KR20220160287A - Novel multi-fused heterocyclic compound and preparation method thereof - Google Patents

Abstract

A novel multi-conjugated heterocyclic compound and a preparation method thereof are provided. One embodiment of the present invention is a novel multi-conjugated heterocyclic compound represented by the following formula 1. In formula 1, R^1 is any one selected from a group consisting of a hydrogen group, a linear or branched alkyl group having 1 to 5 carbon atoms, a linear or branched alkoxy group having 1 to 5 carbon atoms, and a heteroaryl group containing a nitrogen atom; R^2 is a mono- or di-substituted substituent bonded to a carbon-carbon double bond and is a hydrogen group or a linear or branched alkyl group having 1 to 5 carbon atoms; R^3 is a substituted or unsubstituted phenyl group; R^4 is any one selected from a group consisting of a linear or branched alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted heteroaryl group; R^5 is any one selected from a group consisting of a substituted or unsubstituted alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted cycloalkyl group, and a substituted or unsubstituted aryl group.

Description

Novel multi-junction heterocyclic compound and its preparation method {NOVEL MULTI-FUSED HETEROCYCLIC COMPOUND AND PREPARATION METHOD THEREOF}

The present invention relates to a novel multi-junction heterocyclic compound and a method for preparing the same, and more specifically, to a novel compound widely used in pharmaceuticals by reacting a nitrogen atom-containing aromatic zwitterion with a metal compound, a ligand, and a basic compound. It relates to a multi-junction heterocyclic compound of and a method for preparing the same.

Ring compounds containing heteroatoms can be considered as the most central framework of pharmaceuticals, and it is urgent to develop effective synthesis methods for related compounds. In particular, these compounds are hexagonal asymmetric heterocyclic compounds in the form of conjugated with other cyclic compounds, and there is a problem in that they can be obtained through several stages of synthesis.

When conventionally known activated nitrogen-aromatic salts react with electron-rich nucleophiles, 1,2-addition reactions and 1,4-addition reactions occur competitively, making it difficult to control site affinity selectivity. Nitrogen-aromatic zwitterions, which are structurally similar to nitrogen-aromatic salts, are compounds with easy regioselectivity and stereoselectivity control.

In particular, the nitrogen-aromatic zwitterion compound not only provides an economical step-by-step synthesis method, but also has the advantage of being used as an intermediate in synthesizing various target molecules to synthesize structurally diverse heterocyclic compounds.

Korean Patent Registration Publication No. 10-2133202B1, published by the present inventors, simply discloses pyridinium zwitterion and its synthesis method, and is a novel multi-junction heterocyclic compound that can be widely used in pharmaceuticals using the pyridinium zwitterion. and a synthesis method thereof is not disclosed at all.

Korean Registered Patent Publication No. 10-2133202B1 (2020.07.13)

An object of the present invention is to solve the above problems by using a nitrogen-aromatic compound which is an amphoteric ion and an alkyne substituted with an electron-deficient functional group as a reactant under a metal compound used as a catalyst to solve the above problem, a metal-terminated alkyne complex. To induce dearomatization of the nitrogen-aromatic compound by the 1,2-addition reaction of, and finally to provide a novel multi-junction heterocyclic compound synthesized by [5+1] cycloaddition reaction. .

Another object of the present invention is to provide a method for producing the novel multi-conjugated heterocyclic compound.

Another object of the present invention is to induce the [5+1] cycloaddition reaction of the nitrogen-aromatic compound by additionally using a metal compound as a catalyst and a chiral ligand. It is to provide a method for preparing a novel asymmetric multi-conjugated heterocyclic compound that proceeds through a selective reaction.

The objects of the present invention are not limited to the above-mentioned objects, and other objects and advantages of the present invention not mentioned above can be understood by the following description and will be more clearly understood by the examples of the present invention. It will also be readily apparent that the objects and advantages of the present invention may be realized by means of the instrumentalities and combinations indicated in the claims.

One embodiment of the present invention for achieving the above object corresponds to a novel multi-junction heterocyclic compound represented by the following general formula 1.

[Formula 1]

In Formula 1, R ¹ is any one selected from the group consisting of a hydrogen group, a linear or branched alkyl group having 1 to 5 carbon atoms, a linear or branched alkoxy group having 1 to 5 carbon atoms, and a heteroaryl group containing a nitrogen atom. One, R ² is a monosubstituted or disubstituted substituent bonded to a carbon-carbon double bond, a hydrogen group or a linear or branched alkyl group having 1 to 5 carbon atoms, R ³ is a substituted or unsubstituted phenyl group, , R ⁴ is any one selected from the group consisting of a linear or branched alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted heteroaryl group, and R ⁵ is a substituted or unsubstituted group having 1 to 5 carbon atoms It is any one selected from the group consisting of a cyclic alkyl group, a substituted or unsubstituted cycloalkyl group, and a substituted or unsubstituted aryl group.

The novel multi-junction heterocyclic compound represented by Formula 1 is any one selected from the group consisting of compounds represented by Formulas 1 to 20 below.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

[Formula 11]

[Formula 12]

[Formula 13]

[Formula 14]

[Formula 15]

[Formula 16]

[Formula 17]

[Formula 18]

[Formula 19]

[Formula 20]

Another embodiment of the present invention for achieving the above object is a novel multi-junction heterocyclic compound represented by the following general formula 2.

[Formula 2]

In Formula 2, R ⁶ is any one selected from the group consisting of a hydrogen group, a linear or branched alkyl group having 1 to 5 carbon atoms, a linear or branched alkoxy group having 1 to 5 carbon atoms, and a heteroaryl group containing a nitrogen atom. One, R ⁷ is a mono- or di-substituted substituent bonded to a carbon-carbon double bond, a hydrogen group or a linear or branched alkyl group having 1 to 5 carbon atoms, and R ⁸ is a substituted or unsubstituted phenyl group And, R ⁹ is any one selected from the group consisting of a linear or branched alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted heteroaryl group.

The novel multi-junction heterocyclic compound represented by Formula 2 is a compound represented by Formula 21 below.

[Formula 21]

Another embodiment of the present invention for achieving the above object is (S1) mixing a compound represented by the following general formula 3, a metal compound and a basic compound in an organic solvent, (S2) the above (S1) step Corresponds to a method for preparing a novel multi-junction heterocyclic compound comprising the step of preparing a compound represented by the following general formula 1 by adding a compound represented by the following general formula 4 to a mixture of.

[Formula 3]

[Formula 4]

[Formula 1]

In Formulas 1 and 3, R ¹ is a hydrogen group, a linear or branched alkyl group having 1 to 5 carbon atoms, a linear or branched alkoxy group having 1 to 5 carbon atoms, and a heteroaryl group containing a nitrogen atom. any one selected, R ² is a monosubstituted or disubstituted substituent bonded to a carbon-carbon double bond, a hydrogen group or a linear or branched alkyl group having 1 to 5 carbon atoms, and R ³ is substituted or unsubstituted phenyl group, R ⁴ is a linear or branched alkyl group having 1 to 8 carbon atoms, or a substituted or unsubstituted phenyl group, and in Formulas 1 and 4, R ⁵ is a substituted or unsubstituted alkyl group having 1 to 5 carbon atoms , Any one selected from the group consisting of a substituted or unsubstituted cycloalkyl group and a substituted or unsubstituted aryl group.

The metal compound according to the present invention may correspond to a compound containing metal ions.

The compound containing the metal ion may correspond to a compound containing a monovalent copper ion (Cu(I)) or a compound containing a silver ion, and specifically CuI, CuCl, CuBr, Cu ₂ O, CuO, CuCl ₂ , CuOAc, AgOTf, and combinations thereof.

The basic compound according to the present invention may include any one selected from the group consisting of primary to tertiary amine compounds. The basic compound may preferably correspond to a tertiary amine compound, and may be, for example, any one selected from the group consisting of DIPEA (N,N-diisopropylethylamine), Et ₃ N, and Cy ₂ NMe. However, the technical spirit of the present invention is not limited thereto, and any basic compound capable of removing hydrogen (Pk _a = 25) of terminal alkyne can be applied.

Another embodiment of the present invention, (S1) mixing the compound represented by the general formula 3, a metal compound and a basic compound in an organic solvent, (S2) mixing the mixture of the step (S1) with the general formula Adding a compound represented by 4 to prepare a compound represented by the general formula 1, wherein the (S1) step further comprises mixing the compound represented by the general formula 3 with a ligand compound, , The ligand compound is a chiral bidentate ligand or a chiral tridentate ligand, the metal compound is a metal complex, and carbon (*) in Formula 1 is S-type. It may correspond to a method for producing a novel multi-conjugated heterocyclic compound stereoselectively arranged. The method for preparing the novel multi-conjugated heterocyclic compound corresponds to a stereoselective reaction.

,

및

,

및

로 이루어진 군에서 선택된 어느 하나이다.The chiral bidentate ligand,

,

and

,

and

It is any one selected from the group consisting of.

이다. 다만 본 발명의 기술사상이 상기 리간드 화합물의 종류에 제한되는 것은 아니고, 반응성이 낮은 금속 화합물과 배위 결합이 가능한 리간드 화합물이면 본 발명에 모두 적용될 수 있다.The chiral tridentate ligand,

to be. However, the technical concept of the present invention is not limited to the type of the ligand compound, and any ligand compound capable of coordinating with a metal compound having low reactivity can be applied to the present invention.

The metal complex is, for example, any one selected from the group consisting of Cu(MeCN) ₄ BF _{4 ,} CuOTf and CuOAc. The metal complex has a relatively lower reactivity than CuI, and can induce a stereoselective reaction.

The organic solvent, in order to induce the stereoselective reaction, preferably contains an ether-based compound, and more preferably may include a 1,4-dioxane compound.

