention, pyrimidine-2-amine compounds in which various amino functional groups are selectively introduced at the 2-position of pyrimidine across the salt intermediate of the pyrimidine-2-iminium skeleton using a nucleophilic imine type reagent are prepared. can be synthesized efficiently. In addition, since the reaction is performed in situ and requires only one purification step to isolate the final product, it may have a process advantage.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for explaining the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

All reactions, which are not sensitive to air and moisture, were carried out under ambient air. Concentration was performed by rotary evaporation at 25 to 40 °C at appropriate pressure. The purified compound was further dried under reduced pressure (0.1 to 1 Torr). The yield represents a purified and spectroscopically pure compound. All air- and moisture-sensitive manipulations were performed using oven-dried glassware (130° C. for a minimum of 12 hours) including standard Schlenk techniques under an argon atmosphere. Air-sensitive liquids and solutions were transferred via syringe or cannula using degassed solvent.

[menstruum]

Acetonitrile, dichloromethane, and methanol were purchased from Duksan Pharmaceutical Co., Ltd. and used without further purification. Anhydrous solvent was obtained from an Innovative Technology Solvent Drying System. All deuterated solvents were purchased from Euriso-top.

[Chromatography]

Thin layer chromatography (TLC) was performed using pre-coated silica gel 60 F254 plates, visualized by fluorescence quenching under UV light. Flash chromatography was performed using a CombiFlash ^® R _f ⁺ system equipped with a RediSep ^® R _f silica column (230 to 400 mesh) using an appropriate eluent system.

[Spectroscopy and instruments]

¹ H NMR spectra were obtained using a Bruker AV-400 (400 MHz), Bruker AV-500 (500 MHz), or Agilent Technologies DD2 (600 MHz). ¹³ C{ ¹ H} NMR spectra were obtained using a Bruker AV-500 (125 MHz) or Agilent Technologies DD2 (150 MHz), and were completely decoupled by broad-band proton decoupling. ¹⁹ F NMR spectra were obtained using a Bruker AS-400 (376 MHz), Bruker AVHD-400 (376 MHz), Bruker AV-500 (470 MHz), or Agilent Technologies DD2 (564 MHz). Chemical shifts are expressed in ppm with solvent resonance as an internal standard. For ¹ H NMR: CDCl ₃ , δ 7.26; CD ₃ CN, δ 1.94; CD ₂ Cl ₂ , δ 5.32; (CD ₃ ) ₂ CO, δ 2.05. For ¹³ C NMR: CDCl ₃ , δ 77.16; CD ₃ CN, δ 1.32; CD ₂ Cl ₂ , δ 53.84; (CD ₃ ) ₂ CO, δ 29.84. Infrared (IR) spectra were obtained using a Bruker Alpha FT-IR Spectrometer. High-resolution mass spectrum (HRMS) was performed using the ESI (electrospray ionization) method at the KAIST Analysis center for Research Advancement (Daejeon), and the FAB (fast-atom bombardment) or EI (electronization) method at the Korea Basic Science Institute (Daegu). ionization) method. Melting point (mp) was measured using a Buchi Melting Point M-565. X-Ray Diffraction (XRD) data were obtained on a Bruker D8 QUEST APEX3 coated with paraton- N oil under a flow of N ₂ (g) at 173 K.

[starting material]

Unless otherwise specified, all commercially available substrates were used without further purification. TCI chemical company, (4-Chlorophenyl)boronic acid, pyrimidine N -oxide, N -methylbenzamide, N -methylacetamide, and acetanilide were purchased from Sigma-Aldrich, and 1-(Benzofuran-2-yl)ethan-1-one was purchased from Alfa Aesar, and 1-(4-Fluorophenyl)cyclopropan-1-amine and 5-bromo-4-ethylpyrimidine were purchased from Combi-Blocks. Varenicline tartrate and N -cyclopropyl-2-phenylacetamide were purchased from BLDPharm, Ruxolitinib was purchased from Habo Hong Kong, and N -Allylacetamide was purchased from Oakwood Chemical. N -Cyclopropyl-2-phenylacetamide, 2-(pyrimidin-4-yl)ethan-1-ol, methyl 3-[(2,6-difluorophenyl)sulfonamide]-2-fluorobenzoate, 4-(3-iodo-1- isopropyl- 1H- pyrazol-4-yl)pyrimidine, {3-[( tert -butoxycarbonyl)amino]phenyl}boronic acid pinacol ester, 4-cyclohexylpyrimidine, N- (pyrimidin-4-yl)benzamide, ( E )- 4-(4-chlorostyryl)pyrimidine, 4-(pyridin-3-yl)pyrimidine, and N -Cbz-varenicline were previously reported [ J. Am. Chem. Soc. 2021, 143 , 11969-11975; WO 2003037895 A1; ACS Med. Chem. Lett. 2013, 4 , 358-362; WO 2009016460 A2; Angew. Chem., Int. Ed. 2016, 55 , 16101-16105; Heterocycles 2005, 65 , 2593-2603; Inorg. Chem. 2017, 56 , 12514-12519; J. Org. Chem. 2012, 77 , 4087-4096; RSC Adv. 2015, 5 , 76759-76763; Org. Lett. 2019, 21 , 6488-6493] and used.

Preparation Example: Preparation of Starting Materials

[Preparation Example 1] Preparation of N- (2,2,2-Trifluoroethyl)acetamide (S1)

In an oven-dried 100 mL round bottom flask under an argon atmosphere, stirrer bar, 2,2,2-trifluoroethan-1-amine (1.00 mL, 1.26 g, 12.7 mmol, 1.0 equiv), and anhydrous dichloromethane (25 mL) was filled. The stirred solution was cooled to 0 °C and then triethylamine (1.86 mL, 1.35 g, 13.4 mmol, 1.0 equiv) was added via syringe. While stirring at 0°C, acetyl chloride (952 μL, 1.05 g, 13.4 mmol, 1.0 equiv) was added dropwise through a syringe. The mixture was warmed to 23° C. over 5 minutes and then stirred at the same temperature for 4 hours. After diluting the reaction mixture with dichloromethane (25 mL), it was washed with 1N hydrochloric acid aqueous solution (10 mL × 3). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the desired compound S1 as a white solid (292 mg, 16% yield).

mp: 61-63 °C; ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 6.60 (br s, 1H), 3.96-3.80 (m, 2H), 2.01 (s, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 171.0, 124.8 (q, J = 278.5 Hz), 40.8 (q, J = 34.5 Hz), 22.9; ¹⁹ F NMR (470 MHz, CD ₂ Cl ₂ ) δ -73.1; IR (cm ⁻¹ ): 3263, 3082, 2964, 2864, 1653, 1562, 1377, 1257, 1147, 985, 834; HRMS (EI): Calculated for C ₄ H ₆ F ₃ NO [M] ⁺ : 141.0401; Found: 141.0403.

[Preparation Example 2] Preparation of N- [1-(4-Fluorophenyl)cyclopropyl]acetamide (S2)

Under an argon atmosphere, an oven-dried 50 mL round bottom flask was charged with a stirring bar, 1-(4-fluorophenyl)cyclopropan-1-amine (302 mg, 2.00 mmol, 1.0 equiv), and anhydrous dichloromethane (10 mL). The stirred solution was cooled to 0 °C and then triethylamine (279 μL, 202 mg, 2.00 mmol, 1.0 equiv) was added via syringe. While stirring at 0°C, acetyl chloride (142 μL, 157 mg, 2.00 mmol, 1.0 equiv) was added dropwise through a syringe. The mixture was warmed to 23° C. over 5 minutes and then stirred at the same temperature for 4 hours. The reaction mixture was diluted with dichloromethane (25 mL), washed with saturated aqueous sodium bicarbonate solution (25 mL), and the organic layer was separated. The aqueous layer was extracted with dichloromethane (25 mL × 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a solvent mixture of n-hexane/ethyl acetate (100/0 to 0/100 (v/v)) to give the desired compound S2 as a beige solid (325 mg, 84% yield).

mp: 127-129 °C; ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 7.25-7.18/7.18-7.13 (m, 2H, rotameric), 7.06-7.00/7.00-6.93 (m, 2H, rotameric), 6.34/6.25 (br s, 1H, rotameric), 1.92/1.91 (s, 3H, rotameric), 1.35-1.31/1.24-1.15 (m, 4H, rotameric); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 175.1/170.5 (rotameric), 161.8(4)/161.7(9) (d, J = 244.4 Hz, rotameric), 139.2/139.1 (d, J = 3.0 Hz, rotameric), 127.8/126.4 (d, J = 8.0 Hz, rotameric), 115.7/115.2 (d, J = 21.4 Hz, rotameric), 36.4/34.8 (rotameric), 23.5/21.7 (rotameric), 20.4/17.9 (rotameric); ¹⁹ F NMR (470 MHz, CD ₂ Cl ₂ ) δ -117.8(0)/-117.8(1) (rotameric); IR (cm ⁻¹ ): 3287, 3095, 3068, 2934, 1658, 1506, 1365, 1329, 1294, 1213, 1157, 1104, 1035, 1012, 824; HRMS (EI): Calculated for C ₁₁ H ₁₂ FNO [M] ⁺ : 193.0903; Found: 193.0905.

