KR102323972B1 - Preparation method of 4-aryl-2-halopyridine derivatives - Google Patents

Abstract

The present invention relates to a method for preparing a 4-aryl-2-halopyridine derivative, wherein the method according to the present invention comprises forming γ-enamine of single-activated α,β-unsaturated nitrile, followed by halogen Compared to the conventional method using a double-activated substrate through intramolecular cyclization using a source, there is an effect of high yield and efficient formation of a 4-aryl-2-halopyridine compound under mild conditions.

Description

Preparation method of 4-aryl-2-halopyridine derivatives {Preparation method of 4-aryl-2-halopyridine derivatives}

The present invention relates to a method for preparing a 4-aryl-2-halopyridine derivative.

Heterocyclic compounds containing a pyridine group, such as niacin (vitamin B3), pyridoxine (vitamin B6), nicotine, etc., have received considerable attention due to their unique roles and constraints in various biological activities and their presence in various important molecules. receive From a pharmaceutical standpoint, pyridine-containing compounds are at the center of drug development, such as atazanavir for HIV and imatinib mesylate for chronic myeloid leukemia. In addition, this moiety is used in coordination chemistry as a catalyst in organic chemistry, as a chelating agent as indicators and bases, as a herbicide and pesticide in pesticides. As a result, tremendous efforts have been made in the synthesis of functionalized pyridines by various researchers over the past few decades.

The synthesis of pyridines containing halide groups is one of the most attractive phenomena, mainly due to its interesting properties and possibilities for further functionalization. In particular, the synthesis of 2-halopyridines is important for medicinal chemistry purposes.

In this regard, the synthesis of vinyl logus enamino malononitriles from alkylidenemalononitrile has been achieved, which is a target 2-bromonicotinonitrile ( 2-bromonicotinonitriles) was easily transformed (Fig. 1, X = Br). However, the method involved two electron withdrawing groups (EWG), making it difficult to obtain the necessary precursors for the specified cyclization. In addition, removal of residual nitriles proved to be very difficult. In the course of research on the synthesis of potent inhibitors of melanogenesis, a versatile synthesis of CGA (chlorogenic acid) derivatives having a pyridine moiety was attempted, but all attempts to remove unnecessary nitrile groups in the cyclized product were unsuccessful (Fig. 2). .

Accordingly, the present inventors devised γ functionalization of a single-activated substrate instead of a conventional double-activated substrate (Fig. 1), and enaminonitrile with only one EWG ( As a result of studying the synthesis method of enamino nitriles), it is possible to efficiently form 2-halopyridine compounds through intramolecular cyclization using a halogen source after formation of γ-enamine of a single activated α,β-unsaturated nitrile. By confirming that there is, the present invention was completed.

Korea Registered Patent No. 10-1808950

It is an object of the present invention to provide a method for preparing a 4-aryl-2-halopyridine derivative.

In order to achieve the above object,

The present invention, as shown in Scheme 1 below,

preparing a compound represented by Formula 3 by dissolving a compound represented by Formula 2 and an ammonium compound in an organic solvent, and then adding and heating N,N-Dimethylformamide dimethyl acetal (DMF-DMA) to prepare a compound represented by Formula 3 (step 1); and

preparing a compound represented by Formula 1 by dissolving the compound represented by Formula 3 in a mixed solvent of ethyl acetate (EA) and water (H ₂ O) and adding acetyl halogen (AcX) dropwise (step 2);

It provides a method for preparing a 4-aryl-2-halopyridine derivative comprising:

[Scheme 1]

In Scheme 1,

R ¹ and R ³ are independently H, nitrile, or C _6-8 arylcarbonyl;

R ² is C _6-8 aryl, 5-6 membered heteroaryl containing at least one hetero atom selected from the group consisting of N, O and S, naphthalene, or 1,3-benzodioxole, wherein the C _{6- 8} aryl includes C _1-5 straight or branched chain alkyl, C _1-3 straight or branched alkoxy, C _1-3 alkylsulfinyl, halogen, C _1-3 alkyl halide, nitro and nitrile One or more substituents selected from may be substituted;

said R ² and R ³ together with the carbon atom to which they are connected may form dihydronaphthalene;

X is halogen.