Another embodiment of the present invention, (S10) mixing a compound represented by the following general formula 3, a metal compound and a basic compound in an organic solvent, (S20) the mixture of the (S10) step It is a method for preparing a novel multi-junction heterocyclic compound comprising the step of preparing a compound represented by the following general formula 2 by adding a compound represented by -1.

[Formula 3]

[Formula 4-1]

[Formula 2]

In Formula 3, R ¹ is any selected from the group consisting of a hydrogen group, a linear or branched alkyl group having 1 to 5 carbon atoms, a linear or branched alkoxy group having 1 to 5 carbon atoms, and a heteroaryl group containing a nitrogen atom. One, R ² is a monosubstituted or disubstituted substituent bonded to a carbon-carbon double bond, a hydrogen group or a linear or branched alkyl group having 1 to 5 carbon atoms, and R ³ is a substituted or unsubstituted phenyl group And, R ⁴ is any one selected from the group consisting of a linear or branched alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted heteroaryl group, and in Formula 2, R ⁶ is hydrogen group, a linear or branched alkyl group having 1 to 5 carbon atoms, a linear or branched alkoxy group having 1 to 5 carbon atoms, and a heteroaryl group containing a nitrogen atom, and R ⁷ is carbon-carbon A mono- or di-substituted substituent bonded to a double bond, which is a hydrogen group or a linear or branched alkyl group having 1 to 5 carbon atoms, R ⁸ is a substituted or unsubstituted phenyl group, and R ⁹ is a linear or branched alkyl group. It is any one selected from the group consisting of an alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted heteroaryl group.

The novel multi-junction heterocyclic compound represented by Formula 2 is a compound represented by Formula 21 below.

[Formula 21]

The basic compound includes any one selected from the group consisting of primary to tertiary amine compounds. The tertiary amine compound is N,N-diisopropylethylamine or triethylamine.

According to the present invention, it is possible to provide a novel multi-conjugated heterocyclic compound that can be used as a pharmaceutical using a nitrogen-aromatic compound as a reactant, as well as a method for producing a novel asymmetric multi-conjugated heterocyclic compound in high yield. can do.

In addition to the above effects, specific effects of the present invention will be described together while explaining specific details for carrying out the present invention.

In the present specification, the scope of rights for compounds not showing a chiral center is defined as extending to both R-type compounds and S-type compounds. This is because methods for separating the R-type compound and the S-type compound are obvious to those skilled in the art.

In the present specification, when the parent is a cyclic structure, a heteroaryl group or a compound having a parent structure substituted with an aryl group is defined as having a monocyclic or bicyclic molecular structure.

In the present specification, Synthesis Example n corresponds to a method for synthesizing Example n, which is a compound represented by Formula n (provided that n is a natural number equal to or greater than 1). For convenience of description, reactants are referred to using compounds represented by the following general formulas 3 and 4.

[Formula 3]

[Formula 4]

Hereinafter, each configuration of the present invention will be described in more detail so that those skilled in the art can easily practice it, but this is only one example, and the scope of the present invention is Not limited.

In this specification, ¹ H NMR was measured with Bruker DPX FT (400 MHz) and JEOL (300 MHz), ¹³ C NMR was measured with Bruker DPX FT (100 MHz) and JEOL (75 MHz), and IR was measured with JASCO FT/IR Measured with -4700 and FT/IR-4200 FT-IR spectrometer.

[Example 1: Synthesis of nitrogen-aromatic zwitterion]

4-phenyl-1-toluenesulfonyl-1,2,3-triazole (2.0 equiv.), Rh ₂ (OPiv) ₄ (4.0 mol %) and p -xylene (2.0 mL) was added. After adding this stirred reaction mixture to N-heteroaromatic compound (0.2 mmol), it was stirred at 110 °C. Thereafter, the resulting product was cooled to room temperature and then concentrated under reduced pressure to remove the solvent. The organic residue from which the solvent was removed was purified by silica gel chromatography to synthesize a nitrogen-aromatic zwitterion compound represented by Formula 3 above. The N-heteroaromatic compound may be structurally diverse to correspond to the compound represented by Formula 3.

[Example 1]

(E)-ethyl 2-(1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 1 corresponds to a compound represented by Formula 1 below.

[Formula 1]

[Synthesis Example 1]

In a test tube with a triangular stirring bar, R ₁ and R _{2 =} hydrogen group, R ₃ = phenyl group, -SO ₂ R ₄ = quinolinium zwitterion represented by the tosyl group in the above general formula 3 (0.2 mmol) and a terminal alkyne (1.2 eq) in which R ⁵ is represented by an ethyl group in Formula 4, CuI (5 mol%) and CH ₂ Cl ₂ (2 mL) were added under N ₂ atmosphere. After confirming the completion of the reaction using TLC (Thin Layer Chromatography), the reaction mixture was filtered through a celite pad and washed with EtOAc (10 mLx3). After removing the organic solvent under reduced pressure, the organic residue was purified by silica gel chromatography to obtain Example 1 (97%, 79.7 mg) as a pale yellow solid. The TLC was performed on a Merck pre-coated silica gel 60 F254 plate.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 139-140 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.71 (d, J = 8.26 Hz, 2H), 7.46-7.43 (m, 2H), 7.34-7.28 (m, 5H), 7.19 (s, 1H), 6.91- 6.89 (m, 1H), 6.83-6.77 (m, 1H), 6.71-6.66 (m, 1H), 6.62 (s, 1H), 6.42 (d, J = 9.80 Hz, 1H), 6.17 (d, J = 8.01 Hz, 1H), 5.68 (dd, J = 9.77 Hz, J = 5.70 Hz, 1H), 4.13-4.03 (m, 2H), 3.29 (d, J = 5.70 Hz, 1H), 2.44 (s, 3H) , 1.26 (t, J = 7.14 Hz, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 166.3, 144.9, 138.9, 135.0, 134.5, 134.0, 129.9, 128.9, 128.6, 127.9, 127.5, 127.4, 127.0, 126.2, 125.3, 122.3, 120.3, 120.3, 118.5, 116.1 , 113.5, 60.6, 54.7, 21.7, 13.9; IR (solid) n 2922, 2853, 1718, 1487, 1343, 1167, 665 cm ^-1 ; HRMS (FAB) m/z calcd. for C ₂₉ H ₂₇ N ₂ O ₄ S [M+H] ⁺ : 499.1692, found: 499.1689.

[Example 1a]

(S,E)-ethyl 2-(1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 1a corresponds to a compound represented by Formula 1a below.

[Formula 1a]

[Synthesis Example 1a]

In a test tube with a triangular stirring bar under a nitrogen atmosphere, R ₁ and R _{2 =} hydrogen group, R ₃ = phenyl group, -SO ₂ R ₄ = quinolinium represented by tosyl group in the above general formula 3 A stirred reaction mixture was prepared by adding the zwitterion, DIPEA (0.5 eq.) and 1,4-dioxane (1 mL). A first mixture was prepared by adding Cu(MeCN) ₄ BF ₄ (5 mol%) and ( S )-DM-SegPhos (6 mol%) in 1,4-dioxane (1 mL) to the stirred reaction mixture. . Thereafter, at room temperature for 4 hours, a terminal alkyne (1.2 equivalent) in which R ⁵ is represented by an ethyl group in 1,4-dioxane (1 mL) in 1,4-dioxane (1 mL) was added dropwise to the first mixture, A second mixture was prepared. After 24 hours, the second mixture was filtered through a celite pad and the filtrate was washed with EtOAc (10 mL x 3). Thereafter, the organic solvent was removed under reduced pressure, and the organic residue was purified by silica gel chromatography to finally synthesize Example 1a (96%, 95.4 mg) as a pale yellow solid.

[Example 2]

(E)-ethyl 2-(5-methyl-1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 2 corresponds to a compound represented by Formula 2 below.

[Formula 2]

[Synthesis Example 2]

It is synthesized in the same manner as in Synthesis Example 1, but instead of the quinolinium zwitterion represented by R ₁ and R _{2 =} hydrogen group, R ₃ = phenyl group, -SO ₂ R ₄ = tosyl group in Formula 3, R _{1 =} hydrogen group _, R _{2 =} methyl group, R ₃ = phenyl group, -SO ₂ R ₄ = using the quinolinium zwitterion represented by the tosyl group, Example 2 (91%, 93.1 mg) as a pale yellow solid was finally obtained. synthesized.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 148-151 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.73 (d, J = 8.17 Hz, 2H), 7.45 (d, J = 6.38 Hz, 2H), 7.36-7.26 (m, 5H), 7.14 (s, 1H) , 6.86 (d, J = 7.19 Hz, 1H), 6.80–6.75 (m, 1H), 6.69 (t, J = 7.23 Hz, 1H), 6.51 (s, 1H), 6.24 (s, 1H), 6.18 ( d, J = 7.92 Hz, 1H), 4.09–3.87 (m, 2H), 2.80 (s, 1H), 2.44 (s, 3H), 1.62 (s, 3H), 1.13 (t, J = 7.13 Hz, 3H) ); ¹³ C NMR (75 MHz, CDCL ₃ ) D 165.2, 144.8, 137.7, 134.5, 134.1, 132.3, 129.9, 128.9, 127.9, 127.7, 127.7, 126.4, 126.2, 125.4, 125.0, 123.7, 120.4, 118.5, 117.8, 117.8, 117.8 , 113.5, 60.5, 59.0, 22.0, 21.6, 13.7; IR (solid) n 1722, 1487, 1204, 1665, 1073, 692, 666 cm ^-1 ; HRMS (EI) m/z calcd. for C ₃₀ H ₂₈ N ₂ O ₄ S [M] ⁺ : 512.1770, found: 512.1772.