[Production Example 3] Preparation of N- (3,3-Difluorocyclobutyl)acetamide (S3)

Under an argon atmosphere, an oven-dried 50 mL round bottom flask was charged with a stirring bar, 3,3-difluorocyclobutan-1-amine hydrochloride (287 mg, 2.00 mmol, 1.0 equiv), and anhydrous dichloromethane (10 mL). The stirred solution was cooled to 0 °C and then triethylamine (557 μL, 404 mg, 4.00 mmol, 2.0 equiv) was added via syringe. While stirring at 0°C, acetyl chloride (142 μL, 157 g, 2.00 mmol, 1.0 equiv) was added dropwise through a syringe. The mixture was warmed to 23° C. over 5 minutes and then stirred at the same temperature for 4 hours. After diluting the reaction mixture with dichloromethane (25 mL), it was washed with 1N hydrochloric acid aqueous solution (10 mL × 3). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the desired compound S3 as a white solid (100 mg, 34% yield).

mp: 97-99 °C; ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 6.34 (br s, 1H), 4.29-4.11 (m, 1H), 3.06-2.86 (m, 2H), 2.60-2.39 (m, 2H), 1.93 ( s, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 170.4, 119.4 (dd, J = 280.8, 271.2 Hz), 43.2 (dd, J = 23.7, 21.9 Hz), 35.0 (dd, J = 17.1 , 7.4 Hz), 23.2; ¹⁹ F NMR (470 MHz, CD ₂ Cl ₂ ) δ -85.0 (d, J = 197.7 Hz), -97.9 (d, J = 197.7 Hz); IR (cm ⁻¹ ): 3304, 3083, 2958, 2925, 2849, 1654, 1550, 1439, 1369, 1244, 1159, 1075, 949, 896; HRMS (EI): Calculated for C ₆ H ₉ F ₂ NO [M] ⁺ : 149.0652; Found: 149.0653.

[Preparation Example 4] Preparation of 4-{2-[(Triisopropylsilyl)oxy]ethyl}pyrimidine (S4)

Stirring bar, 2-(pyrimidin-4-yl)ethan-1-ol (123 mg, 0.991 mmol, 1.0 equiv), and anhydrous N , N -dimethylformamide (4.0 mL) was filled. To the stirred solution was added imidazole (202 mg, 2.97 mmol, 3.0 equiv) at 23 °C. Then, triisopropylsilyl chloride (319 μL, 287 mg, 1.49 mmol, 1.5 equiv) was added dropwise through a syringe. The mixture was stirred at 23 °C for 4 hours. After diluting the reaction mixture with ethyl acetate (50 mL), it was washed with a saturated aqueous solution of lithium chloride (20 mL × 3). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a solvent mixture of n-hexane/ethyl acetate (100/0 to 0/100 (v/v)) to give the desired compound S4 as a colorless oil (236 mg, 85 % transference number).

¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 9.06 (d, J = 1.4 Hz, 1H), 8.56 (d, J = 5.1 Hz, 1H), 7.27 (dd, J = 5.1, 1.4 Hz, 1H), 4.08 (t, J = 6.2 Hz, 2H), 2.95 (t, J = 6.2 Hz, 2H), 1.09–0.96 (m, 21H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 168.8, 159.0, 156.6, 122.1, 62.5, 41.7, 18.1, 12.3; ²⁹ Si NMR (470 MHz, CD ₂ Cl ₂ ) δ 13.3; IR (cm ⁻¹ ): 2941, 2891, 2865, 1581, 1548, 1463, 1386, 1099, 992, 925, 881, 829; HRMS (FAB): Calculated for C ₁₅ H ₂₉ N ₂ OSi [M+H] ⁺ : 281.2044; Found: 281.2046.

[Preparation Example 5] Preparation of 5-(4-Chlorophenyl)-4-ethylpyrimidine (S5)

Stirring bar, 5-bromo-4-ethylpyrimidine (935 mg, 5.00 mmol, 1.0 equiv), (4-chlorophenyl)boronic acid (1173 mg, 7.501 mmol, 1.5 equiv), palladium in a 100 mL round bottom flask equipped with a reflux condenser. (II) Acetate (17 mg, 76 μmol, 1.5 mol%), potassium phosphate (3185 mg, 15.00 mmol, 3.0 equiv), and 50% (v/v) aqueous isopropanol (40 mL) were charged. The mixture was heated to 80° C. and stirred at the same temperature for 16 hours. The reaction mixture was cooled to 23 °C and then diluted with ethyl acetate (50 mL) and brine (50 mL). After separating the organic layer, the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a solvent mixture of n-hexane/ethyl acetate (100/0 to 0/100 (v/v)) to give the desired compound S5 as a pale yellow oil (989 mg, 90% yield).

¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 9.06 (s, 1H), 8.46 (s, 1H), 7.49-7.42 (m, 2H), 7.31-7.25 (m, 2H), 2.73 (q, J = 7.5 Hz, 2H), 1.19 (t, J = 7.5 Hz, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 169.0, 158.0, 156.6, 134.9, 134.6, 133.6, 130.8, 129.2, 28.4, 12.9; IR (cm ⁻¹ ): 3032, 2973, 2935, 2875, 1570, 1538, 1490, 1440, 1398, 1091, 999, 827, 741, 686; HRMS (FAB): Calculated for C ₁₂ H ₁₂ ClN ₂ [M+H] ⁺ : 219.0684; Found: 219.0689.

[Preparation Example 6] Preparation of 4-(Benzofuran-2-yl)pyrimidine (S6)

Stirring bar, 1-(benzofuran-2-yl)ethan-1-one (1602 mg, 10.00 mmol, 1.0 equiv), 1,3,5-triazine (1622 mg, 20.00 equiv) in a 100 mL round bottom flask equipped with a reflux condenser. mmol, 2.0 equiv), and methanol (50 mL). To the stirred mixture, triethylamine (139 μL, 101 mg, 1.00 mmol, 10 mol%) and morpholine (175 μL, 174 mg, 2.00 mmol, 20 mol%) were successively added via syringe. The mixture was heated to 90° C. and stirred at the same temperature for 72 hours. The reaction mixture was cooled to 23° C. then concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a solvent mixture of n-hexane/ethyl acetate (100/0 to 0/100 (v/v)) to give the desired compound S6 as a yellow solid (482 mg, 24 % transference number).

mp: 109-111 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 9.20 (s, 1H), 8.79 (d, J = 5.2 Hz, 1H), 7.79 (d, J = 5.1 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.42 (m, 1H), 7.30 (dd, J = 7.5, 7.5 Hz, 1H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 159.4, 158.3, 156.2, 155.7, 153.4, 128.6, 126.9, 124.0, 122.7, 116.2, 112.0, 108.6; IR (cm ⁻¹ ): 3031, 3011, 1595, 1568, 1527, 1452, 1384, 1329, 1260, 1051, 986, 925, 883, 819; HRMS (EI): Calculated for C ₁₂ H ₈ N ₂ O [M] ⁺ : 196.0637; Found: 196.0632.

[Preparation Example 7] Preparation of N- {3-[2-( tert -Butyl)-5-(pyrimidin-4-yl)thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (S7)

Stirring bar, methyl 3-{(2,6-difluorophenyl)sulfonamido}-2-fluorobenzoate (1.08 g, 3.13 mmol, 1.0 equiv), and anhydrous THF (10 mL ) was filled. After the mixture was cooled to 0° C., a THF solution of 1M LiHMDS (10.5 mL, 10.5 mmol, 3.4 equiv) was added dropwise via syringe. After the mixture was stirred at 0 °C for 10 min, a solution of 4-methylpyrimidine (343 μL, 354 mg, 3.76 mmol, 1.2 equiv) in anhydrous THF (6.0 mL) was added dropwise. The mixture was warmed to 23 °C over 1 hour. The volume of the mixture was reduced to half in vacuo, then 6N aqueous hydrochloric acid solution (10 mL) was added. After separating the aqueous layer, it was washed with ethyl acetate (10 mL). Then, the aqueous layer was basified with saturated aqueous sodium carbonate solution (15 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a solvent mixture of ethyl acetate/diethyl ether (1:1 (v/v)), transferred to an oven-dried 50 mL round bottom flask, and N , N -dimethylacetamide (20 mL ) was dissolved in To the stirred mixture was added N -chlorosuccinimide (334 mg, 2.50 mmol, 0.80 equiv) in one portion. The mixture was stirred at 23 °C for 12 h, then 2,2-dimethylpropanethioamide (293 mg, 2.50 mmol, 0.80 equiv) was added. The reaction vessel was sealed with a rubber septum, and the mixture was heated to 65° C. and stirred at the same temperature for 16 hours. The reaction mixture was cooled to 23 °C and diluted with water (50 mL) and ethyl acetate (50 mL). After separating the organic layer, the aqueous layer was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed successively with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a solvent mixture of n-hexane/ethyl acetate (100/0 to 0/100 (v/v)) to give the desired compound S7 as a brown solid (458 mg, 29 % transference number).

mp: 190-192 °C; ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 9.02 (s, 1H), 8.67 (br s, 1H), 8.36 (d, J = 5.4 Hz, 1H), 7.75-7.66 (m, 1H), 7.57 - 7.47 (m, 1H), 7.44-7.37 (m, 1H), 7.30-7.23 (m, 1H), 7.05-6.95 (m, 2H), 6.88 (d, J = 5.4 Hz, 1H), 1.47 (s , 9H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 184.1, 160.1 (dd, J = 259.0, 3.5 Hz), 159.0, 158.6, 157.1, 151.5 (d, J = 248.6 Hz), 146.7, 135.8 (t, J = 11.1 Hz), 133.6, 128.5 (d, J = 2.2 Hz), 125.6 (d, J = 4.3 Hz), 125.3 (d, J = 12.8 Hz), 124.4 (d, J = 13.8 Hz) , 124.1, 117.4 (t, J = 15.6 Hz), 117.2, 113.6 (dd, J = 23.0, 3.5 Hz), 38.5, 30.8; ¹⁹ F NMR (470 MHz, CD ₂ Cl ₂ ) δ -107.7 (d, J = 3.5 Hz), -129.2 (t, J = 3.5 Hz); IR (cm ⁻¹ ): 3171, 3067, 3031, 2966, 2927, 2817, 2763, 1611, 1579, 1464, 1392, 1355, 1276, 1172, 1070, 1002, 895, 845; HRMS (EI): Calculated for C ₂₃ H ₁₉ F ₃ N ₄ O ₂ S ₂ [M] ⁺ : 504.0902; Found: 504.0900.

