KR102660894B1 - Method for producing pyrimidin-2-amine - Google Patents

Abstract

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

Description

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

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

N-heteroaryl amine is an important molecular framework that exists in many molecules that exhibit various biological activities or medicinal effects. In particular, 2-aminopyrimidine is a key structural motif that is widespread in bioactive molecules. However, it is difficult to introduce an amine functional group to carbon 2 of pyrimidine through direct functionalization.

Since 29 of the 100 best-selling small molecule drugs in 2020 are N-heteroaryl amines, the selective and efficient preparation of aminated N-heteroarenes can facilitate the discovery of biologically active molecules. Frequently used approaches for the synthesis of N-heteroaryl amines include nucleophilic aromatic substitution and transition-metal-mediated cross-coupling. Direct carbon-hydrogen (C-H) functionalization involves inherent problems in controlling selectivity due to the localization of C-H bonds in organic molecules, but can be an attractive alternative because it does not require prior pre-functionalization of the substrate. Regioselective heteroarene C-H amination reactions allow rapid access to synthetic intermediates. Strategies such as C–H metalation, 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.

In fact, the Chichibabin reaction and aromatic nitration are representative approaches for the C2- and C3-selective amination of pyridines, respectively, and the 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 important backbones 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 pyrimidin-2-amine through C2-selective amination of pyrimidine, which acts as an important structural core motif in medicine, pesticides, and various chemical fields.

Adv. Heterocycle. 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 amminate C2 of pyrimidines, the present inventors have discovered that all types of pyrimidines can be produced through a combination of activated pyrimidines and nucleophilic imine-type reagents (electron-deficient pyridine compounds or imidoyl chloride compounds). Pyridinyl-2-iminium salts that can serve as branch points for subsequent conversion to -2-amines (1°, 2°, and 3° amine forms) are synthesized and amine derivatized. It was confirmed that the pyrimidin-2-amine compound was synthesized.

The object of the present invention is 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. .

The object of the present invention is to provide a method for producing pyrimidin-2-amine compounds that can be usefully used as core structures in various fields such as medicine and pesticides.

The present invention provides a method for producing a pyrimidin-2-amine compound, in which various amino functional groups are selectively added to the 2-position of pyrimidine through a pyrimidine-2-iminium salt intermediate using a nucleophilic imine type reagent. It includes a method of producing a pyrimidin-2-amine compound introduced into the method.

One aspect of the present invention includes the steps of 1) preparing a pyrimidine-N-oxide intermediate by catalytic oxidation of a pyrimidine compound of the following formula (2); 2) Following step 1), the pyrimidine-N-oxide intermediate is activated in situ in the presence of trifluoromethanesulfonic anhydride (Tf ₂ O) and reacted with the pyridine reagent of the following formula 3-1 to produce pyrimidine. -Preparing 2-pyridinium salt; and 3) following step 2), aminoly decomposing the pyrimidine-2-pyridinium salt to prepare a pyrimidin-2-amine compound of the following formula 1-1, including 1) and 2) above. Provided is a method for producing a pyrimidin-2-amine compound, wherein the steps are carried out in a continuous process in-situ 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 connected to adjacent substituents to form a ring;

R ₄ is haloC1-C20alkyl, cyano, C1-C20alkylcarbonyl or C6-C20arylcarbonyl;

R' is hydrogen or C1-C20 alkyl;

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

The 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 any 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 includes the steps of 1) preparing a pyrimidine-N-oxide intermediate by catalytic oxidation of a pyrimidine compound of the following formula (2); 2) Following step 1), the pyrimidine-N-oxide intermediate is activated in situ in the presence of trifluoromethanesulfonic anhydride (Tf ₂ O) and reacted with a pyridine reagent of the following formula 3-2 to produce pyrimidine. -Preparing 2-pyridinium salt; and 3) following step 2), partial reduction of the pyrimidine-2-pyridinium salt to prepare a cyclic (2-enamino)pyrimidine compound of the following formula 1-2; And 2) provides a method for producing a cyclic (2-enamino) pyrimidine compound, in which step is carried out in a continuous process in-situ 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 connected to adjacent substituents to form a ring;

R ₅ is haloC1-C20alkyl, cyano, C1-C20alkylcarbonyl or C6-C20arylcarbonyl;

R' is hydrogen or C1-C20 alkyl;