[Example 3]

(E)-ethyl 2-(9-methyl-1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 3 corresponds to a compound represented by Formula 3 below.

[Formula 3]

[Synthesis Example 3]

It is synthesized in the same manner as in Synthesis Example 1, but instead of the quinolinium zwitterion represented by R ₁ and R _{2 =} hydrogen group, R ₃ = phenyl group, -SO ₂ R ₄ = tosyl group in Formula 3, R _{1 =} methyl group (7th position monosubstitution) _, R _{2 =} hydrogen group, R ₃ = phenyl group, -SO ₂ R ₄ = using a quinolinium zwitterion represented by a tosyl group, and finally a pale yellow solid Example 3 ( 79%, 81.4 mg) was synthesized.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 148.0-149.7 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.70 (d, J = 8.26 Hz, 2H), 7.45-7.43 (m, 2H), 7.33-7.28 (m, 5H), 7.18 (s, 1H), 6.79 ( d, J = 7.60 Hz, 1H), 6.62 (s, 1H), 6.49 (d, J = 7.33 Hz, 1H), 6.39 (d, J = 9.80 Hz, 1H), 5.98 (s, 1H), 5.60 ( dd, J = 9.73 Hz, 5.64 Hz, 1H), 4.13–4.03 (m, 2H), 3.25 (d, J = 5.47 Hz, 1H), 2.44 (s, 3H), 1.96 (s, 3H), 1.22 ( t, J = 7.14 Hz, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 166.3, 144.9, 138.7, 138.5, 135.0, 134.5, 134.0, 128.8, 127.8, 127.5, 127.3, 126.8, 126.3, 125.3, 121.1, 119.8, 119.7, 119.4, 119.3, 115.3 , 113.4, 60.6, 54.7, 21.6, 21.6, 13.9; IR (solid) n 2923, 2853, 1719, 1342, 1166, 1077, 1027, 666 cm ^-1 ; HRMS (EI) m/z calcd. for C ₃₀ H ₂₈ N ₂ O ₄ S [M] ⁺ : 512.1770, found: 512.1768.

[Example 4]

(E)-ethyl 2-(1-(4-methoxyphenyl)-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 4 corresponds to a compound represented by Formula 4 below.

[Formula 4]

[Synthesis Example 4]

It is synthesized in the same manner as in Synthesis Example 1, but instead of the quinolinium zwitterion represented by R ₁ and R _{2 =} hydrogen group, R ₃ = phenyl group, -SO ₂ R ₄ = tosyl group in Formula 3, R _{1 and Example 4} (65% _, 68.5 mg ) was synthesized.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 153-156 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.70 (d, J = 8.21 Hz, 2H), 7.38-7.31 (m, 4H), 7.07 (s, 1H), 6.91-6.78 (m, 4H), 6.68 ( t, J = 7.02 Hz, 1H), 6.60 (s, 1H), 6.41 (d, J = 9.76 Hz, 1H), 6.19 (d, J = 7.95 Hz, 1H), 5.67 (q, J = 5.12 Hz, 1H), 4.13-4.03 (m, 2H), 3.80 (s, 3H), 3.30 (d, J = 5.65 Hz, 1H), 2.44 (s, 3H), 1.24-1.19 (m, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 166.3, 159.5, 144.8, 138.9, 135.2, 134.0, 129.9, 128.5, 127.5, 127.3, 126.9, 126.7, 126.2, 122.4, 120.8, 120.3, 118.5, 115.8, 114.3, 114.3 , 60.6, 55.3, 54.8, 21.6, 13.9; IR (solid) n 2921, 2853, 1715, 1598, 1173, 1160, 665 cm ^-1 ; HRMS (EI) m/z calcd. for C ₃₀ H ₂₈ N ₂ O ₅ S [M] ⁺ : 528.1719, found: 528.1716.

[Example 5]

(E)-ethyl 2-(3-tosyl-1-(4-(trifluoromethyl)phenyl)-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 5 corresponds to a compound represented by Formula 5 below.

[Formula 5]

[Synthesis Example 5]

It is synthesized in the same manner as in Synthesis Example 1, but instead of the quinolinium zwitterion represented by R ₁ and R _{2 =} hydrogen group, R ₃ = phenyl group, -SO ₂ R ₄ = tosyl group in Formula 3, R ₁ and R _{2 =} hydrogen group, R ₃ =4-(trifluoromethyl)phenyl group, -SO ₂ R ₄ =using quinolinium zwitterion represented by tosyl group, and finally Example 5 (94%) as a pale yellow solid , 106.1 mg) was synthesized.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 142-146 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.70 (d, J = 8.22 Hz, 2H), 7.55 (s, 4H), 7.34 (d, J = 8.14 Hz, 2H), 7.27 (d, J = 7.61 Hz) , 2H), 6.92 (d, J = 7.20 Hz, 1H), 6.83 (t, J = 7.07 Hz, 1H), 6.72 (t, J = 7.22 Hz, 2H), 6.64 (s, 1H), 6.44 (d , J = 9.81 Hz, 1H), 6.09 (d, J = 7.99 Hz, 1H), 5.69 (q, J = 5.15 Hz, 1H), 4.12–4.03 (m, 2H), 3.25 (d, J = 5.65 Hz) , 1H), 2.45 (s, 3H), 1.24-1.19 (m, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 166.1, 145.2, 138.5, 138.1, 138.1, 134.6, 134.6, 133.8, 130.0, 130.0, 129.9, 129.4, 128.8, 128.7, 127.5, 127.5, 127.5, 127.2, 127.2, 126.2 , 125.9, 125.9, 125.9, 125.3, 124.7, 122.4, 122.3, 120.7, 120.6, 118.4, 116.6, 115.2, 60.7, 54.6, 21.7, 13.9; IR (solid) n 1718, 1326, 1187, 1071, 751, 668 cm ^-1 ; HRMS (EI) m/z calcd. for C ₃₀ H ₂₅ F ₃ N ₂ O ₄ S [M] ⁺ : 566.1487, found: 566.1484.

[Example 6]

(E)-ethyl 2-(1-(3-fluorophenyl)-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 6 corresponds to a compound represented by Formula 6 below.

[Formula 6]

[Synthesis Example 6]

It is synthesized in the same manner as in Synthesis Example 1, but instead of the quinolinium zwitterion represented by R ₁ and R _{2 =} hydrogen group, R ₃ = phenyl group, -SO ₂ R ₄ = tosyl group in Formula 3, R ₁ and R _{2 =} hydrogen group, R ₃ =3-fluorophenyl group, -SO ₂ R ₄ =tosyl group using a quinolinium zwitterion represented by Example 6 (85%, 87.8 mg) as a pale yellow solid. was synthesized.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 147.3-149.8 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.71 (d, J = 8.26 Hz, 2H), 7.33 (d, J = 8.16 Hz, 2H), 7.29-7.22 (m, 3H), 7.13-7.09 (m, 1H), 6.98-6.90 (m, 2H), 6.85-6.80 (m, 1H), 6.71 (t, J = 7.12 Hz, 1H), 6.62 (s, 1H), 6.43 (d, J = 9.81 Hz, 1H) ), 6.16 (d, J = 8.03 Hz, 1H), 5.67 (q, J = 5.16 Hz 1H), 4.13–4.03 (m, 2H), 3.25 (d, J = 5.68 Hz, 2H), 2.44 (s, 3H), 1.21 (t, J = 7.14 Hz, 2H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 166.2, 164.9, 161.6, 145.1, 138.7, 137.0, 136.9, 134.7, 133.9, 130.5, 130.4, 130.0, 128.7, 127.5, 127.5, 127.1, 125.0, 125.0, 122.4, 120.7 , 120.7, 120.6, 120.5, 118.3, 116.4, 114.9, 114.6, 114.4, 112.4, 112.1, 60.7, 54.6, 21.7, 13.9; IR (solid) n 2953, 2928, 1719, 1488, 1188, 1168, 667 cm ^-1 ; HRMS (ESI) m/z calcd. for C ₂₉ H ₂₆ FN ₂ O ₄ S [M+H] ⁺ : 517.1592, found: 517.1597

[Example 7]

(E)-methyl 2-(1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 7 corresponds to a compound represented by Formula 7 below.

[Formula 7]

[Synthesis Example 7]

Synthesized in the same manner as in Synthesis Example 1, but using a terminal alkyne in which R ⁵ is represented by a methyl group instead of a terminal alkyne in which R ⁵ is represented by an ethyl group in the above general formula 4, finally Example 7 (93 %, 89.9 mg) was synthesized.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 155-156 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.69 (d, J = 8.13, 2H), 7.43 (d, J = 6.56, 2H), 7.33-7.24 (m, 5H), 7.19 (s, 1H), 6.91 (d, J = 7.07, 1H), 6.80–6.75 (m, 1H), 7.00–6.65 (m, 1H), 6.61 (s, 1H), 6.45 (d, J = 9.78, 1H), 6.17 (d, J = 7.99, 1H), 5.67 (dd, J = 9.71, J = 5.70 Hz 1H), 3.61 (s, 3H), 3.32 (d, J = 5.61 Hz, 1H), 2.42 (s, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) d 166.6, 144.9, 138.8, 135.2, 134.4, 134.0, 129.9, 128.9, 128.5, 127.9, 127.4, 127.2, 127.0, 126.2, 125.3, 122.3, 120.3, 120.3, 118.4, 115.3 , 113.4, 54.7, 51.4, 21.6, 21.6,13.9; IR (solid) n 2925, 2853, 1721, 1487, 1170, 682 cm ^-1 ; HRMS (EI) m/z calcd. for C ₂₈ H ₂₄ N ₂ O ₄ S [M] ⁺ : 484.1457, found: 484.1460.