In an embodiment of the present invention, R ¹ is H, nitrile, or benzoyl;

R ² is phenyl, 5-membered heteroaryl containing one S atom, naphthalene or 1,3-benzodioxole, wherein the phenyl is C _1-3 straight-chain alkyl, methoxy, methylthio, halogen, trifluoro One or more substituents selected from the group consisting of romethyl, nitro and nitrile may be substituted;

R ³ is H or nitrile;

said R ² and R ³ together with the carbon atom to which they are connected may form dihydronaphthalene;

X may be Br or Cl.

In one embodiment of the present invention, the ammonium compound may be at least one selected from the group consisting _{of ammonium acetate (NH 4} OAc) and ammonium carbonate ((NH ₄ ) ₂ CO _{3 ).}

The preparation method according to the present invention is a conventional double-activated (double-activated) method through intramolecular cyclization using a halogen source after formation of γ-enamine of single-activated α,β-unsaturated nitrile. Compared to the method using a substrate, there is an effect that a 4-aryl-2-halopyridine compound can be formed in a high yield and efficiently under mild conditions.

1 shows a method for preparing 2-halonicotinonitrile from a conventional double-activated substrate.
2 shows the results of synthesizing a CGA (chlorogenic acid) derivative having a pyridine moiety in a previous study.
Figure 3 shows the mechanism of the 4-aryl-2-halopyridine preparation method according to the present invention.
4 shows the results of synthesizing the compound by varying some conditions of the preparation method according to the present invention.

Hereinafter, the present invention will be described in detail.

Method for preparing 4-aryl-2-halopyridine derivatives

The present invention, as shown in Scheme 1 below,

preparing a compound represented by Formula 3 by dissolving a compound represented by Formula 2 and an ammonium compound in an organic solvent, and then adding and heating N,N-Dimethylformamide dimethyl acetal (DMF-DMA) to prepare a compound represented by Formula 3 (step 1); and

preparing a compound represented by Formula 1 by dissolving the compound represented by Formula 3 in a mixed solvent of ethyl acetate (EA) and water (H ₂ O) and adding acetyl halogen (AcX) dropwise (step 2);

It provides a method for producing a 4-aryl-2-halopyridine derivative comprising a.

[Scheme 1]

In Scheme 1,

R ¹ and R ³ are independently H, nitrile, or C _6-8 arylcarbonyl;

R ² is C _6-8 aryl, 5-6 membered heteroaryl containing at least one hetero atom selected from the group consisting of N, O and S, naphthalene, or 1,3-benzodioxole, wherein the C _{6- 8} aryl includes C _1-5 straight or branched chain alkyl, C _1-3 straight or branched alkoxy, C _1-3 alkylsulfinyl, halogen, C _1-3 alkyl halide, nitro and nitrile One or more substituents selected from may be substituted;

said R ² and R ³ together with the carbon atom to which they are connected may form dihydronaphthalene;

X is halogen.

In the preparation method according to the present invention, R ¹ is H, nitrile, or benzoyl;

R ² is phenyl, 5-membered heteroaryl containing one S atom, naphthalene or 1,3-benzodioxole, wherein the phenyl is C _1-3 straight-chain alkyl, methoxy, methylthio, halogen, trifluoro One or more substituents selected from the group consisting of romethyl, nitro and nitrile may be substituted;

R ³ is H or nitrile;

said R ² and R ³ together with the carbon atom to which they are connected may form dihydronaphthalene;

X may be Br or Cl.

In the manufacturing method according to the present invention, the ammonium compound of step 1 may be at least one selected from the group consisting _{of ammonium acetate (NH 4} OAc) and ammonium carbonate ((NH ₄ ) ₂ CO _{3 ).} Preferably, it may be ammonium acetate (NH ₄ OAc), and when the ammonium acetate is used as an ammonium compound additive, there is an effect that an intermediate compound having the highest yield can be prepared within the shortest reaction time.