[Preparation Example 8] Preparation of tert -Butyl {3-[1-isopropyl-4-(pyrimidin-4-yl)-1H - pyrazol-3-yl]phenyl}carbamate (S8)

Stirring bar, 4-(3-iodo-1-isopropyl-1 H -pyrazol-4-yl)pyrimidine (935 mg, 2.98 mmol, 1.0 equiv), [3-{( tert -butoxycarbonyl)amino}phenyl]boronic acid pinacol ester (1234 mg, 3.866 mmol, 1.3 equiv), {1,1'-bis(diphenylphosphino)ferrocene}palladium(II) dichloride (242 mg, 0.296 mmol, 10 mol%), sodium carbonate (1261 mg, 11.90 mmol, 4.0 equiv), toluene (60 mL), and water (12 mL) were charged. The mixture was heated to 80° C. and stirred at the same temperature for 2 hours. The reaction mixture was cooled to 23 °C, then diluted with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (50 mL × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a solvent mixture of n-hexane/ethyl acetate (100/0 to 0/100 (v/v)) to give the desired compound S8 as an orange solid (384 mg, 34 % transference number).

mp: 163-165 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 9.04 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.53 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.31 (dd, J = 7.8, 7.8 Hz, 1H), 7.21–7.09 (m, 3H), 4.55 (sept, J = 6.6 Hz, 1H), 1.56 (d, J = 6.6 Hz, 6H), 1.48 (s, 9H); ¹³ C{ ¹ H} NMR (150 MHz, CD ₂ Cl ₂ ) δ 159.9, 159.2, 156.8, 153.1, 150.2, 139.5, 134.8, 129.7, 129.4, 123.8, 119.2, 118.6, 118.2 (5), 118.2 (1) , 80.6, 54.8, 28.4, 23.0; IR (cm ⁻¹ ): 3239, 3038, 2975, 2932, 2874, 1722, 1581, 1390, 1365, 1236, 1154, 1055, 851; HRMS (EI): Calculated for C ₂₁ H ₂₅ N ₅ O ₂ [M] ⁺ : 379.2008; Found: 379.2006.

[Preparation Example 9] Preparation of N -Tosyl-ruxolitinib (S9)

Stirring bar, ruxolitinib (1022 mg, 3.336 mmol, 1.0 equiv), and anhydrous dichloromethane (15 mL) were charged to an oven-dried 50 mL round bottom flask under an argon atmosphere. To the stirred mixture was added triethylamine (1.53 mL, 1.11 g, 11.0 mmol, 3.3 equiv) via syringe, the mixture was cooled to 0 °C, and 4-methylbenzenesulfonyl chloride (2099 mg, 11.01 mmol, 3.3 equiv) was added. did The mixture was warmed to 23° C. over 5 minutes and then stirred at the same temperature for 16 hours. After adding dichloromethane (50 mL) and saturated aqueous ammonium chloride solution (50 mL), the organic layer was separated. The aqueous layer was extracted with dichloromethane (50 mL × 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a solvent mixture of dichloromethane/methanol (100/0 to 90/10 (v/v)) to give the desired compound S9 as a brown solid (1.23 g, 80% yield). .

mp: 72-74 °C; ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.86 (s, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 8.10-8.02 (m, 2H), 7.78 (d, J = 4.1 Hz, 1H), 7.35–7.30 (m, 2H), 6.88 (d, J = 4.1 Hz, 1H), 4.25 (ddd, J = 9.8, 8.9, 3.9 Hz, 1H), 3.11 (dd, J = 17.0, 8.9 Hz, 1H), 2.93 (dd, J = 17.0, 3.9 Hz, 1H), 2.62-2.47 (m, 1H), 2.38 (s, 3H), 1.99-1.89 (m, 1H), 1.76-1.56 (m , 3H), 1.55-1.44 (m, 2H), 1.35-1.13 (m, 2H); ¹³ C{ ¹ H} NMR (100 MHz, CD ₂ Cl ₂ ) δ 153.5, 152.4, 152.3, 146.5, 140.2, 135.2, 130.7, 130.2, 128.6, 126.9, 121.1, 117.2, 116.2, 40.4.8, 40.4.1, , 30.3, 25.8, 25.2, 23.9, 21.8; IR (cm ⁻¹ ): 3138, 3117, 3050, 2950, 2868, 2251, 1577, 1348, 1175, 1146, 1087, 981, 903, 809; HRMS (ESI): Calculated for C ₂₄ H ₂₄ N ₆ O ₂ S [M] ⁺ : 460.1681; Found: 460.1679.

[Example 1] Synthesis and separation of reaction intermediate 1

Stirring bar, pyrimidine N -oxide (192 mg, 2.00 mmol, 1.0 equiv) and anhydrous dichloromethane (10.0 mL) were charged to an oven-dried 100 mL round bottom flask under an argon atmosphere. The stirred solution was cooled to 0°C and then 3-(trifluoromethyl)pyridine (462 μL, 590 mg, 4.00 mmol, 2.0 equiv) was added via syringe. While stirring at 0 °C, trifluoromethanesulfonic anhydride (337 μL, 565 mg, 2.00 mmol, 1.0 equiv) was added dropwise through a syringe, at which time rapid precipitation was observed. The mixture was warmed to 23 °C over 5 minutes and then stirred at the same temperature for 30 minutes. The reaction mixture was filtered over a glass frit and the residue was washed with ethyl acetate (5 mL x 3) to give 560 mg of intermediate 1 as a pale yellow solid (75% yield).

mp: 199-201 °C; ¹ H NMR (400 MHz, (CD ₃ ) ₂ CO) δ 10.64-10.61 (m, 1H), 10.61-10.58 (m, 1H), 9.51 (d, J = 8.0 Hz, 1H), 9.32 (d, J = 4.8 Hz, 2H), 8.87 (dd, J = 7.2, 7.2 Hz, 1H), 8.10 (t, J = 4.8 Hz, 1H); ¹³ C{1H} NMR (125 MHz, CD ₃ CN) δ 161.6, 155.4, 148.3 (q, J = 3.0 Hz), 145.5, 140.0, 131.6 (q, J = 36.9 Hz), 130.7, 125.8, 122.4 (q , J = 272.6 Hz), 122.1 (q, J = 320.9 Hz); ¹⁹ F NMR (470 MHz, CD ₃ CN) δ -63.5, -79.3; IR (cm ⁻¹ ): 3102, 1645, 1602, 1561, 1398, 1333, 1251, 1144, 1092, 1024, 831; HRMS (FAB): Calculated for C ₁₀ H ₇ F ₃ N ₃ [M] ⁺ : 226.0587; Found: 226.0588.

Example II: Amination of N-heteroarenes

Procedure A : Use of electron-deficient pyridine derivatives

Step 1:

A pyrimidine compound (Formula 2, 0.25 mmol, 1.0 equiv) and dichloromethane (0.20 mL) were added to a 4mL vial equipped with a stirrer, and then methyltrioxorhenium (VII) (MeReO ₃ ) (3.1 mg, 0.012 mmol, 5.0 mol) was added while stirring. %) was added. 50% hydrogen peroxide aqueous solution (28 μL, 34 mg, 0.50 mmol, 2.0 equiv) was added dropwise via syringe while stirring at 23° C., and the vial was sealed with a plastic cap. After stirring at 23° C. for 6 h, the reaction mixture was diluted with dichloromethane (2 mL), dried over sodium sulfate, filtered over cotton into a 50 mL round bottom flask, and then concentrated in vacuo. A stirrer was added to the flask and the residue was dried under reduced pressure for 2 hours and then placed under argon.

Step 2:

Anhydrous dichloromethane (5.00 mL) was added to the reaction vessel under argon, and then a pyridine compound (Formula 3-1 or 3-2, 0.55 mmol, 2.2 equiv) was added dropwise through a syringe while stirring at 23 °C. Then, trifluoromethanesulfonic anhydride (44 μL, 74 mg, 0.26 mmol, 1.0 equiv) was added dropwise through a syringe. After stirring for 15 min at 23° C. under argon, the reaction mixture was transferred to a 20 mL vial and then concentrated in vacuo.

Step 3: For amination, the reaction mixture from step 2 above was subjected to two different conditions.

[Condition 1]

After adding acetonitrile (1.25mL) to the residue of step 2, 28% aqueous ammonia (1.69mL, 1.52g, 25.0mmol, 100 equiv) was added through a syringe while stirring at 23°C. The vial was sealed with a black cap and Teflon tape and then heated to 80°C. After stirring at the same temperature for 2 h, the reaction mixture was cooled to 23 °C and concentrated in vacuo. The crude heteroarylamine was purified by silica gel chromatography eluting with dichloromethane/methanol (100/0 to 90/10 (v/v)) to obtain the desired product, pyrimidin-2-amine compound (Formula 1- 1) was obtained.

** If 3-benzoylpyridine is used as an amination reagent, the reagent can be recovered in a chromatographic separation.

[Condition 2]

The residue from step 2 above was dried under reduced pressure for 1 hour, then absolute ethanol (1.25 mL) and PtO ₂ (2.9 mg, 0.013 mmol, 5.0 mol%) were added. The reaction mixture was stirred for 2 h at 23° C. under H ₂ atmosphere, then filtered through a short pad of celite and concentrated in vacuo. Dichloromethane (20 mL) was added to this residue, and the mixture was washed with saturated aqueous sodium bicarbonate solution (20 mL). The aqueous layer was extracted with dichloromethane (20 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with n-hexane/dichloromethane (100/0 to 80/20 (v/v)) to obtain the desired product, a cyclic (2-enamino)pyrimidine compound (Formula 1 -2) was obtained.

Procedure B : Use of imidoyl chloride

Step 1-a:

Heteroarene substrate (0.25 mmol, 1.0 equiv) and dichloromethane (0.20 mL) were added to a 4mL vial equipped with a stirrer, and then methyltrioxorhenium(VII) (MeReO ₃ ) (3.1 mg, 0.012 mmol, 5.0 mol%) was added while stirring. did 50% hydrogen peroxide aqueous solution (28 μL, 34 mg, 0.50 mmol, 2.0 equiv) was added dropwise via syringe while stirring at 23° C., and the vial was sealed with a plastic cap. After stirring at 23° C. for 6 h, the reaction mixture was diluted with dichloromethane (2 mL), dried over sodium sulfate, filtered over cotton into a 50 mL round bottom flask, and then concentrated in vacuo. A stirrer was added to the flask and the residue was dried under reduced pressure for 2 hours and then placed under argon. Anhydrous dichloromethane (2.5 mL) was added to the reaction vessel under argon, then the mixture was cooled to 0 °C (mixture A).