[Example 8]

(E)-tert-butyl 2-(1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 8 corresponds to a compound represented by Formula 8 below.

[Formula 8]

[Synthesis Example 8]

Synthesized in the same manner as in Synthesis Example 1, but using a terminal alkyne in which R ⁵ is represented by a tert-butyl group instead of a terminal alkyne in which R ⁵ is represented by an ethyl group in Formula 4, and finally Example 8 (96%, 101.6 mg) was synthesized as a pale yellow solid.

[Data]

R _f = 0.5 (hexane/EtOAc = 1:4); mp 112-116 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.70 (d, J = 8.14 Hz, 2H), 7.45-7.43 (m, 2H), 7.33-7.25 (m, 5H), 7.17 (s, 1H), 6.92 ( d, J = 6.70 Hz, 1H), 6.81–6.79 (m, 1H), 6.71–6.66 (m, 1H), 6.60 (s, 1H), 6.41 (d, J = 9.77 Hz, 1H), 6.17 (d , J = 7.96 Hz, 1H), 5.74 (dd, J = 9.71 Hz, 5.68 Hz, 1H), 3.19 (d, J = 5.59 Hz, 1H), 2.43 (s, 3H), 1.43 (s, 9H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 165.2, 144.9, 138.8, 134.6, 134.2, 133.9, 129.9, 128.9, 128.5, 127.8, 127.8, 127.6, 126.8, 126.2, 125.3, 122.3, 121.1, 120.2, 118.6, 118.4, 118.4 , 113.6, 81.7, 54.7, 28.0, 21.7; IR (solid) n 2926, 2854, 1715, 1457, 1016, 668 cm ^-1 ; HRMS (EI) m/z calcd. for C ₃₁ H ₃₀ N ₂ O ₄ S [M] ⁺ : 526.1926, found: 526.1929.

[Example 8a]

(S,E)-tert-butyl 2-(1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 8a corresponds to a compound represented by Formula 8a below.

[Formula 8a]

[Synthesis Example 8a]

Synthesized in the same manner as in Synthesis Example 1a, but using a terminal alkyne in which R ⁵ is represented by a tert-butyl group instead of a terminal alkyne in which R ⁵ is represented by an ethyl group in Formula 4, and finally Example 8a (88%, 92.9 mg) was synthesized as a pale yellow solid.

[Data]

R _f = 0.5 (hexane/EtOAc = 1:4); mp 112-116 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.70 (d, J = 8.14 Hz, 2H), 7.45-7.43 (m, 2H), 7.33-7.25 (m, 5H), 7.17 (s, 1H), 6.92 ( d, J = 6.70 Hz, 1H), 6.81–6.79 (m, 1H), 6.71–6.66 (m, 1H), 6.60 (s, 1H), 6.41 (d, J = 9.77 Hz, 1H), 6.17 (d , J = 7.96 Hz, 1H), 5.74 (dd, J = 9.71 Hz, 5.68 Hz, 1H), 3.19 (d, J = 5.59 Hz, 1H), 2.43 (s, 3H), 1.43 (s, 9H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 165.2, 144.9, 138.8, 134.6, 134.2, 133.9, 129.9, 128.9, 128.5, 127.8, 127.8, 127.6, 126.8, 126.2, 125.3, 122.3, 121.1, 120.2, 118.6, 118.4, 118.4 , 113.6, 81.7, 54.7, 28.0, 21.7; IR (solid) n 2926, 2854, 1715, 1457, 1016, 668 cm ^-1 ; HRMS (EI) m/z calcd. for C ₃₁ H ₃₀ N ₂ O ₄ S [M] ⁺ : 526.1926, found: 526.1929; HPLC analysis: 72% ee (CHIRALPAK AD-H, hexane/i-PrOH = 90/10, flow rate: 0.5 mL/min, T = 25 °C, 254 nm), tR (major) = 10.868 min, tR (minor) = 13.620 min.

[Example 9]

(E)-phenyl 2-(1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 9 corresponds to a compound represented by Formula 9 below.

[Formula 9]

[Synthesis Example 9]

Synthesized in the same manner as in Synthesis Example 1, but using a terminal alkyne represented by a phenyl group as R ⁵ instead of a terminal alkyne represented by an ethyl group in Formula 4, and finally Example 9 ( ⁷⁹ %, 86.4 mg) was synthesized.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 118-119 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.73 (d, J = 8.23 Hz, 2H), 7.48-7.46 (m, 2H), 7.40-7.20 (m, 9H), 7.03-6.96 (m, 3H), 6.85-6.79 (m, 2H), 6.74-6.72 (m, 1H), 6.50 (d, J = 9.83 Hz, 1H), 6.22 (d, J = 7.96 Hz, 1H), 5.80 (dd, J = 9.77 Hz) , 5.68 Hz, 1H), 3.43 (d, J =5.65 Hz, 1H), 2.42 (s, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) d 164.50, 150.41, 145.12, 138.73, 137.24, 134.19, 134.02, 129.99, 129.41, 128.93 , 121.21, 120.59, 118.69, 114.26, 113.40, 55.01, 21.65; IR (solid) n 3058, 2920, 1733, 1487, 1167, 1079, 665 cm ^-1 ; HRMS (FAB) m/z calcd. for C ₃₃ H ₂₇ N ₂ O ₄ S [M+H] ⁺ : 547.1692, found: 547.1694.

[Example 10]

(E)-naphthalen-2-yl 2-(1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 10 corresponds to a compound represented by Formula 10 below.

[Formula 10]

[Synthesis Example 10]

Synthesized in the same manner as in Synthesis Example 1, but using a terminal alkyne represented by a naphthalen-2-yl group as R ⁵ instead of a terminal alkyne represented by an ethyl group as R ⁵ in the above general formula 4, and finally a pale yellow solid Example 10 (77%, 91.7 mg) was synthesized.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 108-110 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.87-7.80 (m, 3H), 7.76-7.73 (m, 2H), 7.52-7.47 (m, 6H), 7.35-7.31 (m, 5H), 7.18-7.14 (m, 1H), 7.02-7.00 (m, 1H), 6.88-6.84 (m, 2H), 6.78-6.73 (m, 1H); 6.53 (d, J = 9.92 Hz, 1H), 6.24 (d, J = 8.05 Hz, 1H), 5.83 (q, J = 5.17, 1H), 3.46 (d, J = 5.47 Hz, 1H), 2.44 (s , 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 164.7, 148.1, 145.1, 138.8, 137.4, 134.2, 134.1, 133.7, 131.4, 130.0, 129.4, 128.9, 128.7, 128.1, 127.8, 127.7, 127.5, 127.4, 127.1, 126.6, 126.6 , 126.4, 125.8, 125.4, 122.4, 121.3, 120.8, 120.6, 118.8, 118.3, 114.2, 113.4, 55.1, 21.7; IR (solid) n 2920, 2852, 1738, 1487, 1149, 663 cm ^-1 ; HRMS (ESI) m/z calcd. for C ₃₇ H ₂₈ N ₂ NaO ₄ S [M+Na] ⁺ : 619.1667, found: 619.1665.

[Example 10a]

(S,E)-naphthalen-2-yl 2-(1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 10a corresponds to a compound represented by Formula 10a below.

[Formula 10a]

[Synthesis Example 10a]

Synthesized in the same manner as in Synthesis Example 1a, but using a terminal alkyne represented by a naphthalen-2-yl group as R ^{5 instead of a terminal alkyne represented by an ethyl group as R 5 in} Formula 4, and finally obtained as a pale yellow solid Example 10a (88%, 105.3 mg) was synthesized.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 108-110 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.87-7.80 (m, 3H), 7.76-7.73 (m, 2H), 7.52-7.47 (m, 6H), 7.35-7.31 (m, 5H), 7.18-7.14 (m, 1H), 7.02-7.00 (m, 1H), 6.88-6.84 (m, 2H), 6.78-6.73 (m, 1H); 6.53 (d, J = 9.92 Hz, 1H), 6.24 (d, J = 8.05 Hz, 1H), 5.83 (q, J = 5.17, 1H), 3.46 (d, J = 5.47 Hz, 1H), 2.44 (s , 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 164.7, 148.1, 145.1, 138.8, 137.4, 134.2, 134.1, 133.7, 131.4, 130.0, 129.4, 128.9, 128.7, 128.1, 127.8, 127.7, 127.5, 127.4, 127.1, 126.6, 126.6 , 126.4, 125.8, 125.4, 122.4, 121.3, 120.8, 120.6, 118.8, 118.3, 114.2, 113.4, 55.1, 21.7; IR (solid) n 2920, 2852, 1738, 1487, 1149, 663 cm ^-1 ; HRMS (ESI) m/z calcd. for C ₃₇ H ₂₈ N ₂ NaO ₄ S [M+Na] ⁺ : 619.1667, found: 619.1665; HPLC analysis: 42% ee (CHIRALPAK AD-H, hexane/i-PrOH = 90/10, flow rate: 1 mL/min, T = 25 °C, 254 nm), tR (minor) = 20.887 min, tR ( major) = 39.446 min.

[Example 11]

(E)-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-(1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 11 corresponds to a compound represented by Formula 11 below.

[Formula 11]

[Synthesis Example 11]

Synthesized in the ^same manner as in Synthesis Example 1, but using a terminal alkyne in which R ⁵ is represented by a 2-isopropyl-5-methylcyclohexyl group instead of a terminal alkyne represented by an ethyl group in Formula 4 above Finally, Example 11 (80%, 97.5 mg) as a pale yellow solid was synthesized.