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

The 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 any 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 includes the steps of 1) preparing a pyrimidine-N-oxide intermediate by catalytic oxidation of a pyrimidine compound of the following formula (2); 2) Following step 1), the pyrimidine-N-oxide intermediate is reacted with the imidoyl chloride compound of the following formula 4-1 in the presence of trifluoromethanesulfonic anhydride (Tf ₂ O) to produce pyrimidine-2- Preparing an iminium salt; and 3) following step 2), treating the pyrimidine-2-iminium salt with sodium bicarbonate, reducing or hydrolyzing it to prepare a pyrimidine-2-substituted amine compound of the following formula 1-3; Provided is a method for producing 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 connected to adjacent substituents to form a ring;

R'' is hydrogen, -C(=O)R ₁₂ or -CH ₂ R ₁₂ ;

R ₁₁ is C1-C20 alkyl, C6-C20 aryl, allyl, halo C1-C20 alkyl, C6-C20 aryl C1-C20 alkyl or C3-C20 cycloalkyl, and the cycloalkyl is halogen, halo C1-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-C20alkyl, C1-C20alkylcarbonyl or C6-C20arylcarbonyl;

R' is hydrogen or C1-C20 alkyl;

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

The 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 any 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-C20alkyl;

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, the pyrimidine-2-iminium salt intermediate produced by reacting an electron-deficient pyridine compound or imidoyl chloride compound with a pyrimidine activated with a nucleophilic imine reagent is used to form pyrimidine. 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 provides a synthetic handle for divergent synthesis of 2-aminopyrimidine by converting pyrimidine to pyrimidine-2-iminium salt. can be provided.

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 mass production of pyrimidin-2-amine compounds from pyrimidine is possible, making it highly commercially available.

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. Unless otherwise defined, the technical and scientific terms used herein have meanings commonly understood by those skilled in the art to which this invention pertains, and the following description will not unnecessarily obscure the gist of the present invention. Descriptions of possible notification functions and configurations are omitted.

Throughout this specification, unless otherwise required by context, the references to “comprise” and “comprising” include a given step or element, or group of steps or elements, but any other step or element, or It should be understood that this implies that no step or group of components is excluded.

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

In this specification, “C _A -C _B ” means “carbon number is A or more and B or less.”

In this specification, “substitution” means changing a hydrogen atom bonded to a carbon atom of a compound to another substituent, and the position to be substituted is not limited as long as it is the position where the hydrogen atom is substituted, that is, a position where the substituent can be substituted, and 2 or more substitutions In this case, two or more substituents may be the same or different from each other.

The term “alkyl” herein refers to a monovalent straight-chain or branched saturated hydrocarbon radical consisting 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, etc.

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, etc.

The term "aryl" herein refers to an organic radical with a monovalent aromatic ring derived from an aromatic hydrocarbon by removal of one hydrogen, and each ring has suitably 4 to 7 ring atoms, preferably 5 or 6 ring atoms. It may include a single or fused ring system including, and may even include a form in which multiple aryls are connected by a single bond. The ring atom may have 6 to 20 carbon atoms, preferably 6 to 12 carbon atoms. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, etc.

The term "heteroaryl" herein refers to a monovalent heteroaromatic ring radical containing 1 to 4 heteroatoms selected from N, O, and S as aromatic ring skeleton atoms, and being an aryl group where the remaining aromatic ring skeleton atoms are carbon. That is, it is a 5- to 6-membered monocyclic heteroaryl, and a polycyclic heteroaryl condensed with one or more benzene rings, and may be partially saturated. In addition, heteroaryl in the present invention also includes forms in which one or more heteroaryls are linked by a single bond. Examples of the heteroaryl group include pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, imidazolyl, benzoimidazolyl, iso Includes, but is not limited to, oxazolyl, benzoisoxazolyl, thiophenyl, benzothiophenyl, furyl, benzofuryl, etc.

The term “halo” or “halogen” herein refers to elements of the halogen group and includes, for example, fluoro, chloro, bromo, and iodo.

The term “haloalkyl” 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, etc.

The term "cycloalkyl" herein refers to a non-aromatic carbocyclic monovalent radical consisting of one or more rings, and may include saturated or unsaturated monocyclic, multicyclic, or spiroring forms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[1.1.1]pentyl, and bicyclo[3.1.0]hexyl. 3.1.0]hexyl), bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, adamantly, Examples include, but are not limited to, decalinyl.

The term “alkenyl” herein refers to a straight-chain or branched unsaturated hydrocarbon monovalent radical containing one or more double bonds between two or more carbon atoms, and may be partially saturated. Specifically, ethenyl, 1-propenyl, 2-propenyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, Includes, but is not limited to, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, isoprenyl, geranyl, 5-tetradecenyl, etc.