Step 1-b:

Secondary amide substrate (0.55 mmol, 2.2 equiv) and anhydrous dichloromethane (2.75 mL) were added under argon to an oven-dried 20 mL vial equipped with a stirrer and then the mixture was cooled to 0 °C. While stirring, 2,6-lutidine (64 μL, 59 mg, 0.55 mmol, 2.2 equiv) and oxalyl chloride (46 μL, 70 mg, 0.55 mmol, 2.2 equiv) were successively added dropwise through a syringe. Gas evolution was observed upon addition of oxalyl chloride. The mixture was then stirred at 0° C. for 30 min (Mixture B).

Step 2:

Mixture B was transferred via syringe into the flask containing Mixture A. Then, trifluoromethanesulfonic anhydride (44 μL, 74 mg, 0.26 mmol, 1.0 equiv) was added dropwise through a syringe at 0°C. The mixture was stirred at 0° C. under argon for 15 min.

Step 3: For amination, the reaction mixture from step 2 above was subjected to 3 different conditions.

[Condition 1]

The reaction mixture from step 2 above was diluted with dichoromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL) and warmed to 23 °C. After separating the organic layer, the aqueous layer was extracted with dichloromethane (20 mL × 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude heteroarylamine was purified by silica gel chromatography to give the desired product, a pyrimidine-2-substituted amine compound (Formula 1-3A).

[Condition 2]

The reaction mixture from step 2 was concentrated at 0 °C under reduced pressure. To the residue was added anhydrous acetonitrile (5.0 mL) and sodium borohydride (21 mg, 0.55 mmol, 2.2 equiv). The reaction vessel was sealed and the mixture was heated to 60 °C. After stirring at the same temperature for 4 hours, the reaction mixture was cooled to 23 °C and diluted with dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). After separating the organic layer, the aqueous layer was extracted with dichloromethane (20 mL × 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude heteroarylamine was purified by silica gel chromatography to give the desired product, a pyrimidine-2-substituted amine compound (Formula 1-3B).

[Condition 3]

The reaction mixture from step 2 above was diluted with saturated aqueous sodium bicarbonate solution (5 mL) and warmed to 23 °C. After separating the organic layer, the aqueous layer was extracted with dichloromethane (5 mL × 2). The combined organic layers were concentrated in vacuo. To the residue was added methanol (1.25 mL) and 2 N aqueous sodium hydroxide solution (1.25 mL). The vial was sealed with a black cap and Teflon tape and then heated to 60°C. After stirring at the same temperature for 4 hours, the reaction mixture was cooled to 23 °C and diluted with dichloromethane (20 mL) and water (20 mL). After separating the organic layer, the aqueous layer was extracted with dichloromethane (20 mL × 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude heteroarylamine was purified by silica gel chromatography to give the desired product, a pyrimidine-2-substituted amine compound (Formula 1-3C).

The format of the properties of the products prepared using the 2-amination method of pyrimidines described above is as follows: [structure of synthesized compound] [procedure used] [imine-type reagent used] [yield and identification data] ].

[Example 2] Preparation of 4-Phenylpyrimidin-2-amine (2)

[절차 A, 조건 1] [3-benzoylpyridine]

[ Procedure A , condition 1] [3-benzoylpyridine]

Yellow solid (34 mg, 80% yield); mp: 157-159 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.33 (d, J = 5.2 Hz, 1H), 8.05-8.00 (m, 2H), 7.50-7.44 (m, 3H), 7.07 (d, J = 5.2 Hz, 1H), 5.21 (br s, 2H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 165.4, 163.9, 159.2, 137.6, 130.9, 129.1, 127.3, 107.9; IR (cm ⁻¹ ): 3308, 3140, 3117, 2960, 2929, 2873, 2809, 2702, 1649, 1550, 1450, 1211, 818; HRMS (ESI): Calculated for C ₁₀ H ₁₀ N ₃ [M+H] ⁺ : 172.0869; Found: 172.0867.

After chromatographic separation, 94 mg of 3-benzoylpyridine (94% recovery) was obtained.

[Example 3] Preparation of 4-Phenyl-2-[5-(trifluoromethyl)-3,4-dihydropyridin-1(2 H )-yl]pyrimidine (3)

[절차 A, 조건 2] [3-(trifluoromethyl)pyridine]

[ procedure A , condition 2] [3-(trifluoromethyl)pyridine]

White solid (27 mg, 36% yield); mp: 98-100 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.49 (d, J = 5.2 Hz, 1H), 8.36 (s, 1H), 8.15-8.07 (m, 2H), 7.57-7.47 (m, 3H), 7.24 (d, J = 5.2 Hz, 1H), 4.07–3.97 (m, 2H), 2.31 (t, J = 5.9 Hz, 2H), 2.04 (p, J = 5.9 Hz, 2H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 164.9, 159.1, 158.9, 137.2, 131.4, 129.2, 129.0 (q, J = 7.3 Hz), 127.4, 126.1 (q, J = 268.1 Hz) , 109.3, 104.2 (q, J = 31.2 Hz), 42.3, 21.3, 20.0; ¹⁹ F NMR (376 MHz, CD ₂ Cl ₂ ) δ -65.9; IR (cm ^-1 ): 3106, 3059, 2990, 2955, 2922, 2879, 2855, 1672, 1552, 1460, 1361, 1319, 1273, 1209, 1160, 1141, 1078, 1043, 989, 80 80, 920, ; HRMS (EI): Calculated for C ₁₆ H ₁₄ F ₃ N ₃ [M] ⁺ : 305.1140; Found: 305.1137.

[Example 4] Preparation of N -Allyl- N - (4-phenylpyrimidin-2-yl) acetamide (4)

[절차 B, 조건 1] [N-acetylallylamine]

[ Procedure B , condition 1] [N-acetylallylamine]

White solid (58 mg, 91% yield); mp: 68-70 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.66 (d, J = 5.2 Hz, 1H), 8.14-8.08 (m, 2H), 7.56-7.50 (m, 3H), 7.49 (d, J = 5.2 Hz, 1H), 6.01-5.91 (m, 1H), 5.22-5.14 (m, 1H), 5.10-5.05 (m, 1H), 4.80-4.74 (m, 2H), 2.51 (s, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 172.1, 165.1, 161.5, 158.9, 136.7, 134.6, 131.7, 129.4, 127.5, 116.2, 112.5, 48.4, 26.0; IR (cm ⁻¹ ): 3078, 2963, 963, 1653, 1572, 1550, 1420, 1396, 1368, 1344, 1305, 1267, 1238, 1150, 1116, 1017, 976, 928, 891, 853; HRMS (EI): Calculated for C ₁₅ H ₁₅ N ₃ O [M] ⁺ : 253.1215; Found: 253.1211.

[Example 5] Preparation of N -Benzyl- N -methyl-4-phenylpyrimidin-2-amine (5)

[절차 B, 조건 2] [N-methylbenzamide]

[ procedure B , condition 2] [N-methylbenzamide]

Opaque oil (44 mg, 65% yield); ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.39 (d, J = 5.1 Hz, 1H), 8.12-8.05 (m, 2H), 7.50-7.44 (m, 3H), 7.34-7.28 (m, 4H) ), 7.28–7.21 (m, 1H), 6.99 (d, J = 5.1 Hz, 1H), 5.00 (s, 2H), 3.22 (s, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 164.4, 162.9, 158.8, 139.4, 138.2, 130.8, 129.0, 128.8, 127.7, 127.3, 127.2(7), 105.5, 52.7, 35.2; IR (cm ⁻¹ ): 3060, 3026, 2922, 2853, 1587, 1549, 1510, 1450, 1403, 1346, 1001, 817; HRMS (EI): Calculated for C ₁₈ H ₁₇ N ₃ [M] ⁺ : 275.1422; Found: 275.1423.

[Example 6] Preparation of N -Methyl-4-phenylpyrimidin-2-amine (6)

[절차 B, 조건 3] [N-methylacetamide]

[ Procedure B , Condition 3] [N-methylacetamide]

White solid (41.7 mg, 90% yield); mp: 93-95 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.33 (d, J = 5.1 Hz, 1H), 8.12-8.00 (m, 2H), 7.51-7.44 (m, 3H), 6.99 (d, J = 5.1 Hz, 1H), 5.26 (br s, 1H), 3.05 (d, J = 5.0 Hz, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 164.8, 163.8, 159.0, 138.0, 130.8, 129.0, 127.3, 106.6, 28.6.

[Example 7] Preparation of N ,4-Diphenylpyrimidin-2-amine (7)

[절차 B, 조건 3] [acetanilide]

[ procedure B , condition 3] [acetanilide]

White solid (53.8 mg, 87% yield); mp: 123-125 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.48 (d, J = 5.2 Hz, 1H), 8.14-8.07 (m, 2H), 7.77-7.71 (m, 2H), 7.55-7.48 (m, 3H) ), 7.41–7.29 (m, 3H), 7.21 (d, J = 5.2 Hz, 1H), 7.07–7.03 (m, 1H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 165.1, 160.8, 159.0, 140.3, 137.5, 131.2, 129.2(3), 129.2(1), 127.4, 122.6, 119.5, 108.8; IR (cm ^-1 ): 3249, 3088, 3031, 2972, 2887, 2851, 1598, 1565, 1537, 1468, 1444, 1392, 1324, 1066, 814.