[Data]

R _f = 0.6 (hexane/EtOAc = 1:4); dr: 1:1; mp104-107 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.72-7.68 (m, 2H), 7.45-7.42 (m, 2H), 7.34-7.28 (m, 5H), 7.21 (s, 0.5H), 7.17(s, 0.5H), 6.89-6.85 (m, 1H), 6.82-6.74 (m, 1H), 6.70-6.60 (m, 2H), 6.39 (d, J = 4.43 Hz, 0.5H), 6.36 (d, J = 4.43 Hz, 0.5H), 6.16 (d, J = 8.00 Hz, 1H), 5.82–5.77 (m, 0.5H), 5.76–5.72 (m, 0.5H), 4.71–4.59 (m, 1H), 3.32 ( d, J = 5.62 Hz, 0.5H), 3.27 (d, J = 5.52 Hz, 0.5H), 2.44 (s, 3H), 2.03–1.99 (m, 1H), 1.67–1.65 (m, 3H), 1.48 (m, 1H), 1.32-1.28 (m, 1H), 0.97-0.92 (m, 4H), 0.88-0.75 (m, 8H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 165.6, 165.4, 144.9, 138.5, 138.5, 134.4, 134.4, 134.4, 133.9, 133.9, 129.9, 128.9, 128.4, 128.3, 127.9, 127.6, 127.6, 127.5, 126.9 , 126.9, 126.6, 126.2, 125.3, 125.3, 122.3, 121.2, 121.1, 120.2, 120.1, 118.5, 118.5, 116.6, 115.9, 113.5, 113.4, 75.1, 74.9, 54.9, 54.8, 46.6, 46.6, 40.7, 40.5 , 34.0, 31.4, 31.3, 26.0, 25.5, 23.2, 23.2, 22.1, 22.0, 21.7, 20.8, 20.7, 16.4, 16.2; IR (solid) n 2952, 2869, 1713, 1487, 1366, 1170, 665 cm ^-1 ; HRMS (FAB) m/z calcd. for C ₃₇ H ₄₁ N ₂ O ₄ S [M+H] ⁺ : 609.2782, found: 609.2787.

[Example 11a]

(E)-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-((S)-1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH) -ylidene)acetate

Example 11a corresponds to a compound represented by Formula 11a below.

[Formula 11a]

[Synthesis Example 11a]

Synthesized in the same manner as in Synthesis Example 1a, but using a terminal alkyne in which R ⁵ is represented by a 2-isopropyl-5-methylcyclohexyl group instead of a terminal alkyne in which R ⁵ is represented by an ethyl group in the above general formula 4 Finally, Example 11a (85%, 103.6 mg) as a pale yellow solid was synthesized.

[Data]

R _f = 0.6 (hexane/EtOAc = 1:4); dr; 9:1; mp 104-107 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.72-7.68 (m, 2H), 7.45-7.42 (m, 2H), 7.33-7.28 (m, 5H), 7.22 (s, 0.9H), 7.17 (s, 0.1H), 6.89-6.86 (m, 1H), 6.80-6.74 (m, 1H), 6.70-6.63 (m, 1H), 6.60 (s, 1H), 6.40-6.35 (m, 1H), 6.16 (d , J = 7.99 Hz, 1H), 5.79 (dd, J = 9.80, 5.63 Hz, 0.9H), 5.75–5.72 (m, 0.1H), 4.71–4.59 (m, 1H), 3.32 (d, J = 5.64 Hz, 0.9H), 3.27 (d, J = 5.68 Hz, 0.1H) 2.44 (s, 3H), 2.06-2.03 (m, 1H), 1.68-1.64 (m, 3H), 1.48-1.46 (m, 1H) ), 1.32-1.28 (m, 1H), 1.28-0.92 (m, 4H), 0.88-0.75 (m, 8H); ¹³ C NMR (75 MHz, CDCL ₃ ) d 165.4, 144.97, 138.5, 134.4, 134.0, 129.9, 128.9, 128.3, 127.9, 127.6, 126.9, 126.6, 126.2, 125.3, 122.3, 121.2, 120.1, 118 .. 5, 116.0, 113.5, 75.0, 54.9, 46.6, 40.7, 34.1, 31.4, 25.5, 23.2, 22.0, 21.7, 20.9, 16.4; IR (solid) n 2952, 2869, 1713, 1487, 1366, 1170, 665 cm ^-1 ; HRMS (FAB) m/z calcd. for C ₃₇ H ₄₁ N ₂ O ₄ S [M+H] ⁺ : 609.2782, found: 609.2787; HPLC analysis: 80% ee (CHIRALPAK OD-H, hexane/i-PrOH = 90/10, flow rate: 0.5 mL/min, T = 25 °C, 254 nm), tR (major) = 9.500 min, tR (minor) = 10.380 min.

[Example 12]

(E)-ethyl 2-(10-phenyl-8-tosyl-6aH-pyrazino[2,1-c][4,7]phenanthrolin-7(8H)-ylidene)acetate

Example 12 corresponds to a compound represented by Formula 12 below.

[Formula 12]

[Synthesis Example 12]

It is synthesized in the same manner as in Synthesis Example 1, but instead of the quinolinium zwitterion represented by R ₁ and R _{2 =} hydrogen group, R ₃ = phenyl group and -SO ₂ R ₄ = tosyl group in Formula 3, R ₁ = benzene ring and conjugated pyridyl (pyridyl) group, R _{2 =} hydrogen group, R ₃ = phenyl group and -SO ₂ R ₄ = yellow solid using quinolinium zwitterion represented by = tosyl group Example 12 (95%, 104.6 mg) was synthesized.

[Data]

R _f = 0.5 (hexane/EtOAc = 2:1); mp 108-112; ^1H NMR (300 MHz, CDCl ₃ ) d 8.69-8.68 (m, 1H), 8.20 (d, J = 8.51 Hz, 1H), 7.73 (d, J = 8.26 Hz, 2H), 7.58 (d, J = 9.24 Hz, 1H), 7.49–7.46 (m, 2H), 7.36–7.30 (m, 7H), 7.13 (d, J = 10.06 Hz, 1H), 6.78 (d, J = 9.23 Hz, 1H), 6.65 ( s, 1H), 5.89 (dd, J = 9.98 Hz, J = 5.86 Hz, 1H), 4.11-3.98 (m, 2H), 3.52 (d, J = 5.86 Hz, 1H), 2.44 (s, 3H), 1.06 (t, J = 7.13 Hz, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 166.1, 147.9, 145.1, 143.7, 137.4, 135.4, 134.2, 134.0, 130.1, 130.0, 129.6, 129.2, 129.1, 129.1, 128.2, 127.5, 125.8, 125.3, 125.0, 115.8 , 114.7, 114.0, 60.7, 54.7, 21.7, 13.8; IR (solid) n 1717.78, 1374.03, 1186.97, 1172.03, 668.21 cm ^-1 ; HRMS (FAB) m/z calcd. for C ₃₂ H ₂₇ N ₃ O ₄ S [M+H] ⁺ : 550.1801, found: 550.1804.

[Example 13]

(E)-ethyl 2-(4-phenyl-2-tosyl-2,13a-dihydro-1H-pyrazino[1,2-i][1,7]phenanthrolin-1-ylidene)acetate

Example 13 corresponds to a compound represented by Formula 13 below.

[Formula 13]

[Synthesis Example 13]

It is synthesized in the same manner as in Synthesis Example 1, but instead of the quinolinium zwitterion represented by R ₁ and R _{2 =} hydrogen group, R ₃ = phenyl group and -SO ₂ R ₄ = tosyl group in Formula 3, R ₁ = benzene ring and conjugated pyridyl (pyridyl) group, R _{2 =} hydrogen group, R ₃ = phenyl group and -SO ₂ R ₄ = yellow solid using quinolinium zwitterion represented by = tosyl group Example 13 (78%, 85.5 mg) was synthesized.

[Data]

R _f = 0.2 (hexane/EtOAc = 1:3); mp 165-166; ^1H NMR (300 MHz, CDCl ₃ ) d 8.76-8.74 (m, 1H), 7.86-7.72 (m, 4H), 7.50-7.47 (m, 2H), 7.36-7.23 (m, 7H), 7.15 (dd , J = 8.12 Hz, J = 4.22 Hz, 1H), 6.71 (s, 1H), 6.60 (d, J = 8.96 Hz, 1H), 5.78 (dd, J = 10.01 Hz, J = 5.70 Hz, 1H), 4.11–3.99 (m, 2H), 3.39 (d, J = 5.71 Hz, 1H), 2.44 (s, 3H), 0.94 (t, J = 7.13 Hz, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 166.3, 150.0, 145.1, 144.6, 139.7, 135.8, 134.5, 133.8, 130, 130, 129.1, 128.1, 127.6, 127.5, 125.6, 125.2, 123.3, 122.8, 119.7, 119.1, 118.9, 118.9 , 117.1, 116.5, 114.2, 60.9, 54.8, 21.7, 13.5; IR (solid) n 1718.75, 1500.83, 1365.84, 1172.51, 735.23 cm ^-1 ; HRMS (FAB) m/z calcd. for C ₃₂ H ₂₇ N ₃ O ₄ S [M+H] ⁺ : 550.1801, found: 550.1800.

[Example 14]

(S,E)-ethyl 2-(8-methyl-1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 14 corresponds to a compound represented by Formula 14 below.