The term “alkylene” herein refers to a divalent straight-chain or branched saturated hydrocarbon divalent group consisting only of carbon and hydrogen atoms, specifically methylene, ethylene, propylene, isopropylene, butylene, isobutylene, and t-butyl. Includes, but is not limited to, lene, pentylene, hexylene, octylene, nonylene, etc.

The term "arylene" herein refers to a divalent aromatic ring derived from an aromatic hydrocarbon, a single or fused ring system containing 4 to 7, preferably 5 or 6 ring atoms in each ring. It includes a form in which multiple aryls are connected by a single bond. For example, naphthylene, biphenylene, terphenylene, anthrylene, indenylene, fluorenylene, pyrene, phenanthrylene, triphenylenylene, pyrenylene, peryleneylene, chrysenylene, naphthacenyl. It includes, but is not limited to, lene, fluoranthenylene, etc., or combinations thereof.

The present invention relates to a method for producing a pyrimidin-2-amine compound, and more specifically, to produce a pyrimidine compound by reacting it with activated pyrimidine using an electron-deficient pyridine compound or an imidoyl chloride compound as a nucleophilic imine type reagent. About a method for efficiently producing a pyrimidin-2-amine compound in which various amine functional groups ranging from primary to tertiary amines are selectively introduced at the 2-position of pyrimidine through a pyrimidine-2-iminium salt intermediate. will be.

According to one aspect of the present invention, 1) preparing a pyrimidine-N-oxide intermediate by catalytic oxidation of a pyrimidine compound of the following formula (2); 2) Following step 1), the pyrimidine-N-oxide intermediate is activated in situ in the presence of trifluoromethanesulfonic anhydride (Tf ₂ O) and reacted with the pyridine reagent of the following formula 3-1 to produce pyrimidine. -Preparing 2-pyridinium salt; and 3) following step 2), aminoly decomposing the pyrimidine-2-pyridinium salt to prepare a pyrimidin-2-amine compound of the following formula 1-1, including 1) and 2) above. A method for producing a pyrimidin-2-amine compound is provided, 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 connected to adjacent substituents to form a ring;

R ₄ is haloC1-C20alkyl, cyano, C1-C20alkylcarbonyl or C6-C20arylcarbonyl;

R' is hydrogen or C1-C20 alkyl;

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

The 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 any 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 producing the pyrimidin-2-amine compound of Formula 1-1 according to the present invention involves catalytic oxidation and activation of a pyrimidine compound of Formula 2 as a starting material, followed by catalytic oxidation and activation of an electron-deficient pyridine compound as a reagent in the form of a nucleophilic imine. A pyrimidin-2-amine compound in which an amine functional group is selectively introduced at the 2-position of pyrimidine can be efficiently produced through reaction with and aminolysis process. According to the present invention, a wide range of substrates with various substituents introduced can be introduced as starting materials.

In step 1), the catalytic oxidation may be performed in the presence of an oxidizing agent and methyltrioxolenium (MeReO ₃ ), and the amount of methyltrioxolenium used is not particularly limited, but is 1.0 to 1.0 relative to the pyrimidine compound of Formula 2. It can be used in the range of 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 may be used, and more specifically, a 50% aqueous hydrogen peroxide solution may be used.

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

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

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

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

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

In step 3), amino decomposition may be performed in the presence of ammonia water. During amine derivatization of pyrimidine-2-pyridinium salt, the primary amine product (Formula 1-1) can be obtained by using ammonia as the amino source.

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

In one embodiment, all of the reactions in the above steps can 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, the organic solvents include dichloromethane (DCM), dichloroethane, tetrachloroethane, acetonitrile (MeCN), nitromethane, toluene, Benzene, ethanol (EtOH), etc. can be used alone or in a mixture of two or more. Specifically, one or more selected from dichloromethane, acetonitrile, and ethanol may be used as the reaction solvent.

The manufacturing process of the pyrimidin-2-amine compound of Chemical Formula 1-1 through steps 1) to 3) is shown in Scheme 1 below. As shown in 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 By reacting with a reagent, the pyrimidine-2-pyridinium salt of Chemical Formula A-1 is formed as a core intermediate, and the pyrimidin-2-amine compound of Chemical Formula 1-1 can be prepared by immediately aminoly decomposing it without separation and purification.

[Scheme 1]

In Scheme 1, R ₁ to R ₄ 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 3-1의 R₄은 할로C1-C10알킬 또는 C6-C20아릴카보닐일 수 있다.In one embodiment, R ₁ , R ₂ and R ₃ of 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-C10cycloalkyl, C6-C12aryl, haloC6-C12aryl, C1-C10alkoxy, -CH=CH-Ar, C3-C10heteroaryl or -NHC(=O)Ar ₁ , or the above. R ₂ and R ₃ are

can be connected 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-C12aryl or haloC6-C12aryl; Ar ₁ is C6-C12aryl; The heteroaryl of R ₁ to R ₃ may be further substituted with any 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, and b may be an integer from 1 to 10; R ₄ in Formula 3-1 may be haloC1-C10alkyl or C6-C20arylcarbonyl.