In the preparation method according to the present invention, the organic solvent of step 1 is dimethyl sulfoxide (DMSO), dimethylformamide (DMF), benzene, toluene, acetic acid (AcOH), glacial acetic acid, 1,4-dioxane, Acetonitrile (MeCN), ethanol (EtOH), tetrahydrofuran (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylacetamide (DMA), dichloromethane (DCM), It may be at least one selected from the group consisting of chlorobenzene, acetone, carbon tetrachloride (CCl ₄ ) and chloroform (CHCl ₃ ), and the organic solvent may be used alone or in combination. Preferably, the organic solvent of step 1 may be at least one selected from the group consisting of dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and benzene, and more preferably dimethyl sulfoxide (DMSO). ) or dimethylformamide (DMF). Dimethyl sulfoxide (DMSO) is particularly preferred, and when the solvent is used in step 1, the yield of the intermediate compound and the final compound is high.

In the manufacturing method according to the present invention, step 1 may be heating at a temperature of 110 to 130° C. for 10 to 240 minutes. More preferably, it may be heated at a temperature of 115 to 125°C for 10 to 30 minutes or 170 to 190 minutes, and even more preferably, it may be heated at a temperature of 115 to 125°C for 15 to 25 minutes. have. It may be most preferable to heat at a temperature of 118 to 122° C. for 18 to 23 minutes, and when step 1 is performed at the above temperature and time range, the compound can be efficiently produced. It is particularly preferred to heat at a temperature of 119 to 121° C. for 19 to 21 minutes.

In the preparation method according to the present invention, the mixed solvent of step 2 may be a mixture of ethyl acetate (EA) and water (H ₂ O) in a volume ratio of 4:1 to 1:4. Preferably, it may be mixed in a volume ratio of 3:0.8 to 1:3, and more preferably, mixed in a volume ratio of 3:0.8 to 3:1.2. When the mixed solvent mixed in the above volume ratio range is used, the final compound production yield is high. It is particularly preferable to mix in a volume ratio of 3:0.9 to 3:1.1, and when a mixed solvent mixed in the above volume ratio range is used, the final compound production yield can be further improved.

In the preparation method according to the present invention, the acetyl halogen in step 2 may be acetyl bromide (AcBr) or acetyl chloride (AcCl). When AcBr is used as the acetyl halogen, 4-aryl-2-bromopyridine can be produced as the final compound, and when AcCl is used as the acetyl halogen, 4-aryl-2-chloropyridine can be produced as the final compound.

In the manufacturing method according to the present invention, step 2 may be performed at room temperature for 1 to 24 hours. Preferably, it may be carried out for 1 to 8 hours, more preferably, it may be carried out for 2 to 5 hours, and even more preferably, it may be carried out for 3 to 5 hours.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following examples.

<Example 1-20> Preparation of 4-aryl-2-halopyridine derivatives

The steps for preparing the 4-aryl2-halopyridine derivative of Examples 1 to 20 are as shown in Scheme 1 below. At this time, all reactants or reagents were purchased from Aldrich, TCI, Alpha Esar and acro, and used directly without further purification.

[Scheme 1]

In this case, in the following Examples and Experimental Examples, the compounds represented by Chemical Formulas 1 to 3 in Scheme 1 were denoted as Compounds 1 to 3, respectively.

Step 1: Preparation of compound 3

DMF-DMA (3.25 mmol, 5.0 equiv) in DMSO (0.65 mL) of substituted α,β-unsaturated nitrile (compound 2, 0.65 mmol, 1.0 equiv) and NH _{4 OAc (0.78 mmol, 1.2 equiv)} ) was added. The mixture was heated at 120° C. until the reaction was complete as monitored by TLC. Then, the reacted mixture was cooled to room temperature, diluted with water and extracted with chloroform. The combined organic layer was washed with saturated NaCl solution, _{dried over anhydrous MgSO 4} and evaporated to obtain an enamine compound (Compound 3). The obtained enamine compound (Compound 3) was subjected to the following reaction without further purification.

Step 2: Preparation of target compound 1

AcBr (13.0 as an acetyl halogen compound) in a solution of 0.65 mmol (1.0 equiv) of the enamine compound (alkylidene nitrile, compound 3) in ethyl acetate (EA, 1.3 mL) and H _{2 O (0.4 mL)} mmol, 20.0 equiv) or AcCl (13.0 mmol, 20.0 equiv) were slowly added dropwise in an ice bath at 0°C. The ice bath was removed and the resulting mixture was warmed to room temperature and stirred for 4 hours. After the reaction was completed by monitoring by TLC, it was quenched with a saturated aqueous solution of _{NaHCO 3 .} After separation of the organic layer, the resulting mixture was extracted with ethyl acetate, and the mixed organic phase was dried over anhydrous MgSO ₄ . After filtration and evaporation of the solvent, the crude residue was purified by silica gel chromatography (Kieselgel 60 F254 plate, Merk; 4-10% ethyl acetate in hexane) to the 4-aryl-2-halo of Examples 1 to 20. A pyridine derivative (Compound 1) was obtained.