[Formula 14]

[Synthesis Example 14]

Under a nitrogen atmosphere, in a test tube with a triangular stirring bar, R ₁ in Formula 3 = monosubstituted methyl group at position 6, R _{2 =} hydrogen group, R ₃ = phenyl group, -SO ₂ R ₄ = tosyl group A stirred reaction mixture was prepared by adding the indicated quinolinium zwitterion (0.2 mmol), DIPEA (0.5 eq) and 1,4-dioxane (1 mL). A first mixture was prepared by adding Cu(MeCN) ₄ BF ₄ (5 mol%) and ( S )-DM-SegPhos (6 mol%) in 1,4-dioxane (1 mL) to the stirred reaction mixture. . Then, at room temperature for 4 hours, a terminal alkyne (1.2 eq) in which the R ⁵ group is represented by an ethyl group in 1,4-dioxane (1 mL) in 1,4-dioxane (1 mL) was added dropwise to the first mixture. A second mixture was prepared. After 24 hours, the second mixture was filtered through a celite pad and the filtrate was washed with EtOAc (10 mL x 3). Thereafter, the organic solvent was removed under reduced pressure, and the organic residue was purified by silica gel chromatography to finally synthesize Example 14 (96%) as a pale yellow oil.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 136-137 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.70 (d, J = 8.29 Hz, 2H), 7.46-7.43 (m, 2H), 7.34-7.28 (m, 5H), 7.16 (s, 1H), 6.72( s, 1H), 6.61–6.59 (m, 2H), 6.39 (d, J = 9.79 Hz, 1H), 6.06 (d, J = 8.21 Hz, 1H), 5.66 (dd, J = 9.74 Hz, 5.70 Hz, 1H), 4.14–4.03 (m, 2H), 3.24 (d, J = 5.68 Hz, 1H), 2.44 (s, 3H), 2.13 (s, 3H), 1.23 (t, J = 7.15 Hz, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 166.4, 144.9, 136.5, 135.0, 134.0, 129.9, 129.5, 129.2, 128.9, 127.9, 127.6, 127.5, 127.5, 126.4, 125.3, 122.2, 120.7, 118.4, 116.0, 113.2 , 60.6, 54.7, 21.7, 20.3, 13.9; IR (solid) n 2981, 2912, 1715, 1492, 1186, 969, 665 cm ^-1 ; HRMS (FAB) m/z calcd. For C ₃₀ H ₂₉ N ₂ O ₄ S [M+H] ⁺ 513.1848, found: 513.1844; HPLC analysis: 92% ee (CHIRALPAK AD-H, hexane/i-PrOH = 90/10, flow rate: 0.15 mL/min, T = 25 °C, 254 nm), tR (major) = 66.350 min, tR (minor) = 75.923 min.

[Example 15]

(S,E)-ethyl 2-(8-methoxy-1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 15 corresponds to a compound represented by Formula 15 below.

[Formula 15]

[Synthesis Example 15]

It is synthesized in the same manner as in Synthesis Example 1a, but instead of the quinolinium zwitterion represented by R ₁ and R ₂ =hydrogen group, R ₃ =phenyl group, -SO ₂ R ₄ =tosyl group in Formula 3, R ₁ = A monosubstituted methoxy group at position 6 and R ₂ =hydrogen group, R ₃ =phenyl group, -SO ₂ R ₄ =a quinolinium zwitterion represented by a tosyl group is finally obtained as a pale yellow solid Example 15 (86%, 91.1 mg) was synthesized.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 147-148; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.72 (d, J = 8.22, 2H), 7.44-7.42 (m, 2H), 7.34-7.28 (m, 5H), 7.13 (s, 1H), 6.60 (s , 1H), 6.50 (d, J = 2.81, 1H), 6.40–6.35 (m, 2H), 6.10 (d, J = 8.80 Hz, 1H), 5.71 (dd, J = 9.73 Hz, 5.65 Hz, 1H) , 4.14-4.03 (m, 2H), 3.65 (s, 3H), 3.30 (d, J = 5.62 Hz, 1H), 2.44 (m, 3H), 1.23 (t, J = 7.14 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) d 166.3, 153.6, 144.9, 135.2, 134.6, 134.0, 132.7, 129.9, 128.8. 127.9, 127.5, 127.2, 126.6, 125.5, 123.6, 122.1, 119.6, 115.7, 113.4, 112.7, 112.7, 60.6, 55.4, 54.8, 21.7, 14.0; IR (solid) n 2963, 2921, 1721, 1488, 1166, 1079, 664 cm ^-1 ; HRMS (FAB) m/z calcd. for C ₃₀ H ₂₉ N ₂ O ₅ S [M+H] ⁺ : 529.1797, found: 529.1796; HPLC analysis: 98%ee (CHIRALPAK AD-H, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, T = 25 °C, 254 nm), tR (minor) = 12.446 min, tR (major) = 33.910 min.

[Example 16]

(S,E)-ethyl 2-(1-(4-fluorophenyl)-8-methyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 16 corresponds to a compound represented by Formula 16 below.

[Formula 16]

[Synthesis Example 16]

It is synthesized in the same manner as in Synthesis Example 1a, but instead of the quinolinium zwitterion represented by R ₁ and R ₂ =hydrogen group, R ₃ =phenyl group, -SO ₂ R ₄ =tosyl group in Formula 3, R ₁ = Monosubstituted methyl group at position 6, R ₂ = Hydrogen group, R ₃ = 4-fluorophenyl group, -SO ₂ R ₄ = Use of a quinolinium zwitterion represented by a tosyl group to finally obtain a pale yellow oil Example 16 (98%, 103.5 mg) was synthesized.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 133-134 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.70 (d, J = 8.28 Hz, 2H), 7.42-7.32 (m, 4H), 7.09 (s, 1H), 6.99 (t, J = 8.65 Hz, 2H) , 6.72 (s, 1H), 6.63–6.59 (m, 2H), 6.38 (d, J = 9.79 Hz, 1H), 6.03 (d, J = 8.20 Hz, 1H), 5.66 (dd, J = 9.74 Hz, 5.68 Hz, 1H), 4.13–4.03 (m, 2H), 3.26 (d, J = 5.63 Hz, 1H), 2.44 (s, 3H), 2.14 (s, 3H), 1.22 (t, J = 7.14 Hz, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D166.3, 164.1, 160.8, 145.0, 136.4, 135.0, 134.0, 130.7, 130.6, 129.9, 129.8, 129.1, 127.7, 127.5, 127.5, 127.1, 127.0, 125.6, 122.4 120.8, 118.4, 116.0, 115.9, 115.7, 112.8, 60.7, 54.8, 21.7, 20.3, 13.9; IR (solid) n 2975, 2924, 1716, 1492, 1168, 662 cm ^-1 ; HRMS (FAB) m/z calcd. for C ₃₀ H ₂₈ FN ₂ O ₄ S [M+H] ⁺ : 531.1754, found: 531.1756; HPLC analysis: 80% ee (CHIRALPAK AD-H, hexane/i-PrOH = 30/70, flow rate: 0.2 mL/min, T = 25 °C, 254 nm), tR (major) = 35.841 min, tR (minor) = 42.194 min.

[Example 17]

(S,E)-ethyl 2-(1-(4-chlorophenyl)-8-methoxy-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 17 corresponds to a compound represented by Formula 17 below.

[Formula 17]

[Synthesis Example 17]

It is synthesized in the same manner as in Synthesis Example 1a, but instead of the quinolinium zwitterion represented by R ₁ and R ₂ =hydrogen group, R ₃ =phenyl group, -SO ₂ R ₄ =tosyl group in Formula 3, R ₁ = Monosubstituted methoxy group at position 6, R ₂ = Hydrogen group, R ₃ = 4-chlorophenyl group, -SO ₂ R ₄ = Using quinolinium zwitterion represented by a tosyl group, a light yellow solid is finally obtained. Example 17 (94%, 106.2 mg) was synthesized.

[Data]

R _f = 0.5 (hexane/EtOAc = 1:4); mp 133-134 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.70 (d, J = 8.16 Hz, 2H), 7.37-7.24 (m, 6H), 7.11 (s, 1H), 6.59 (s, 1H), 6.51-6.50 ( m, 1H), 6.40–6.37 (m, 2H), 6.05 (d, J = 8.78 Hz, 1H), 5.70 (dd, J = 9.72 Hz, 5.65 Hz, 1H), 4.13–4.03 (m, 2H), 3.66 (s, 3H), 3.27 (d, J = 5.55 Hz, 1H), 2.44 (s, 3H), 1.25–1.20 (m, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 166.2, 153.8, 145.0, 135.0, 133.9, 133.5, 133.1, 132.4, 129.9, 129.0, 127.5, 127.2, 126.7, 125.5, 123.7, 122.1, 119.5, 115.8, 113.3, 112.9 , 112.9, 60.7, 55.4, 54.7, 21.7, 14.0; IR (solid) n 2920, 2852, 1716, 1488, 1363, 1167, 1077, 658 cm ^-1 ; HRMS (FAB) m/z calcd. For C ₃₀ H ₂₈ ClN ₂ O ₅ S [M+H] ⁺ : 563.1407, found: 563.1404; HPLC analysis: 99% ee (CHIRALPAK AD-H, hexane/i-PrOH = 70/30, flow rate: 1.0 mL/min, T = 25 °C, 254 nm), tR (minor) = 11.587 min, tR (major) = 29.693 min.

[Example 18]

(S,E)-ethyl 2-(1-(4-bromophenyl)-8-methoxy-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 18 corresponds to a compound represented by Formula 18 below.

[Formula 18]

[Synthesis Example 18]

It is synthesized in the same manner as in Synthesis Example 1a, but instead of the quinolinium zwitterion represented by R ₁ and R ₂ =hydrogen group, R ₃ =phenyl group, -SO ₂ R ₄ =tosyl group in Formula 3, R ₁ = Monosubstituted methoxy group at position 6, R ₂ = Hydrogen group, R ₃ = 4-bromophenyl group, -SO ₂ R ₄ = Using quinolinium zwitterion represented by a tosyl group, finally a pale yellow solid Phosphorus Example 18 (64%, 77.2 mg) was synthesized.