According to another aspect of the present invention, 1) preparing a pyrimidine-N-oxide intermediate by catalytic oxidation of a pyrimidine compound of the following formula (2); 2) Following step 1), the pyrimidine-N-oxide intermediate is activated in situ in the presence of trifluoromethanesulfonic anhydride and reacted with a pyridine reagent of the following formula 3-2 to produce pyrimidine-2-pyridinium. preparing salt; and 3) following step 2), partial reduction of the pyrimidine-2-pyridinium salt to prepare a cyclic (2-enamino)pyrimidine compound of the following formula 1-2; And 2) provides a method for producing 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 connected to adjacent substituents to form a ring;

R ₅ is haloC1-C20alkyl, cyano, C1-C20alkylcarbonyl or C6-C20arylcarbonyl;

R' is hydrogen or C1-C20 alkyl;

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

The 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 any 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 producing the cyclic (2-enamino)pyrimidine compound of Formula 1-2 according to the present invention involves catalytic oxidation and activation of the pyrimidine compound of Formula 2 as a starting material, followed by electron-deficient reagent in the form of a nucleophilic imine. Through reaction with a pyridine compound and a partial reduction process, 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 produced. . According to the present invention, a wide range of substrates with various substituents introduced 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) above is a C2-selective nucleophilic functionalization platform that provides a synthetic handle for divergent synthesis of 2-aminopyrimidine. It can work.

In step 3), the partial reduction may be performed in the presence of hydrogen gas and a platinum group metal catalyst containing platinum, palladium, rhodium, and/or ruthenium, and specifically, may be performed in the presence of hydrogen gas and PtO ₂ 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, all of the reactions in the above steps may be performed under mild conditions, and the reaction temperature may be any temperature commonly used in organic synthesis. Specifically, the catalytic oxidation in step 1) may be carried out at 20 to 30 °C. ℃, step 2) can be performed at 0 to 30 ℃, and step 3) can be performed at 20 to 30 ℃, and can be adjusted appropriately as needed. The reaction time may vary depending on the reactant, amount of reactant, type of solvent, and amount of solvent, and is not particularly limited.

In one embodiment, all of the reactions in the above steps can 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, the organic solvents include dichloromethane (DCM), dichloroethane, tetrachloroethane, acetonitrile (MeCN), nitromethane, toluene, Benzene, ethanol (EtOH), etc. can be used alone or in a mixture of two or more. Specifically, one or more selected from dichloromethane, acetonitrile, and ethanol may be used as the reaction solvent.

The manufacturing process of 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 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 By reacting with a reagent, the pyrimidine-2-pyridinium salt of Formula A-2 is formed as a core intermediate, and the cyclic (2-enamino)pyrimidine compound of Formula 1-2 can be prepared by partial reduction directly without separation and purification. You 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 of 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-C10cycloalkyl, C6-C12aryl, haloC6-C12aryl, C1-C10alkoxy, -CH=CH-Ar, C3-C10heteroaryl or -NHC(=O)Ar ₁ , or the above. R ₂ and R ₃ are

can be connected 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-C12aryl or haloC6-C12aryl; Ar ₁ is C6-C12aryl; The heteroaryl of R ₁ to R ₃ may be further substituted with any 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, and b may be an integer from 1 to 10; R ₅ in Formula 3-2 may be haloC1-C10alkyl.

According to another aspect of the present invention, 1) preparing a pyrimidine-N-oxide intermediate by catalytic oxidation of a pyrimidine compound of the following formula (2); 2) Following step 1), the pyrimidine-N-oxide intermediate is reacted with the imidoyl chloride compound of the following formula 4-1 in the presence of trifluoromethanesulfonic anhydride to prepare pyrimidine-2-iminium salt. steps; and 3) following step 2), treating the pyrimidine-2-iminium salt with sodium bicarbonate, reducing or hydrolyzing it to prepare a pyrimidine-2-substituted amine compound of the following formula 1-3; Provided is a method for producing 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 connected to adjacent substituents to form a ring;

R'' is hydrogen, -C(=O)R ₁₂ or -CH ₂ R ₁₂ ;

R ₁₁ is C1-C20 alkyl, C6-C20 aryl, allyl, halo C1-C20 alkyl, C6-C20 aryl C1-C20 alkyl or C3-C20 cycloalkyl, and the cycloalkyl is halogen, halo C1-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-C20alkyl, C1-C20alkylcarbonyl or C6-C20arylcarbonyl;

R' is hydrogen or C1-C20 alkyl;

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

The 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 any 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-C20alkyl;

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 producing the pyrimidine-2-substituted amine compound of Formula 1-3 according to the present invention involves catalytic oxidation of the pyrimidine compound of Formula 2 as a starting material, subsequent activation, and imidoyl chloride compound as a reagent in the form of a nucleophilic imine. 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 produced through reaction with and post-treatment. According to the present invention, a wide range of substrates with various substituents introduced can be introduced as starting materials.