[Example 8] Preparation of N -Benzyl-4-phenylpyrimidin-2-amine (8)

[절차 B, 조건 3] [N-benzylacetamide]

[ Procedure B , condition 3] [N-benzylacetamide]

White solid (32.7 mg, 50% yield); mp: 126-128 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.32 (d, J = 5.1 Hz, 1H), 8.09-8.00 (m, 2H), 7.51-7.43 (m, 3H), 7.43-7.37 (m, 2H) ), 7.37-7.30 (m, 2H), 7.30-7.23 (m, 1H), 7.02 (d, J = 5.1 Hz, 1H), 5.77 (br s, 1H), 4.72 (d, J = 6.0 Hz, 2H) ); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 164.9, 163.1, 159.1, 140.3, 137.8, 130.9, 129.0, 128.9, 127.8, 127.4, 127.3, 107.1, 45.7; IR (cm ⁻¹ ): 3247, 3061, 3028, 2947, 2897, 2851, 1588, 1564, 1493, 1444, 1408, 1352, 1324, 1133, 1067, 1027, 815.

[Example 9] Preparation of 4-Phenyl- N- (2,2,2-trifluoroethyl)pyrimidin-2-amine (9)

[절차 B, 조건 3] [S1]

[ procedure B , condition 3] [S1]

White solid (9.5 mg, 15% yield); mp: 163-165 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.39 (d, J = 5.1 Hz, 1H), 8.09-8.02 (m, 2H), 7.53-7.45 (m, 3H), 7.14 (d, J = 5.1 Hz, 1H), 5.54 (br s, 1H), 4.33–4.23 (m, 2H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 165.2, 162.3, 159.2, 137.4, 131.2, 129.1, 127.4, 125.4 (q, J = 279 Hz), 108.5, 43.1 (q, J = 34.1 Hz); ¹⁹ F NMR (376 MHz, CD ₂ Cl ₂ ) δ -73.2; IR (cm ⁻¹ ): 3248, 3118, 3087, 3060, 2984, 1567, 1461, 1440, 1420, 1328, 1261, 1137, 959, 821; HRMS (EI): Calculated for C ₁₂ H ₁₀ F ₃ N ₃ [M] ⁺ : 253.0827; Found: 253.0824.

[Example 10] Preparation of N -Cyclopropyl-4-phenylpyrimidin-2-amine (10)

[절차 B, 조건 3] [N-cyclopropyl-2-phenylacetamide]

[ Procedure B , condition 3] [ N -cyclopropyl-2-phenylacetamide]

White solid (36 mg, 69% yield); mp: 118-120 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.36 (d, J = 5.1 Hz, 1H), 8.12-8.01 (m, 2H), 7.52-7.44 (m, 3H), 7.04 (d, J = 5.1 Hz, 1H), 5.53 (br s, 1H), 2.89–2.81 (m, 1H), 0.87–0.77 (m, 2H), 0.61–0.52 (m, 2H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 164.8, 164.2, 159.0, 137.9, 130.8, 129.0, 127.3, 107.2, 24.4, 7.4; IR (cm ⁻¹ ): 3227, 3107, 3051, 3033, 2973, 1561, 1528, 1438, 1413, 1356, 1324, 1208, 1069, 1018, 823.

[Example 11] Preparation of N- (Bicyclo[1.1.1]pentan-1-yl)-4-phenylpyrimidin-2-amine (11)

[절차 B, 조건 3] [N-(bicyclo[1.1.1]pentan-1-yl)acetamide]

[ Procedure B , condition 3] [ N- (bicyclo[1.1.1]pentan-1-yl)acetamide]

White solid (40 mg, 67% yield); mp: 198-200 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.31 (d, J = 5.2 Hz, 1H), 8.10-8.03 (m, 2H), 7.51-7.45 (m, 3H), 7.04 (d, J = 5.2 Hz, 1H), 5.72 (br s, 1H), 2.51 (s, 1H), 2.21 (s, 6H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 164.7, 163.0, 159.0, 137.9, 130.8, 129.1, 127.3, 107.2, 52.8, 50.4, 25.3; IR (cm ⁻¹ ): 3219, 3159, 3097, 3041, 2973, 2911, 2868, 1555, 1525, 1434, 1410, 1322, 1276, 1203, 993, 824; HRMS (FAB): Calculated for C ₁₅ H ₁₆ N ₃ [M+H] ⁺ : 238.1339; Found: 238.1347.

[Example 12] Preparation of N- [1-(4-Fluorophenyl)cyclopropyl]-4-phenylpyrimidin-2-amine (12)

[절차 B, 조건 3] [S2]

[ procedure B , condition 3] [S2]

Slightly yellow solid (60 mg, 79% yield); mp: 129-131 °C; ^1H NMR (600 MHz, CD ₂ Cl ₂ ) δ 8.33 (d, J = 5.1 Hz, 1H), 8.03-7.96 (m, 2H), 7.49-7.42 (m, 3H), 7.40-7.25 (br s, 2H), 7.04 (d, J = 5.1 Hz, 1H), 6.98–6.92 (m, 2H), 6.14 (br s, 1H), 1.38–1.32 (m, 4H); ¹³ C{ ¹ H} NMR (150 MHz, CD ₂ Cl ₂ ) δ 164.9 (br), 163.2, 161.6 (d, J = 243.4 Hz), 159.0, 140.3 (d, J = 2.9 Hz), 137.8, 130.9, 129.1, 127.6 (br), 127.3, 115.1 (d, J = 21.3 Hz), 107.6 (br), 35.8, 19.3; ¹⁹ F NMR (564 MHz, CD ₂ Cl ₂ ) δ -118.5; IR (cm ⁻¹ ): 3219, 3060, 3034, 3013, 2970, 2929, 1562, 1508, 1435, 1407, 1278, 1218, 1153, 1024, 836, 813; HRMS (EI): Calculated for C ₁₉ H ₁₆ FN ₃ [M] ⁺ : 305.1328; Found: 305.1324.

[Example 13] Preparation of N- (3,3-Difluorocyclobutyl)-4-phenylpyrimidin-2-amine (13)

[절차 B, 조건 3] [S3]

[ procedure B , condition 3] [S3]

White solid (31 mg, 47% yield); mp: 159-161 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.35 (d, J = 5.1 Hz, 1H), 8.11-8.01 (m, 2H), 7.54-7.45 (m, 3H), 7.08 (d, J = 5.1 Hz, 1H), 5.83 (br s, 1H), 4.49–4.33 (m, 1H), 3.17–3.00 (m, 2H), 2.67–2.48 (m, 2H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 165.0, 162.5, 159.0, 137.6, 131.1, 129.1, 127.3, 119.9 (dd, J = 282.1, 270.5 Hz), 107.6, 43.6 (dd, J = 23.1, 21.3 Hz), 36.9 (dd, J = 17.8, 6.7 Hz); ¹⁹ F NMR (470 MHz, CD ₂ Cl ₂ ) δ -84.3 (d, J = 196.9 Hz), -97.7 (d, J = 197.0 Hz); IR (cm ⁻¹ ): 3259, 3088, 2993, 1566, 1535, 1422, 1284, 1234, 1156, 1057, 889, 820; HRMS (EI): Calculated for C ₁₄ H ₁₃ F ₂ N ₃ [M] ⁺ : 261.1078; Found: 261.1075.

[Example 14] Preparation of Pyrimidin-2-amine (14)

[절차 A, 조건 1] [3-benzoylpyridine]

[ Procedure A , condition 1] [3-benzoylpyridine]

White solid (16 mg, 67% yield); mp: 125-127 °C; ¹ H NMR (500 MHz, CD ₃ CN) δ 8.24 (d, J = 4.8 Hz, 2H), 6.59 (t, J = 4.8 Hz, 1H), 5.47 (br s, 2H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₃ CN) δ 164.7, 159.2, 112.0; IR (cm ^-1 ): 3324, 3159. 2955, 2922, 2852, 2778, 2681, 1644, 1555, 1471, 1355, 1222, 800.

After chromatographic separation, 88 mg of 3-benzoylpyridine (87% recovery) was obtained.

[Example 15] Preparation of 4-Cyclohexylpyrimidin-2-amine (15)

[절차 A, 조건 1] [3-benzoylpyridine]

[ Procedure A , condition 1] [3-benzoylpyridine]

White solid (23 mg, 52% yield); mp: 104-106 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.14 (d, J = 5.1 Hz, 1H), 6.48 (d, J = 5.1 Hz, 1H), 4.91 (br s, 2H), 2.47-2.40 (m , 1H), 1.90-1.78 (m, 4H), 1.76-1.69 (m, 1H), 1.49-1.31 (m, 4H), 1.30-1.22 (m, 1H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 176.4, 163.5, 158.4, 109.3, 46.4, 32.3, 26.7, 26.4; IR (cm ⁻¹ ): 3332, 3305, 3164, 2925, 2852, 1636, 1558, 1471, 1346, 1260, 1207, 806; HRMS (EI): Calculated for C ₁₀ H ₁₅ N ₃ [M] ⁺ : 177.1266; Found: 177.1264.

After chromatographic separation, 96 mg of 3-benzoylpyridine (95% recovery) was obtained.

[Example 16] Preparation of 4-Methoxypyrimidin-2-amine (16)

[절차 A, 조건 1] [3-benzoylpyridine]

[ Procedure A , condition 1] [3-benzoylpyridine]

Yellow solid (22 mg, 70% yield); mp: 108-110 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 7.97 (d, J = 5.7 Hz, 1H), 6.05 (d, J = 5.7 Hz, 1H), 5.28 (br s, 2H), 3.85 (s, 3H) ); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 170.9, 163.6, 158.4, 98.3, 53.5; IR (cm ⁻¹ ): 3439, 3319, 3150, 3130, 3084, 3011, 2998, 2957, 2861, 2794, 2733, 1649, 1564, 1461, 1340, 1294, 1240, 1023, 908, 804; HRMS (ESI): Calculated for C ₅ H ₈ N ₃ O [M+H] ⁺ : 126.0662; Found: 126.0667.

After chromatographic separation, 96 mg of 3-benzoylpyridine (95% recovery) was obtained.

[Example 17] Preparation of 4,6-Dimethylpyrimidin-2-amine (17)

[절차 A, 조건 1] [3-benzoylpyridine]

[ Procedure A , condition 1] [3-benzoylpyridine]

Yellow solid (17 mg, 55% yield); mp: 143-145 °C; ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 6.38 (s, 1H), 4.91 (br s, 2H), 2.25 (s, 6H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 168.2, 163.3, 110.8, 23.9; IR (cm ⁻¹ ): 3396, 3307, 3151, 2917, 1627, 1561, 1459, 1367, 951.