[Data]

R _f = 0.5 (hexane/EtOAc = 1:4); mp 142-143 ^o C; ^1H NMR (300 MHz, CDCl ₃ ) d 7.70 (d, J = 8.09 Hz, 2H), 7.43-7.40 (m, 2H), 7.34-7.27 (m, 4H), 7.12 (s, 1H), 6.59( s, 1H), 6.50 (d, J = 2.59 Hz, 1H), 6.41–6.37 (m, 2H), 6.05 (d, J = 8.77 Hz, 1H), 5.70 (dd, J = 9.70 Hz, 5.65 Hz, 1H), 4.15–4.03 (m, 2H), 3.66 (s, 3H), 3.26 (d, J = 5.58 Hz, 1H), 2.44 (s, 3H), 1.22 (t, J = 7.13 Hz, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 166.2, 153.8, 145.0, 135.0, 133.9, 133.6, 132.4, 132.0, 129.9, 127.5, 127.2, 127.0, 125.5, 123.7, 122.1, 121.7, 119.5, 115.9, 113.3, 113.3, 113.3 , 112.9, 60.7, 55.4, 54.7, 21.7, 14.0; IR (solid) n 2983, 1717, 1488, 1167, 1078, 667 cm ^-1 ; HRMS (FAB) m/z calcd. for C ₃₀ H ₂₇ BrN ₂ O ₅ S [M+H] ⁺ : 607.0902, found: 607.0900; HPLC analysis: 94% ee (CHIRALPAK AD-H, hexane/i-PrOH = 80/20, flow rate: 1.0 mL/min, T = 25 °C, 254 nm), tR (minor) = 17.033 min, tR (major) = 42.194 min.

[Example 19]

(S,E)-ethyl 2-(1-(3-fluorophenyl)-8-methoxy-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 19 corresponds to a compound represented by Formula 19 below.

[Formula 19]

[Synthesis Example 19]

It is synthesized in the same manner as in Synthesis Example 1a, but instead of the quinolinium zwitterion represented by R ₁ and R ₂ =hydrogen group, R ₃ =phenyl group, -SO ₂ R ₄ =tosyl group in Formula 3, R ₁ = monosubstituted methoxy group at position 6, R ₂ = hydrogen group, R ₃ = 3-fluorophenyl group, -SO ₂ R ₄ = using quinolinium zwitterion represented by a tosyl group to finally obtain a pale yellow solid Example 19 (77%, 84.2 mg) was synthesized.

[Data]

R _f = 0.4 (hexane/EtOAc = 1:4); mp 145-146 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.70 (d, J = 8.29 Hz, 2H), 7.34 (d, J = 8.06 Hz, 2H), 7.28-7.22 (m, 2H), 7.16 (s, 1H) , 7.10 (d, J = 9.84 Hz, 1H), 6.97–6.91 (m, 1H), 6.60 (s, 1H), 6.51–6.50 (m, 1H), 6.42–6.37 (m, 2H), 6.08 (d , J = 8.78 Hz, 1H), 5.71 (dd, J = 9.72 Hz, 5.70 Hz, 1H), 4.14–4.03 (m, 2H), 3.66 (s, 3H), 3.24 (d, J = 5.55 Hz, 1H) ), 2.44 (s, 3H), 1.23 (t, J = 7.14 Hz, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 166.2, 164.8, 161.6, 153.8, 145.1, 137.2, 137.1, 134.9, 134.0, 132.5, 130.4, 130.3, 130.0, 127.5, 127.3, 125.4, 125.4, 123.7, 122.0, 120.9 , 120.9, 119.4, 116.0, 114.8, 114.6, 113.5, 113.4, 112.8, 112.6, 112.2, 60.7, 55.4, 54.7, 21.7, 14.0; IR (solid) n 2986, 2901, 1721, 1226, 1049, 664 cm ^-1 ; HRMS (FAB) m/z calcd. for C ₃₀ H ₂₈ FN ₂ O ₅ S [M+H] ⁺ : 547.1707, found: 547.1707; HPLC analysis: 98% ee (CHIRALPAK AD-H, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, T = 25 °C, 254 nm), tR (minor) = 13.012 min, tR (major) = 34.082 min.

[Example 20]

(S,E)-ethyl 2-(1-(3,5-difluorophenyl)-8-methoxy-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetate

Example 20 corresponds to a compound represented by Formula 20 below.

[Formula 20]

[Synthesis Example 20]

It is synthesized in the same manner as in Synthesis Example 1a, but instead of the quinolinium zwitterion represented by R ₁ and R ₂ =hydrogen group, R ₃ =phenyl group, -SO ₂ R ₄ =tosyl group in Formula 3, R ₁ = monosubstituted methoxy group at position 6, R ₂ = hydrogen group, R ₃ = 3,5-difluorophenyl group, -SO ₂ R ₄ = final using quinolinium zwitterion represented by tosyl group Example 20 (54%, 61.0 mg) was synthesized as a pale yellow solid.

[Data]

R _f = 0.5 (hexane/EtOAc = 1:4); mp 142-143 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.70 (d, J = 8.27 Hz, 2H), 7.35 (d, J = 8.10 Hz, 2H), 7.19 (s, 1H), 6.96-6.93 (m, 2H) , 6.72–6.65 (m, 1H), 6.60 (s, 1H), 6.52 (d, J = 2.78 Hz, 1H), 6.45–6.37 (m, 2H), 6.06 (d, J = 8.75 Hz, 1H), 5.71 (dd, J = 9.74 Hz, J = 5.73 Hz, 1H), 4.13-4.03 (m, 2H), 3.67 (s, 3H), 3.18 (d, J = 5.68 Hz, 1H), 2.45 (s, 3H) ), 1.23 (t, J = 7.15 Hz, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 166.1, 165.1, 164.9, 161.8, 161.7, 153.9, 145.2, 138.5, 138.4, 138.3, 134.5, 133.8, 132.3, 130.0, 127.5, 127.4, 124.5, 124.5, 124.4 , 121.8, 119.2, 116.3, 114.4, 113.5, 113.0, 108.2, 107.9, 103.4, 103.1, 102.7, 60.7, 55.4, 54.6, 21.7, 14.0; IR (solid) n 2987, 2865, 1722, 1490, 1168, 657 cm ^-1 ; HRMS (FAB) m/z calcd. for C ₃₀ H ₂₇ F ₂ N ₂ O ₅ S [M+H] ⁺ : 565.1609, found: 565.1613; HPLC analysis: 96% ee (CHIRALPAK AD-H, hexane/i-PrOH = 90/10, flow rate: 1.0 mL/min, T = 25 °C, 254 nm), tR (minor) = 9.840 min, tR (major) = 26.895 min.

For convenience of description, reactants are referred to using the following general formulas 2 and 3 and formula 4-1.

[Formula 3]

[Formula 4-1]

[Formula 2]

[Example 21]

(E)-N,N-dimethyl-2-(1-phenyl-3-tosyl-3H-pyrazino[1,2-a]quinolin-4(4aH)-ylidene)acetamide

Example 21 corresponds to a compound represented by Formula 21 below.

[Formula 21]

[Synthesis Example 21]

Synthesized in the same manner as in Synthesis Example 1, but using a terminal alkyne represented by Formula 4-1 instead of a terminal alkyne (1.2 equivalent) in which R ⁵ is represented by an ethyl group in Formula 4, and finally a pale yellow solid Example 21 (79%, 78.6 mg) was synthesized.

[Data]

R _f = 0.5 (hexane/EtOAc = 2:1); mp166-167 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 7.77 (d, J = 8.05 Hz, 2H), 7.44 (d, J = 6.94 Hz, 2H), 7.35-7.26 (m, 5H), 7.17 (s, 1H) , 6.89 (d, J = 7.06 Hz, 1H), 6.79–6.74 (m, 2H), 6.66 (t, J = 7.23 Hz, 1H), 6.40 (d, J = 9.78 Hz, 1H), 6.18 (d, J = 7.96 Hz, 1H), 5.77 (q, J = 5.11 Hz, 1H), 3.11 (d, J = 5.55 Hz, 2H), 2.81 (s, 3H), 2.42 (s, 3H), 2.27 (s, 3H); ¹³ C NMR (75 MHz, CDCL ₃ ) D 166.3, 144.8, 139.1, 134.6, 133.7, 133.7, 132.3, 129.9, 128.9, 128.5, 127.8, 126.6, 126.0, 125.9, 125.2, 122.9, 121.4, 121.2, 120.1, 118.3 , 113.9, 54.8, 37.8, 33.8, 21.6; IR (solid) n 2921, 2853, 1646, 1358, 1341, 1174, 666 cm ^-1 ; HRMS (ESI) m/z calcd. for C ₂₉ H ₂₇ N ₃ NaO ₃ S [M+Na] ⁺ : 520.1665, found: 520.1668.

[Experimental Example 1: Yield and E/Z ratio measurement according to changing conditions]

In the reaction proceeding with the following Reaction Scheme 1, entry1 was set as standard conditions, and the yield and E/Z ratio of the final product were measured according to the changing conditions according to Table 1 below.

[Scheme 1]

entry change condition Yield (%) ²⁾ E/Z ratio ³⁾ One Standard conditions ¹⁾ 99 >99:1 2 In the absence of CuI 0 - 3 AgOTf instead of CuI 42 >99:1 4 Et ₃ N instead of DIPEA 99 78:22 5 Cy ₂ NMe instead of DIPEA 99 93:7 6 Dioxane instead of CH ₂ Cl ₂ 99 95:5 7 Phenylacetylene instead of the terminal alkyne (reactant) in Scheme 1 0 - 1) Standard conditions: CuI (5 mol%), DIPEA (0.5 equivalent) and CH reactants quinolinium zwitterion (0.2 mmol), terminal alkyne (1.2 equivalent) as shown in Scheme 1 at 25 ° C for 4 hours ₂ Cl ₂ (3mL) was added to proceed with the reaction according to entry 1.
2) Yield measurement through ¹ H NMR (based on CH ₂ Br ₂ )
3) determined by ¹ H NMR (measuring equipment: Bruker DPX FT (400 MHz) and JEOL (300 MHz)).