Step 1) is the same as detailed above.

The imidoyl chloride compound of Formula 4-1 in step 2) may be prepared by reacting an amide compound of Formula 4 below with oxalyl chloride in the presence of an organic base. It is prepared immediately before use and can be prepared immediately without separation and purification. The pyrimidine-N-oxide intermediate formed in step 1) can be reacted in the presence of trifluoromethanesulfonic acid 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, 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 used in the amount of 1 equivalent or more, specifically 1 to 3 equivalents, or 1 to 2 equivalents, based on the pyrimidine compound of Formula 2. It can be used in an equivalent weight range.

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

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

Step 3) may be a step of preparing a pyrimidin-2-amide compound of the following formula 1-3A by treatment with sodium bicarbonate.

[Formula 1-3A]

In Formula 1-3A, R ₁ to R ₃ , R ₁₁ and R ₁₂ are the same as the definitions 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. This may be a step of preparing a pyrimidine-2-disubstituted amine compound of the following formula 1-3B by reduction with a reducing agent selected from LiBH ₃ CN.

[Formula 1-3B]

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

Step 3) may be a step of forming a secondary amine product through hydrolysis, and specifically, a step of preparing a pyrimidin-2-monolysubstituted amine compound of the following formula 1-3C by treatment with methanol and sodium hydroxide. It 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, all of the reactions in the above steps may be performed under mild conditions, and the reaction temperature may be any temperature commonly used in organic synthesis. Specifically, the catalytic oxidation in step 1) may be carried out at 20 to 30 °C. ℃, step 2) can be performed at 0 to 30 ℃, and step 3) can be performed at 20 to 70 ℃, and can be adjusted appropriately as needed. The reaction time may vary depending on the reactant, amount of reactant, type of solvent, and amount of solvent, and is not particularly limited.

In one embodiment, all of the reactions in the above steps can 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, the organic solvents include dichloromethane (DCM), dichloroethane, tetrachloroethane, acetonitrile (MeCN), nitromethane, toluene, Benzene, ethanol (EtOH), etc. can be used alone or in a mixture of two or more. Specifically, one or more selected from dichloromethane, acetonitrile, and ethanol may be used as the reaction solvent.

The production process of 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, It reacts with the imidoyl chloride reagent of 4-1 to form pyrimidine-2-iminium salt of Chemical Formula A-3 as a key intermediate, and then immediately treats it with sodium bicarbonate without separation and purification, or reduces or hydrolyzes it to obtain Chemical 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 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; In one embodiment, R ₁ , R ₂ and R ₃ of 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 R ₂ and R ₃ are

can be connected 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-C12aryl or haloC6-C12aryl; Ar ₁ is C6-C12aryl; The heteroaryl of R ₁ to R ₃ may be further substituted with any 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, and b may be an integer from 1 to 10;

R ₁₁ of the formulas 1-3A, 1-3B, 1-3C and 4 is C1-C10 alkyl, C6-C12aryl, allyl, haloC1-C10alkyl, C6-C12arylC1-C10alkyl or C3-C10cyclo. alkyl, and the cycloalkyl may be further substituted with one or more selected from halogen, haloC1-C10 alkyl, and haloC6-C12 aryl; R ₁₂ may be C1-C10 alkyl or C6-C12 aryl.

The present invention is a very effective method for efficiently synthesizing pyrimidin-2-amine in one step through C2-selective amination of pyrimidine, which serves as an important structural core motif in medicine, pesticides, and various chemical fields. According to the present invention, a pyrimidin-2-amine compound in which various amino functional groups are selectively introduced at the 2-position of pyrimidine through a salt intermediate of the pyrimidine-2-iminium skeleton using a reagent in the form of a nucleophilic imine is produced. Can be synthesized efficiently. Additionally, the reaction can be performed in-situ, which can have a process advantage because it requires only one purification process to separate the final product.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating 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 were insensitive to air and moisture, were performed under ambient atmosphere. 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). Yields represent purified and spectroscopically pure compounds. All air- and moisture-sensitive manipulations were performed using oven-dried glassware (130°C for a minimum of 12 hours) using standard Schlenk techniques under an argon atmosphere. Air-sensitive liquids and solutions were transferred via syringes or cannulas using degassed solvents.