The chemical structural formulas and compound names of α,β-unsaturated nitrile (Compound 2) used in the preparation of the 4-aryl-2-halopyridine derivatives (Compound 1) of Examples 1 to 20 are summarized and shown in Table 1 below. .

Example α,β-unsaturated nitrile
(Compound 2) Example α,β-unsaturated nitrile
(Compound 2) One
(1a)

3-phenylbut-2-ennitrile
(3-Phenylbut-2-enenitrile) 11
(1k)

3-(2-nitrophenyl)but-2-ennitrile
(3- (2-Nitrophenyl) but-2-enenitrile) 2
(1b)

3-( o -Tolyl)but-2-ennitrile
(3-(o-Tolyl)but-2-enenitrile) 12
(1l)

3-(4-(trifluoromethyl)phenyl)but-2-ennitrile
(3-(4-(Trifluoromethyl)phenyl)but-2-enenitrile) 3
(1c)

3-( m -tolyl)but-2-ennitrile
(3-( m- Tolyl)but-2-enenitrile) 13
(1m)

4-(1-cyanoprop-1-en-2-yl)benzonitrile
(4-(1-Cyanoprop-1-en-2-yl)benzonitrile) 4
(1d)

3-(4-propylphenyl)but-2-ennitrile
(3-(4-Propylphenyl)but-2-enenitrile) 14
(1n)

3-(naphthalen-2-yl)but-2-ennitrile
(3-(Naphthalen-2-yl)but-2-enenitrile) 5
(1e)

3-(4-Methoxyphenyl)but-2-ennitrile
(3-(4-Methoxyphenyl)but-2-enenitrile) 15
(1o)

3-(thiophen-2-yl)but-2-ennitrile
(3-(Thiophen-2-yl)but-2-enenitrile) 6
(1f)

3-(3,4-dimethoxyphenyl)but-2-ennitrile
(3-(3,4-Dimethoxyphenyl)but-2-enenitrile) 16
(1p)

(E)-3-phenylpent-2-enedinitrile
((E)-3-Phenylpent-2-enedinitrile) 7
(1 g)

2-(benzo[d][1,3]dioxol-5-yl)but-2-enenitrile
(3-(Benzo[d][1,3]dioxol-5-yl)but-2-enenitrile) 17
(1q)

2-(1-phenylethylidene)malononitrile
(2-(1-Phenylethylidene)malononitrile) 8
(1h)

3-(4-(methoxythio)phenyl)but-2-ennitrile
(3-(4-(Methylthio)phenyl)but-2-enenitrile) 18
(1r)

2-(3,4-dihydronaphthalene-1(2H)-ylidene)malononitrile
(2-(3,4-dihydronaphthalen-1(2H)-ylidene)malononitrile) 9
(1i)

3-(4-Chlorophenyl)but-2-ennitrile
(3-(4-Chlorophenyl)but-2-enenitrile) 19
(1s)

(E)-2-benzoyl-3-phenylbut-2-ennitrile
((E)-2-Benzoyl-3-phenylbut-2-enenitrile) 10
(1j)

3-(3-bromophenyl)but-2-ennitrile
(3-(3-Bromophenyl)but-2-enenitrile) 20
(1a)

3-phenylbut-2-ennitrile
(3-Phenylbut-2-enenitrile)

Compound 3 produced through the reaction of Step 1 with Compound 2 (1a to 1j) of Examples 1 to 19 was carried out in Step 2 by dropwise addition of AcBr with acetylhalogen, and Compound 2 (1a) of Example 20 was prepared in step Compound 3 produced through the reaction of 1 was subjected to step 3 by dropwise addition of AcCl with acetylhalogen, to obtain final products of each of Compound 1 in Examples 1 to 20.

Table 2 below summarizes the chemical structural formulas, compound names and yields of the 4-aryl-2-halopyridine derivatives (Compound 1) of Examples 1 to 20 finally produced.