Referring to Table 1, in order for the [5+1] cycloaddition reaction to proceed according to the present invention, metal compounds including CuI and AgOTf and terminal alkynes containing electron withdrawing groups are essential. It can be seen that

[Experimental Example 2: [5+1] asymmetric cycloaddition reaction]

After setting standard conditions as shown in Scheme 2 below, yield, E/Z ratio and ee (%) were measured while varying the ligand and solvent according to Table 2 below.

[Scheme 2]

Entry ¹⁾ Ligand (L*) menstruum Yield (%) ²⁾ E/Z ratio ³⁾ ee(%) ⁴⁾ One ( S ) -i Pr-BOX CH ₂ Cl ₂ 98 91:9 0 2 ( S ) -i Pr-PyBOX CH ₂ Cl ₂ 94 >99:0 4 3 ( R )-BINAP CH ₂ Cl ₂ 100 99:1 11 4 ( S )-SegPhos CH ₂ Cl ₂ 96 85:15 16 5 ( S )-SegPhos 1,2-DCE 93 92:8 20 6 ( S )-SegPhos 1,4-dioxane 84 >99:0 66 7 ( S )-DM-SegPhos 1,4-dioxane 99 >99:0 78 8 ( S )-DM-SegPhos 1,4-dioxane 99 >99:0 80 9 ( S )-DTBM-SegPhos 1,4-dioxane 47 95:5 0 1) Standard conditions: Cu- (MeCN) ₄ BF ₄ (5 mol%) to quinolinium zwitterion (0.2 mmol) and terminal alkyne (1.2 equivalent) as shown in Scheme 2 at 25 ° C. for 48 hours , Based on DIPEA (0.5 equivalent), the reaction was carried out according to each entry by changing the solvent (3mL) and the ligand (6 mol%).
2) Isolated yields
3) determined by ¹ H NMR (measuring equipment: Bruker DPX FT (400 MHz) and JEOL (300 MHz)).
4) Chiral HPLC (high-performance liquid chromatography) was measured (measurement equipment: Agilent 1260 Infinity II series).

Referring to Table 2, it can be seen that in order for the [5+1] asymmetric cycloaddition reaction according to the present invention to proceed in high yield, a metal compound having low reactivity with a chiral ligand is required. In particular, it is preferable to use a chiral ligand having a large steric hindrance and a 1,4-dioxane solvent. Although preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto. Various modifications and improvements of those skilled in the art using the basic concept of the present invention defined in the claims of are also within the scope of the present invention.

Claims (18)

A novel multi-junction heterocyclic compound represented by the following general formula 1.
[Formula 1]

(In Formula 1 above,
R ¹ is any one selected from the group consisting of a hydrogen group, a linear or branched alkyl group having 1 to 5 carbon atoms, a linear or branched alkoxy group having 1 to 5 carbon atoms, and a heteroaryl group containing a nitrogen atom;
R ² is a mono- or di-substituted substituent bonded to a carbon-carbon double bond, and is a hydrogen group or a linear or branched alkyl group having 1 to 5 carbon atoms;
R ³ is a substituted or unsubstituted phenyl group;
R ⁴ is any one selected from the group consisting of a linear or branched alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted heteroaryl group;
R ⁵ is any one selected from the group consisting of a substituted or unsubstituted alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted cycloalkyl group, and a substituted or unsubstituted aryl group) According to claim 1,
The novel multi-junction heterocyclic compound represented by Formula 1,
A novel multi-junction heterocyclic compound selected from the group consisting of compounds represented by Formulas 1 to 20 below.
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

[Formula 11]

[Formula 12]

[Formula 13]

[Formula 14]

[Formula 15]

[Formula 16]

[Formula 17]

[Formula 18]

[Formula 19]

[Formula 20]

A novel multi-junction heterocyclic compound represented by the following general formula 2.
[Formula 2]

(In Formula 2 above,
R ⁶ is any one selected from the group consisting of a hydrogen group, a linear or branched alkyl group having 1 to 5 carbon atoms, a linear or branched alkoxy group having 1 to 5 carbon atoms, and a heteroaryl group containing a nitrogen atom;
R ⁷ is a monosubstituted or disubstituted substituent bonded to a carbon-carbon double bond, and is a hydrogen group or a linear or branched alkyl group having 1 to 5 carbon atoms;
R ⁸ is a substituted or unsubstituted phenyl group;
R ⁹ is any one selected from the group consisting of a linear or branched alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted heteroaryl group) According to claim 3,
The novel multi-junction heterocyclic compound represented by Formula 2,
A novel multi-junction heterocyclic compound represented by Formula 21 below.
[Formula 21]

(S1) mixing a compound represented by the following general formula 3 with a metal compound and a basic compound in an organic solvent;
(S2) preparing a compound represented by the following general formula 1 by adding a compound represented by the following general formula 4 to the mixture of the step (S1); containing
Method for preparing a novel multi-junction heterocyclic compound.
[Formula 3]

[Formula 4]

[Formula 1]

(In Formulas 1 and 3 above,
R ¹ is any one selected from the group consisting of a hydrogen group, a linear or branched alkyl group having 1 to 5 carbon atoms, a linear or branched alkoxy group having 1 to 5 carbon atoms, and a heteroaryl group containing a nitrogen atom;
R ² is a mono- or di-substituted substituent bonded to a carbon-carbon double bond, and is a hydrogen group or a linear or branched alkyl group having 1 to 5 carbon atoms;
R ³ is a substituted or unsubstituted phenyl group;
R ⁴ is any one selected from the group consisting of a linear or branched alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted heteroaryl group;
In Formulas 1 and 4 above,
R ⁵ is any one selected from the group consisting of a substituted or unsubstituted alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted cycloalkyl group, and a substituted or unsubstituted aryl group) According to claim 5,
The metal compound,
A method for producing a novel multi-junction heterocyclic compound, which is a compound containing metal ions. According to claim 6,
The compound containing the metal ion,
A compound containing a monovalent copper ion (Cu(I)) or a compound containing a silver ion
Method for preparing a novel multi-junction heterocyclic compound. According to claim 5,
The basic compound,
Method for producing a novel multi-junction heterocyclic compound comprising any one selected from the group consisting of primary to tertiary amine compounds. According to claim 5,
In the step (S1),
Further mixing the compound represented by Formula 3 and a ligand compound,
The ligand compound,
A chiral bidentate ligand or a chiral tridentate ligand,
The metal compound is a metal complex,
In Formula 1, carbon (*) is stereoselectively arranged in an S-type
Method for preparing a novel multi-junction heterocyclic compound. According to claim 9,
The chiral bidentate ligand,

,

,

,

and

Any one selected from the group consisting of
Method for preparing a novel multi-junction heterocyclic compound. According to claim 9,
The chiral tridentate ligand,

A method for producing a phosphorus novel multi-junction heterocyclic compound. According to claim 9,
The metal composite,
Method for preparing a novel multi-junction heterocyclic compound of Cu(MeCN) ₄ BF ₄ . According to claim 9,
The organic solvent is a method for producing a novel multi-junction heterocyclic compound containing an ether-based compound. (S10) mixing a compound represented by the following general formula 3 with a metal compound and a basic compound in an organic solvent;
(S20) preparing a compound represented by the following general formula 2 by adding a compound represented by the following formula 4-1 to the mixture of the step (S10); containing
Method for preparing a novel multi-junction heterocyclic compound.
[Formula 3]

[Formula 4-1]

[Formula 2]

(In Formula 3 above,
R ¹ is any one selected from the group consisting of a hydrogen group, a linear or branched alkyl group having 1 to 5 carbon atoms, a linear or branched alkoxy group having 1 to 5 carbon atoms, and a heteroaryl group containing a nitrogen atom;
R ² is a mono- or di-substituted substituent bonded to a carbon-carbon double bond, and is a hydrogen group or a linear or branched alkyl group having 1 to 5 carbon atoms;
R ³ is a substituted or unsubstituted phenyl group;
R ⁴ is any one selected from the group consisting of a linear or branched alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted heteroaryl group;
In the above general formula 2,
R ⁶ is any one selected from the group consisting of a hydrogen group, a linear or branched alkyl group having 1 to 5 carbon atoms, a linear or branched alkoxy group having 1 to 5 carbon atoms, and a heteroaryl group containing a nitrogen atom;
R ⁷ is a monosubstituted or disubstituted substituent bonded to a carbon-carbon double bond, and is a hydrogen group or a linear or branched alkyl group having 1 to 5 carbon atoms;
R ⁸ is a substituted or unsubstituted phenyl group;
R ⁹ is any one selected from the group consisting of a linear or branched alkyl group having 1 to 8 carbon atoms, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted heteroaryl group) According to claim 14,
The novel multi-junction heterocyclic compound represented by Formula 2,
A novel multi-junction heterocyclic compound represented by Formula 21 below.
[Formula 21]

According to claim 14,
The metal compound,
A method for producing a novel multi-junction heterocyclic compound, which is a compound containing metal ions. According to claim 16,
The compound containing the metal ion,
A compound containing a monovalent copper ion (Cu(I)) or a compound containing a silver ion
Method for preparing a novel multi-junction heterocyclic compound. According to claim 14,
The basic compound,
Method for producing a novel multi-junction heterocyclic compound comprising any one selected from the group consisting of primary to tertiary amine compounds.