[menstruum]

Acetonitrile, dichloromethane, and methanol were purchased from Deoksan Pharmaceutical Co., Ltd. and used without further purification. Anhydrous solvents were obtained from 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 and 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 the appropriate eluent system.

[Spectroscopy and instruments]

^1H NMR spectra were obtained using 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 fully decoupled by broadband 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 were expressed in ppm using 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 electrospray ionization (ESI) method at the KAIST Analysis center for Research Advancement (Daejeon) and the fast-atom bombardment (FAB) or electron (EI) method at the Korea Basic Science Institute (Daegu). ionization) method. Melting point (mp) was measured using 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. 2,2,2-Trifluoroethan-1-amine, 3,3-difluorocyclobutan-1-amine hydrochloride, 3-(trifluoromethyl)pyridine, 4-cyanopyridine, 3-benzoylpyridine, N -benzylacetamide, and methyltrioxorhenium(VII) are TCI chemicals. 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-1 H -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 prepared using a previously reported method [ 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. It was synthesized and used according to [2019, 21 , 6488-6493].

Preparation example: Preparation of starting materials

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

Under argon atmosphere, in an oven-dried 100 mL round bottom flask, 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. The reaction mixture was diluted with dichloromethane (25 mL) and washed with 1N aqueous hydrochloric acid 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℃; 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 Stirling 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℃; 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.

[Preparation 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 Stirling 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 through a 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. The reaction mixture was diluted with dichloromethane (25 mL) and washed with 1N aqueous hydrochloric acid 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℃; 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)

Under argon atmosphere, Stirling bar, 2-(pyrimidin-4-yl)ethan-1-ol (123 mg, 0.991 mmol, 1.0 equiv), and anhydrous N , N -dimethylformamide (4.0%) were added to an oven-dried 25 mL round bottom flask. mL) was filled. Imidazole (202 mg, 2.97 mmol, 3.0 equiv) was added to the stirred solution at 23°C. Subsequently, 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. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous lithium chloride solution (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 mg). % 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)

Stirling 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), and 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)

Stirling bar, 1-(benzofuran-2-yl)ethan-1-one (1602 mg, 10.00 mmol, 1.0 equiv), 1,3,5-triazine (1622 mg, 20.00) in a 100mL 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 continuously added through a 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. and 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℃; ^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)

Under an argon atmosphere, place Stirling's Bar, methyl 3-{(2,6-difluorophenyl)sulfonamido}-2-fluorobenzoate (1.08 g, 3.13 mmol, 1.0 equiv), and anhydrous THF (10 mL) in an oven-dried 25 mL round bottom flask. ) was filled. The mixture was cooled to 0°C, and then 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 by half in vacuum, and then 6N aqueous hydrochloric acid solution (10 mL) was added. The aqueous layer was separated and washed with ethyl acetate (10 mL). The aqueous layer was then 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 N -chlorosuccinimide (334 mg, 2.50 mmol, 0.80 equiv) was added at once to the stirred mixture. The mixture was stirred at 23°C for 12 hours, and 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 sequentially 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℃; ^1H 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)-1 H -pyrazol-3-yl]phenyl}carbamate (S8)

Under an argon atmosphere, add Stirling's Bar, 4-(3-iodo-1-isopropyl-1 H -pyrazol-4-yl)pyrimidine (935 mg, 2.98 mmol, 1.0%) to an oven-dried 250 mL round bottom flask equipped with a reflux condenser. 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 and 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℃; ^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), 1 18.2(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)

Under an argon atmosphere, an oven-dried 50 mL round bottom flask was charged with a Stirling bar, ruxolitinib (1022 mg, 3.336 mmol, 1.0 equiv), and anhydrous dichloromethane (15 mL). To the stirred mixture, triethylamine (1.53 mL, 1.11 g, 11.0 mmol, 3.3 equiv) was added via syringe, the mixture was cooled to 0°C, and then 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 while eluting with a solvent mixture of dichloromethane/methanol (100/0 to 90/10 (v/v)) to obtain the target compound S9 as a brown solid (1.23 g, 80% yield). .

mp: 72-74℃; ^1H 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, 104. 1, 64.8, 44.8, 30.4 , 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