After chromatographic separation, 95 mg of 3-benzoylpyridine (94% recovery) was obtained.

[Example 18] Preparation of 2-(2-Aminopyrimidin-4-yl)ethan-1-ol (18)

[절차 A, 조건 1] [3-benzoylpyridine]

[ Procedure A , condition 1] [3-benzoylpyridine]

White solid (14 mg, 39% yield); mp: 103-105 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.16 (d, J = 5.0 Hz, 1H), 6.50 (d, J = 5.0 Hz, 1H), 5.05 (br s, 2H), 3.90 (t, J = 5.5 Hz, 2H), 3.54 (br s, 1H), 2.79 (t, J = 5.5 Hz, 2H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 170.6, 163.1, 158.7, 111.4, 61.1, 39.2; IR (cm ⁻¹ ): 3330, 3164, 2956, 2912, 2883, 2759, 2659, 1663, 1561, 1427, 1347, 1184, 1054, 868; HRMS (EI): Calculated for C ₆ H ₉ N ₃ O [M] ⁺ : 139.0746; Found: 139.0743.

After chromatographic separation, 90 mg of 3-benzoylpyridine (89% recovery) was obtained.

[Example 19] Preparation of 4-{2-[(Triisopropylsilyl)oxy]ethyl}pyrimidin-2-amine (19)

[절차 A, 조건 1] [3-benzoylpyridine]

[ Procedure A , condition 1] [3-benzoylpyridine]

White solid (38 mg, 51% yield); mp: 96-98 °C; ^1H NMR (600 MHz, CD ₂ Cl ₂ ) δ 8.12 (d, J = 5.0 Hz, 1H), 6.56 (d, J = 5.0 Hz, 1H), 5.18 (br s, 2H), 4.01 (t, J = 6.4 Hz, 2H), 2.76 (t, J = 6.4 Hz, 2H), 1.11–0.96 (m, 21H); ¹³ C{ ¹ H} NMR (150 MHz, CD ₂ Cl ₂ ) δ 169.9, 163.6, 158.0, 112.1, 62.6, 41.7, 18.1, 12.4; ²⁹ Si NMR (80 MHz, CD ₂ Cl ₂ ) δ 13.0; IR (cm ⁻¹ ): 3326, 3164, 2940, 2889, 2864, 2742, 1659, 1567, 1459, 1342, 1223, 1090, 1013, 880, 830; HRMS (EI): Calculated for C ₁₅ H ₂₉ N ₃ OSi [M] ⁺ : 295.2080; Found: 295.2083.

After chromatographic separation, 97 mg of 3-benzoylpyridine (96% recovery) was obtained.

[Example 20] Preparation of N -Methyl- N -(4-phenylpyrimidin-2-yl)acetamide (20)

[절차 B, 조건 1] [N-methylacetamide]

[ Procedure B , condition 1] [N-methylacetamide]

White solid (49 mg, 86% yield); mp: 107-109 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.67 (d, J = 5.2 Hz, 1H), 8.14-8.09 (m, 2H), 7.56-7.50 (m, 3H), 7.48 (d, J = 5.2 Hz, 1H), 3.52 (s, 3H), 2.51 (s, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 172.6, 165.0, 162.1, 158.8, 136.7, 131.6, 129.4, 127.5, 112.3, 33.6, 26.0; IR (cm ⁻¹ ): 3077, 2928, 1677, 1572, 1543, 1448, 1365, 1325, 1294, 1168, 979, 859; HRMS (EI): Calculated for C ₁₃ H ₁₃ N ₃ O [M] ⁺ : 227.1059; Found: 227.1054.

[Example 21] Preparation of N -Methyl- N -(pyrimidin-2-yl)acetamide (21)

[절차 B, 조건 1] [N-methylacetamide]

[ Procedure B , condition 1] [N-methylacetamide]

Slightly yellow solid (24 mg, 65% yield); mp: 49-51 °C; ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.62 (d, J = 4.8 Hz, 2H), 7.04 (dd, J = 4.8, 4.8 Hz, 1H), 3.42 (s, 3H), 2.39 (s, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 172.4, 161.9, 158.1, 118.9, 33.6, 25.7; IR (cm ⁻¹ ): 3133, 3087, 3046, 2994, 2942, 2856, 1664, 1561, 1434, 1394, 1320, 1259, 1158, 981, 937, 813; HRMS (ESI): Calculated for C ₇ H ₁₀ N ₃ O [M+H] ⁺ : 152.0818; Found: 152.0805.

[Example 22] Preparation of N -Methyl- N -(4-methylpyrimidin-2-yl)acetamide (22)

[절차 B, 조건 1] [N-methylacetamide]

[ Procedure B , condition 1] [N-methylacetamide]

Yellow solid (30 mg, 72% yield); mp: 61-63 °C; ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.46 (d, J = 4.9 Hz, 1H), 6.91 (d, J = 4.9 Hz, 1H), 3.41 (s, 3H), 2.48 (s, 3H) , 2.38 (3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 172.5, 168.7, 161.8, 157.6, 116.5, 33.6, 25.6, 24.2; IR (cm ⁻¹ ): 3078, 3005, 2958, 2918, 2850, 1672, 1582, 1555, 1437, 1361, 1322, 1256, 1200, 1168, 1021, 982, 838; HRMS (ESI): Calculated for C ₈ H ₁₂ N ₃ O [M+H] ⁺ : 166.0975; Found: 166.0976.

[Example 23] Preparation of N- (4-Methoxypyrimidin-2-yl) -N -phenylacetamide (23)

[절차 B, 조건 1] [acetanilide]

[ procedure B , condition 1] [acetanilide]

Creamy solid (40 mg, 66% yield); ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.29 (d, J = 5.7 Hz, 1H), 7.45-7.39 (m, 2H), 7.36-7.31 (m, 1H), 7.25-7.19 (m, 2H) ), 6.52 (d, J = 5.7 Hz, 1H), 3.87 (s, 3H), 2.45 (s, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 172.1, 170.6, 161.3, 158.4, 142.0, 129.4, 129.0, 127.7, 104.8, 54.3, 25.7; HRMS (ESI): Calculated for C ₁₃ H ₁₄ N ₃ O ₂ [M+H] ⁺ : 244.1081; Found: 244.1073.

[Example 24] Preparation of N- (4,6-Dimethylpyrimidin-2-yl) -N -methylacetamide (24)

[절차 B, 조건 1] [N-methylacetamide]

[ Procedure B , condition 1] [N-methylacetamide]

Slightly yellow solid (33 mg, 73% yield); mp: 68-70 °C; ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 6.79 (s, 1H), 3.38 (s, 3H), 2.42 (s, 6H), 2.35 (s, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 172.5, 168.1, 161.6, 115.9, 33.6, 25.5, 24.0; IR (cm ⁻¹ ): 3075, 2999, 2958, 2922, 2852, 1665, 1590, 1422, 1365, 1321, 1199, 1028, 865; HRMS (EI): Calculated for C ₉ H ₁₃ N ₃ O [M] ⁺ : 179.1059; Found: 179.1060.

[Example 25] Preparation of N -Methyl- N -[4-(pyridin-3-yl)pyrimidin-2-yl]acetamide (25)

In step 1, trifluoromethanesulfonic acid (22 μL, 37 mg, 0.25 mmol, 1.0 equiv) was added to the reaction mixture to achieve selective oxidation of the pyrimidine ring.

[절차 B, 조건 1] [N-methylacetamide]

[ Procedure B , condition 1] [N-methylacetamide]

Slightly yellow solid (18 mg, 32% yield); mp: 143-145 °C; ^1H NMR (600 MHz, CD ₂ Cl ₂ ) δ 9.29 (s, 1H), 8.73 (d, J = 4.7 Hz, 1H), 8.72 (d, J = 5.2 Hz, 1H), 8.39 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 5.2 Hz, 1H), 7.46 (dd, J = 4.7, 7.9 Hz, 1H), 3.53 (s, 3H), 2.52 (s, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 172.7, 162.9, 162.2, 159.2, 152.3, 149.0, 134.8, 132.4, 124.1, 112.3, 33.6, 26.2; IR (cm ⁻¹ ): 3076, 2960, 2921, 2851, 1676, 1572, 1544, 1433, 1366, 1340, 1296, 1259, 1167, 1022, 980, 861; HRMS (EI): Calculated for C ₁₂ H ₁₂ N ₄ O [M] ⁺ : 228.1011; Found: 228.1012.

[Example 26] Preparation of N- [5-(4-Chlorophenyl)-4-ethylpyrimidin-2-yl] -N- methylacetamide (26)

[절차 B, 조건 1] [N-methylacetamide]

[ Procedure B , condition 1] [N-methylacetamide]

White solid (35 mg, 49% yield); mp: 64-66 °C; ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.39 (s, 1H), 7.49-7.45 (m, 2H), 7.30-7.27 (m, 2H), 3.48 (s, 3H), 2.73 (q, J = 7.5 Hz, 2H), 2.47 (s, 3H), 1.22 (t, J = 7.5 Hz, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 172.6, 170.0, 160.9, 157.6, 134.8, 134.5, 131.0, 129.3, 128.8, 33.6, 28.6, 26.0, 12.6; IR (cm ⁻¹ ): 2969, 2934, 2872, 1901, 1665, 1579, 1540, 1441, 1368, 1310, 1259, 1159, 1086, 1019, 974, 828, 721, 648; HRMS (EI): Calculated for C ₁₅ H ₁₆ ClN ₃ 0 [M] ⁺ : 289.0982; Found: 289.0979.