Under an argon atmosphere, an oven-dried 100 mL round bottom flask was charged with a Stirling bar, pyrimidine N -oxide (192 mg, 2.00 mmol, 1.0 equiv) and anhydrous dichloromethane (10.0 mL). 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 through a syringe. While stirring at 0°C, trifluoromethanesulfonic anhydride (337 μL, 565 mg, 2.00 mmol, 1.0 equiv) was added dropwise through a syringe, and 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℃; 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-heteroarene

Procedure A : Use of electron-deficient pyridine derivatives

Step 1:

Pyrimidine compound (Formula 2, 0.25 mmol, 1.0 equiv) and dichloromethane (0.20 mL) were added to a 4 mL 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. While stirring at 23°C, 50% aqueous hydrogen peroxide solution (28 μL, 34 mg, 0.50 mmol, 2.0 equiv) was added dropwise via syringe, and the vial was sealed with a plastic cap. After stirring at 23°C for 6 hours, the reaction mixture was diluted with dichloromethane (2 mL), dried over sodium sulfate, filtered through cotton, placed in a 50 mL round bottom flask, and 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. Subsequently, trifluoromethanesulfonic anhydride (44 μL, 74 mg, 0.26 mmol, 1.0 equiv) was added dropwise through a syringe. After stirring at 23° C. under argon for 15 minutes, 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]

Acetonitrile (1.25 mL) was added to the residue of step 2, and then 28% aqueous ammonia (1.69 mL, 1.52 g, 25.0 mmol, 100 equiv) was added via 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 hours, 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 give the desired product, a pyrimidin-2-amine compound (Formula 1- 1) was obtained.

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

[Condition 2]

The residue from step 2 was dried under reduced pressure for 1 hour, and 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 at 23° C. under H ₂ atmosphere for 2 hours, 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 × 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 give the desired product, a cyclic (2-enamino)pyrimidine compound (Formula 1) -2) was obtained.

Procedure B : Use of imidoyl chloride

Step 1-a:

Add heteroarene substrate (0.25 mmol, 1.0 equiv) and dichloromethane (0.20 mL) to a 4mL vial equipped with a stirrer, then add methyltrioxorhenium(VII) (MeReO ₃ ) (3.1 mg, 0.012 mmol, 5.0 mol%) while stirring. did. While stirring at 23°C, 50% aqueous hydrogen peroxide solution (28 μL, 34 mg, 0.50 mmol, 2.0 equiv) was added dropwise via syringe, and the vial was sealed with a plastic cap. After stirring at 23°C for 6 hours, the reaction mixture was diluted with dichloromethane (2 mL), dried over sodium sulfate, filtered through cotton, placed in a 50 mL round bottom flask, and 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, and 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 to an oven-dried 20 mL vial equipped with a stirrer under argon, 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 continuously added dropwise through a syringe. Gas evolution was observed immediately upon addition of oxalyl chloride. The mixture was then stirred at 0° C. for 30 minutes (mixture B).

Step 2:

Mixture B was transferred via syringe to 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 minutes.

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

[Condition 1]

The reaction mixture of step 2 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 obtain the desired product, a pyrimidine-2-substituted amine compound (Formula 1-3A).

[Condition 2]

The reaction mixture of step 2 was concentrated at 0°C under reduced pressure. Anhydrous acetonitrile (5.0 mL) and sodium borohydride (21 mg, 0.55 mmol, 2.2 equiv) were added to the residue. 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 obtain the desired product, a pyrimidine-2-substituted amine compound (Formula 1-3B).

[Condition 3]

The reaction mixture of step 2 was diluted with saturated aqueous sodium bicarbonate solution (5 mL) and warmed to 23°C. The organic layer was separated, and 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 obtain the desired product, a pyrimidine-2-substituted amine compound (Formula 1-3C).

The format of the product properties prepared using the above-described 2-amination method of pyrimidines is as follows: [Structure of the 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℃; ^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( 2H )-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℃; ^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, 92 0, 880, 830 ; 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℃; ^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℃; ^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℃; ^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℃; ^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℃; ^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℃; ^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℃; ^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℃; ^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℃; ^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℃; 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℃; ^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℃; ^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, 4; 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℃; 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℃; ^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℃; ^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℃; ^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℃; ^1H 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℃; ^1H 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℃; ^1H 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℃; ^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℃; 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 O [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℃; ^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 O [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℃; ^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, , 26.1; 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℃; ^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℃; ^1H 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℃; ^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, 117. 9, 115.5, 80.8, 55.0 , 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 unidentified N-oxide (0.275 mmol, 30% yield). Obtained as a yellow solid, giving 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℃; ¹ H 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, 112. 4, 104.0, 64.8, 44.8 , 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 description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive.

Claims (19)

1) preparing a pyrimidine-N-oxide intermediate by catalytic oxidation of a pyrimidine compound of the following formula (2);
2) Following step 1), the pyrimidine-N-oxide intermediate is activated in situ in the presence of trifluoromethanesulfonic anhydride and reacted with a pyridine reagent of the following formula 3-1 to produce pyrimidine-2-pyridinium. Preparing salt; and
3) following step 2), aminoly decomposing the pyrimidine-2-pyridinium salt to prepare a pyrimidin-2-amine compound of the following formula 1-1;
A method for producing a pyrimidin-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 connected to adjacent substituents to form a ring;
R ₄ is haloC1-C20alkyl, cyano, C1-C20alkylcarbonyl or C6-C20arylcarbonyl;
R' is hydrogen or C1-C20 alkyl;
Ar ₁ is C6-C20 aryl or C3-C20 heteroaryl;
The 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 any 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 clause 1,
In step 1), the catalytic oxidation is performed in the presence of an oxidizing agent and methyltrioxolenium (MeReO ₃ ). According to clause 2,
A production method wherein the methyltrioxolenium (MeReO ₃ ) is used in an amount of 1.0 to 30.0 mol% based on the pyrimidine compound of Formula 2. According to clause 2,
The method of claim 1, wherein the oxidizing agent is hydrogen peroxide or hydrogen peroxide adduct. According to clause 2,
A production method wherein the oxidizing agent is used in an amount of 1 to 5 equivalents based on the pyrimidine compound of Formula 2. According to clause 1,
In step 2), trifluoromethanesulfonic anhydride is used in an amount of 1 to 3 equivalents based on the pyrimidine compound of Formula 2. According to clause 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 clause 1,
A production method in which the amino decomposition in step 3) is performed in the presence of aqueous ammonia. 1) preparing a pyrimidine-N-oxide intermediate by catalytic oxidation of a pyrimidine compound of the following formula (2);
2) Following step 1), the pyrimidine-N-oxide intermediate is activated in situ in the presence of trifluoromethanesulfonic anhydride and reacted with a pyridine reagent of the following formula 3-2 to produce pyrimidine-2-pyridinium. Preparing salt; and
3) following step 2), partially reducing the pyrimidine-2-pyridinium salt to prepare a cyclic (2-enamino)pyrimidine compound of the following formula 1-2:
A method for producing a cyclic (2-enamino) pyrimidine compound, wherein steps 1) and 2) are performed in 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 connected to adjacent substituents to form a ring;
R ₅ is haloC1-C20alkyl, cyano, C1-C20alkylcarbonyl or C6-C20arylcarbonyl;
R' is hydrogen or C1-C20 alkyl;
Ar ₁ is C6-C20 aryl or C3-C20 heteroaryl;
The 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 any 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 clause 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 clause 9,
In step 3), the partial reduction is performed in the presence of hydrogen gas and PtO ₂ . According to clause 11,
A production method 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 catalytic oxidation of a pyrimidine compound of the following formula (2);
2) Following step 1), the pyrimidine-N-oxide intermediate is reacted with the imidoyl chloride compound of the following formula 4-1 in the presence of trifluoromethanesulfonic anhydride to prepare pyrimidine-2-iminium salt. steps; and
3) following step 2), treating the pyrimidine-2-iminium salt with sodium bicarbonate, reducing or hydrolyzing it to prepare a pyrimidine-2-substituted amine compound of the following formula 1-3: However,
A method for producing 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 connected to adjacent substituents to form a ring;
R'' is hydrogen, -C(=O)R ₁₂ or -CH ₂ R ₁₂ ;
R ₁₁ is C1-C20 alkyl, C6-C20 aryl, allyl, halo C1-C20 alkyl, C6-C20 aryl C1-C20 alkyl or C3-C20 cycloalkyl, and the cycloalkyl is halogen, halo C1-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' is hydrogen or C1-C20 alkyl;
Ar ₁ is C6-C20 aryl or C3-C20 heteroaryl;
The 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 any 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 clause 13,
A method for preparing the imidoyl chloride compound of Formula 4-1 by reacting an amide compound of the following 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 clause 13,
In step 2), trifluoromethanesulfonic anhydride is used in an amount of 1.0 to 3.0 equivalents based on the pyrimidine compound of Formula 2. According to clause 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 clause 13,
Step 3) is a production method of preparing a pyrimidin-2-amide compound of the following formula 1-3A by treatment 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 clause 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 produce a pyrimidine-2-disubstituted amine compound of the following formula 1-3B: Manufacturing step, 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 clause 13,
The step 3) is a step of preparing a pyrimidin-2-monolysubstituted amine compound of the following 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.