[Example 27] Preparation of ( E ) -N- [4-(4-Chlorostyryl)pyrimidin-2-yl] -N -methylacetamide (27)

[절차 B, 조건 1] [N-methylacetamide]

[ Procedure B , condition 1] [N-methylacetamide]

White solid (31 mg, 43% yield); mp: 108-110 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.58 (d, J = 5.1 Hz, 1H), 7.84 (d, J = 15.9 Hz, 1H), 7.59-7.55 (m, 2H), 7.42-7.38 ( m, 2H), 7.07-7.02 (m, 2H), 3.48 (s, 3H), 2.46 (s, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 172.6, 163.2, 161.9, 159.8, 136.3, 135.5, 134.6, 129.5, 129.3, 126.5, 114.7, 33.7, 25.9; IR (cm ⁻¹ ): 3059, 2923, 1668, 1571, 1541, 1454, 1382, 1329, 1165, 1085, 966, 830, 689, 638, 602; HRMS (EI): Calculated for C ₁₅ H ₁₄ ClN ₃ 0 [M] ⁺ : 287.0825; Found: 287.0827.

[Example 28] Preparation of N- [4-(benzofuran-2-yl)pyrimidin-2-yl] -N- methylacetamide (28)

[절차 B, 조건 1] [N-methylacetamide]

[ Procedure B , condition 1] [N-methylacetamide]

White solid (54 mg, 81% yield); mp: 117-119 °C; ^1H NMR (600 MHz, CD ₂ Cl ₂ ) δ 8.71 (d, J = 4.9 Hz, 1H), 7.73-7.69 (m, 1H), 7.63 (s, 1H), 7.61-7.57 (m, 1H), 7.53 (d, J = 4.9 Hz, 1H), 7.46–7.40 (m, 1H), 7.35–7.29 (m, 1H), 3.51 (s, 3H), 2.53 (s, 3H); ¹³ C{ ¹ H} NMR (150 MHz, CD ₂ Cl ₂ ) δ 172.6, 161.9, 159.3, 156.5, 156.2, 153.4, 128.6, 127.1, 124.1, 122.8, 112.1, 111.2, 109.0, 36.1, 23.6; IR (cm ⁻¹ ): 3114, 3067, 2937, 2855, 1673, 1602, 1569, 1534, 1431, 1384, 1326, 1203, 1179, 1124, 983, 842, 809; HRMS (EI): Calculated for C ₁₅ H ₁₃ N ₃ O ₂ [M] ⁺ : 267.1008; Found: 267.1010.

[Example 29] Preparation of N- [2-( N -Methylacetamido)pyrimidin-4-yl]benzamide (29)

[절차 B, 조건 1] [N-methylacetamide]

[ Procedure B , condition 1] [N-methylacetamide]

White solid (57 mg, 84% yield); mp: 144-146 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.74 (br s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 5.6 Hz, 1H), 7.97-7.92 (m , 2H), 7.66-7.61 (m, 1H), 7.58-7.51 (m, 2H), 3.41 (s, 3H), 2.41 (s, 3H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 172.5, 166.5, 161.4, 159.7, 158.5, 133.7, 133.3, 129.3, 127.8, 105.9, 33.7, 25.8; IR (cm ⁻¹ ): 3563, 3213, 3154, 3062, 2924, 2851, 1683, 1573, 1510, 1391, 1296, 1258, 1105, 990, 890, 843; HRMS (EI): Calculated for C ₁₄ H ₁₄ N ₄ O ₂ [M] ⁺ : 270.1117; Found: 270.1115.

[Example 30] Preparation of Dabrafenib (30)

[절차 A, 조건 1] [3-(trifluoromethyl)pyridine]

[ Procedure A , Condition 1] [3-(trifluoromethyl)pyridine]

Light brown solid (77 mg, 59% yield); mp: 217-219 °C; ¹ H NMR (500 MHz, CD ₂ Cl ₂ ) δ 7.88 (d, J = 5.3 Hz, 1H), 7.70-7.64 (m, 1H), 7.53-7.46 (m, 1H), 7.39-7.34 (m, 1H) ), 7.23 (dd, J = 7.9 Hz, 1H), 7.01–6.95 (m, 2H), 6.16 (d, J = 5.3 Hz, 1H), 5.28 (br s, 2H), 1.44 (s, 9H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 183.2, 163.2, 160.1 (dd, J = 258.9, 3.5 Hz), 159.6, 158.5, 152.0 (d, J = 248.6 Hz), 146.0, 135.8 (t, J = 11.2 Hz), 134.3, 129.0 (d, J = 2.3 Hz), 125.3 (d, J = 4.5 Hz), 124.8(4), 124.8(1) (d, J = 12.2 Hz), 124.7 (9) (d, J = 11.5 Hz), 117.4 (t, J = 15.7 Hz), 113.5 (dd, J = 22.9, 3.6 Hz), 107.6, 38.4, 30.8; ¹⁹ F NMR (376 MHz, CD ₂ Cl ₂ ) δ -107.6 (d, J = 4.0 Hz), -129.1 (t, J = 4.0 Hz); IR (cm ⁻¹ ): 3530, 3417, 3081, 2962, 2871, 1607, 1572, 1460, 1352, 1275, 1235, 1173, 999.

[Example 31] Preparation of Encorafenib analog (31)

In step 1 MeReO ₃ (20 mol %) and aq. H ₂ O ₂ (4.0 equiv) was used.

[절차 B, 조건 1] [N-(bicyclo[1.1.1]pentan-1-yl)acetamide]

[ Procedure B , condition 1] [ N- (bicyclo[1.1.1]pentan-1-yl)acetamide]

White solid (29 mg, 23% yield, 32% brsm); mp: 83-85 °C; ^1H NMR (600 MHz, CD ₂ Cl ₂ ) δ 8.43 (d, J = 4.9 Hz, 1H), 8.13 (s, 1H), 7.55 (s, 1H), 7.49-7.42 (m, 1H), 7.38- 7.31 (m, 1H), 7.22-7.15 (m, 1H), 7.02 (d, J = 4.9 Hz, 1H), 6.76 (br s, 1H), 4.56 (sep, 6.5 Hz, 1H), 2.44 (s, 1H), 2.16 (s, 6H), 1.99 (s, 3H), 1.58 (d, J = 6.5 Hz, 6H) (overlap with the signal of residual water), 1.49 (s, 9H); ¹³ C{ ¹ H} NMR (150 MHz, CD ₂ Cl ₂ ) δ 171.4, 161.8, 160.7, 158.6, 153.0, 150.4, 139.4, 134.9, 129.9, 129.5, 123.9, 119.4, 118.7, 115.0, 117.9, , 53.7, 30.1, 28.4, 25.1, 24.4, 23.0; IR (cm ⁻¹ ): 3275, 2976, 2917, 2879, 1722, 1661, 1576, 1554, 1514, 1366, 1335, 1235, 1156, 1066, 1050, 853; HRMS (FAB): Calculated for C ₂₈ H ₃₅ N ₆ O ₃ [M+H] ⁺ : 503.2765; Found: 503.2774.

After chromatographic separation, 26 mg of S8 (28% recovery) was obtained.

[Example 32] Preparation of Ruxolitinib derivative (32)

After N-oxidation of S9 (428 mg, 0.928 mmol) under standard conditions, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a solvent mixture of dichloromethane/methanol (100/0 to 90/10 (v/v)) to give 131 mg of an unknown N-oxide (0.275 mmol, 30% yield). Obtained as a yellow solid, yielding 124 mg of S11 (29% recovery). The obtained N -oxide was directly applied to Procedure B.

[절차 B, 조건 1] [N-methylacetamide]

[ Procedure B , condition 1] [N-methylacetamide]

White solid (99 mg, 68% yield from N -oxide); mp: 93-95 °C; ^1H NMR (500 MHz, CD ₂ Cl ₂ ) δ 8.26 (s, 1H), 8.24 (s, 1H), 8.03-7.98 (m, 2H), 7.73 (d, J = 4.1 Hz, 1H), 7.36 - 7.31 (m, 2H), 6.86 (d, J = 4.1 Hz, 1H), 4.26 (ddd, J = 3.7, 9.6, 9.6 Hz, 1H), 3.50 (s, 3H), 3.13 (dd, J = 9.1, 17.1 Hz, 1H), 2.95 (dd, J = 3.7, 17.1 Hz, 1H), 2.60-2.49 (m, 1H), 2.46 (s, 3H), 2.39 (s, 3H), 1.98-1.89 (m, 1H) ), 1.77-1.43 (m, 5H), 1.33-1.24 (m, 1H), 1.24-1.14 (m, 1H); ¹³ C{ ¹ H} NMR (125 MHz, CD ₂ Cl ₂ ) δ 172.5, 157.4, 153.0, 152.5, 146.6, 140.4, 135.1, 130.9, 130.2, 128.5, 126.4, 120.9, 117.2, 144.8, 114.8, , 34.0, 30.4, 30.3, 25.8, 25.7, 25.1, 23.8, 21.8; IR (cm ⁻¹ ): 3136, 3116, 2946, 2868, 2248, 1664, 1571, 1511, 1443, 1367, 1174, 1143, 1088, 1006, 976, 806; HRMS (EI): Calculated for C ₂₇ H ₂₉ N ₇ O ₃ S [M] ⁺ : 531.2053; Found: 531.2056.

The above description of the present invention is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, the embodiments described above should be understood as illustrative in all respects and not limiting.

Claims (19)

1) preparing a pyrimidine-N-oxide intermediate by catalytically oxidizing a pyrimidine compound represented by Formula 2 below;
2) Following step 1), the pyrimidine-N-oxide intermediate was activated in situ in the presence of trifluoromethanesulfonic anhydride and reacted with a pyridine reagent of Formula 3-1 to obtain pyrimidine-2-pyridinium preparing a salt; and
3) following step 2), preparing a pyrimidin-2-amine compound represented by Formula 1-1 by aminolysis of the pyrimidine-2-pyridinium salt;
Method for producing a pyrimidine-2-amine compound, wherein steps 1) and 2) are performed as an in-situ continuous process without a separation process:
[Formula 1-1]

[Formula 2]

[Formula 3-1]

In Formulas 1-1, 2 and 3-1,
R ₁ , R ₂ and R ₃ are each independently hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C1-C20 alkoxy, C2-C20 alkenyl, C3-C20 heteroaryl or -NR' C(=O)Ar ₁ , or R ₁ to R ₃ may be linked to adjacent substituents to form a ring;
R ₄ is haloC1-C20 alkyl, cyano, C1-C20 alkylcarbonyl or C6-C20 arylcarbonyl;
R' is hydrogen or C1-C20 alkyl;
Ar ₁ is C6-C20 aryl or C3-C20 heteroaryl;
Alkyl, cycloalkyl, aryl, alkoxy, alkenyl and heteroaryl of R ₁ to R ₃ are C1-C20 alkyl, halogen, C1-C20 alkoxy hydroxy, C6-C20 aryl, haloC6-C20 aryl, -OSiR _a1 may be further substituted with one or more selected from R _a2 R _a3 , -L ₁ -NR _b1 -L ₂ -R _b2 and -CHR _c1 R _c2 ;
R _a1 , R _a2 and R _a3 are each independently C1-C20 alkyl, C3-C20 cycloalkyl or C6-C20 aryl;
L ₁ is C6-C20 arylene or haloC6-C20 arylene, L ₂ is SO ₂ or C=O;
R _b1 is hydrogen or C1-C20 alkyl;
R _b2 is C1-C20 alkoxy, C6-C20 aryl or haloC6-C20 aryl;
R _c1 is C3-C20 cycloalkyl;
R _c2 is -L ₃ -R _d1 , L ₃ is C1-C20 alkylene and R _d1 is cyano, halogen or nitro. According to claim 1,
The catalytic oxidation in step 1) is carried out in the presence of an oxidizing agent and methyltrioxorenium (MeReO ₃ ), a manufacturing method. According to claim 2,
The methyltrioxorenium (MeReO ₃ ) is used in an amount of 1.0 to 30.0 mol% based on the pyrimidine compound of Formula 2, the manufacturing method. According to claim 2,
Wherein the oxidizing agent is hydrogen peroxide or a hydrogen peroxide adduct. According to claim 2,
The oxidizing agent is used in an amount of 1 to 5 equivalents relative to the pyrimidine compound of Formula 2, the preparation method. According to claim 1,
In step 2), trifluoromethanesulfonic anhydride is used in an amount of 1 to 3 equivalents relative to the pyrimidine compound of Formula 2. According to claim 1,
In step 2), the pyridine reagent of Formula 3-1 is used in an amount of 2 to 3 equivalents relative to the pyrimidine compound of Formula 2. According to claim 1,
In step 3), aminolysis is performed in the presence of aqueous ammonia. 1) preparing a pyrimidine-N-oxide intermediate by catalytically oxidizing a pyrimidine compound represented by Formula 2 below;
2) Following step 1), the pyrimidine-N-oxide intermediate was activated in situ in the presence of trifluoromethanesulfonic anhydride and reacted with a pyridine reagent of Formula 3-2 to obtain pyrimidine-2-pyridinium preparing a salt; and
3) following step 2), partially reducing the pyrimidine-2-pyridinium salt to prepare a cyclic (2-enamino)pyrimidine compound of Formula 1-2;
Method for preparing a cyclic (2-enamino) pyrimidine compound, wherein steps 1) and 2) are performed as an in-situ continuous process without a separation process:
[Formula 1-2]

[Formula 2]

[Formula 3-2]

In Formulas 1-2, 2 and 3-2,
R ₁ , R ₂ and R ₃ are each independently hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C1-C20 alkoxy, C2-C20 alkenyl, C3-C20 heteroaryl or -NR' C(=O)Ar ₁ , or R ₁ to R ₃ may be linked to adjacent substituents to form a ring;
R ₅ is haloC1-C20 alkyl, cyano, C1-C20 alkylcarbonyl or C6-C20 arylcarbonyl;
R' is hydrogen or C1-C20 alkyl;
Ar ₁ is C6-C20 aryl or C3-C20 heteroaryl;
Alkyl, cycloalkyl, aryl, alkoxy, alkenyl and heteroaryl of R ₁ to R ₃ are C1-C20 alkyl, halogen, C1-C20 alkoxy hydroxy, C6-C20 aryl, haloC6-C20 aryl, -OSiR _a1 may be further substituted with one or more selected from R _a2 R _a3 , -L ₁ -NR _b1 -L ₂ -R _b2 and -CHR _c1 R _c2 ;
R _a1 , R _a2 and R _a3 are each independently C1-C20 alkyl, C3-C20 cycloalkyl or C6-C20 aryl;
L ₁ is C6-C20 arylene or haloC6-C20 arylene, L ₂ is SO ₂ or C=O;
R _b1 is hydrogen or C1-C20 alkyl;
R _b2 is C1-C20 alkoxy, C6-C20 aryl or halo C6-C20 aryl;
R _c1 is C3-C20 cycloalkyl;
R _c2 is -L ₃ -R _d1 , L ₃ is C1-C20 alkylene and R _d1 is cyano, halogen or nitro. According to claim 9,
In step 2), the pyridine reagent of Formula 3-2 is used in an amount of 2 to 3 equivalents relative to the pyrimidine compound of Formula 2. According to claim 9,
The partial reduction in step 3) is carried out in the presence of hydrogen gas and PtO ₂ , a manufacturing method. According to claim 11,
Wherein the PtO ₂ is used in an amount of 1.0 to 20.0 mol% based on the pyrimidine compound of Formula 2. 1) preparing a pyrimidine-N-oxide intermediate by catalytically oxidizing a pyrimidine compound represented by Formula 2 below;
2) Following step 1), the pyrimidine-N-oxide intermediate was reacted with an imidoyl chloride compound of Formula 4-1 in the presence of trifluoromethanesulfonic anhydride to prepare a pyrimidine-2-iminium salt doing; and
3) following step 2), preparing a pyrimidine-2-substituted amine compound of Formula 1-3 by treating, reducing or hydrolyzing the pyrimidine-2-iminium salt with sodium bicarbonate; but
Method for preparing a pyrimidine-2-substituted amine compound, wherein steps 1) and 2) are performed in an in-situ continuous process without a separation process:
[Formula 1-3]

[Formula 2]

[Formula 4-1]

In Formulas 1-3, 2 and 4-1,
R ₁ , R ₂ and R ₃ are each independently hydrogen, C1-C20 alkyl, C3-C20 cycloalkyl, C6-C20 aryl, C1-C20 alkoxy, C2-C20 alkenyl, C3-C20 heteroaryl or -NR' C(=O)Ar ₁ , or R ₁ to R ₃ may be linked to adjacent substituents to form a ring;
R″ is hydrogen, -C(=0)R ₁₂ or -CH ₂ R ₁₂ ;
R ₁₁ is C1-C20 alkyl, C6-C20 aryl, allyl, haloC1-C20 alkyl, C6-C20 arylC1-C20 alkyl or C3-C20 cycloalkyl, wherein said cycloalkyl is halogen, haloC1-C20 alkyl and halo may be further substituted with one or more selected from C6-C20 aryl;
R ₁₂ is C1-C20 alkyl or C6-C20 aryl;
R ₄ is haloC1-C20 alkyl, C1-C20 alkylcarbonyl or C6-C20 arylcarbonyl;
R' is hydrogen or C1-C20 alkyl;
Ar ₁ is C6-C20 aryl or C3-C20 heteroaryl;
Alkyl, cycloalkyl, aryl, alkoxy, alkenyl and heteroaryl of R ₁ to R ₃ are C1-C20 alkyl, halogen, C1-C20 alkoxy hydroxy, C6-C20 aryl, haloC6-C20 aryl, -OSiR _a1 may be further substituted with one or more selected from R _a2 R _a3 , -L ₁ -NR _b1 -L ₂ -R _b2 and -CHR _c1 R _c2 ;
R _a1 , R _a2 and R _a3 are each independently C1-C20 alkyl, C3-C20 cycloalkyl or C6-C20 aryl;
L ₁ is C6-C20 arylene or haloC6-C20 arylene, L ₂ is SO ₂ or C=O;
R _b1 is hydrogen or C1-C20 alkyl;
R _b2 is C1-C20 alkoxy, C6-C20 aryl or halo C6-C20 aryl;
R _c1 is C3-C20 cycloalkyl;
R _c2 is -L ₃ -R _d1 , L ₃ is C1-C20 alkylene and R _d1 is cyano, halogen or nitro. According to claim 13,
An imidoyl chloride compound of Formula 4-1 is prepared by reacting an amide compound of Formula 4 with oxalyl chloride in the presence of an organic base.
[Formula 4]

In Formula 4, R ₁₁ and R ₁₂ are the same as defined in claim 13. According to claim 13,
In step 2), trifluoromethanesulfonic anhydride is used in an amount of 1.0 to 3.0 equivalents relative to the pyrimidine compound of Formula 2. According to claim 13,
In step 2), the imidoyl chloride compound of Formula 4-1 is used in an amount of 2.0 to 3.0 equivalents relative to the pyrimidine compound of Formula 2. According to claim 13,
Step 3) is a step of preparing a pyrimidine-2-amide compound of Formula 1-3A by treating with sodium bicarbonate.
[Formula 1-3A]

In Formula 1-3A, R ₁ to R ₃ , R ₁₁ and R ₁₂ are the same as defined in claim 13. According to claim 13,
In step 3), sodium triacetoxyborohydride (Na(CH ₃ COO) ₃ BH), sodium borohydride (NaBH ₄ ), sodium cyanoborohydride (NaBH ₃ CN), zinc borohydride (Zn (BH ₄ ) ₂ ), lithium aluminum hydride (LiAlH ₄ ) and lithium cyanoborohydride (LiBH ₃ CN) to obtain a pyrimidine-2-disubstituted amine compound of Formula 1-3B by treatment with a reducing agent selected from A manufacturing step, a manufacturing method.
[Formula 1-3B]

In Formula 1-3B, R ₁ to R ₃ , R ₁₁ and R ₁₂ are the same as defined in claim 13. According to claim 13,
Step 3) is a step of preparing a pyrimidine-2-monosubstituted amine compound of formula 1-3C by treatment with methanol and sodium hydroxide.
[Formula 1-3C]

In Formula 1-3C, R ₁ to R ₃ and R ₁₁ are the same as defined in claim 13.