Example 4-Aryl-2-halogenpyridine derivatives
(Compound 1)
Yield (yeild, %) Example 4-Aryl-2-halogenpyridine derivatives
(Compound 1)
Yield (yeild, %) One
(3a)

2-Bromo-4-phenylpyridine
(2-Bromo-4-phenylpyridine) 81 11
(3k)

2-Bromo-4-(2-nitrophenyl)pyridine
(2-Bromo-4-(2-nitrophenyl)pyridine) 71 2
(3b)

2-Bromo-4-(o-tolyl)pyridine
(2-Bromo-4-(o-tolyl)pyridine) 78 12
(3l)

2-Bromo-4-(4-(trifluoromethyl)phenyl)pyridine
(2-Bromo-4-(4-(trifluoromethyl)phenyl)pyridine) 81 3
(3c)

2-Bromo-4-(m-tolyl)pyridine
(2-Bromo-4-(m-tolyl)pyridine) 85 13
(3m)

4-(2-bromopyridin-4-yl)benzonitrile
(4-(2-Bromopyridin-4-yl)benzonitrile) 77 4
(3d)

2-Bromo-4-(4-propylphenyl)pyridine
(2-Bromo-4- (4-propylphenyl) pyridine) 80 14
(3n)

2-Bromo-4-(naphthalen-2-yl)pyridine
(2-Bromo-4-(naphthalen-2-yl)pyridine) 78 5
(3e)

2-Bromo-4-(4-methoxyphenyl)pyridine
(2-Bromo-4-(4-methoxyphenyl)pyridine) 86 15
(3o)

2-Bromo-4-(thiophen-2-yl)pyridine
(2-Bromo-4-(thiophen-2-yl)pyridine) 66 6
(3f)

2-Bromo-4- (3,4-dimethoxyphenyl) pyridine
(2-Bromo-4-(3,4-dimethoxyphenyl)pyridine) 53 16
(3p)

6-Bromo-4-phenylnicotinonitrile
(6-Bromo-4-phenylnicotinonitrile) 74 7
(3g)

2-(benzo[d][1,3]dioxol-5-yl)-2-bromopyridine
(4-(Benzo[d][1,3]dioxol-5-yl)-2-bromopyridine) 79 17
(3q)

2-Bromo-4-phenylnicotinonitrile
(2-Bromo-4-phenylnicotinonitrile) 74 8
(3h)

2-Bromo-4-(4-(methylthio)phenyl)pyridine
(2-Bromo-4-(4-(methylthio)phenyl)pyridine) 86 18
(3r)

2-Bromo-5,6-dihydrobenzo[f]-isoquinoline-1-carbonitrile
(2-Bromo-5,6-dihydrobenzo[f]isoquinoline-1-carbonitrile) 53 9
(3i)

2-Bromo-4- (4-chlorophenyl) pyridine
(2-Bromo-4- (4-chlorophenyl) pyridine) 84 19
(3s)

(2-bromo-4-phenylpyridin-3-yl) (phenyl) methanone
((2-Bromo-4-phenylpyridin-3-yl)(phenyl)methanone) 79 10
(3j)

2-Bromo-4-(3-bromophenyl)pyridine
(2-Bromo-4- (3-bromophenyl) pyridine) 92 20
(10)

2-chloro-4- (4-chlorophenyl) pyridine
(2-Chloro-4- (4-chlorophenyl) pyridine) 78

<Experimental Example 1> Optimization of reaction conditions of step 1 for generating an enamine intermediate

1i (compound 2 of Example 9, 1.0 equivalent) and DMF-DMA (N,N-dimethylformamide dimethyl acetal, 5.0 equivalent) as the starting material, alkylidene nitrile (compound 2), were used as initial basic conditions, and , the type of additive (additive, 1.2 equivalents) and solvent, and the reaction temperature (Temp. The yield (yield, %) of 2i (compound 3 of Example 9) as the enamine compound (enamino nitrile), which is an intermediate compound (enamino nitrile), which is an intermediate compound produced through the reaction of step 1 according to each reaction condition, is shown in Table 3 below. .

Experimental example additive
(Additive,
1.2 equiv.) menstruum
(Solvent) Temperature
(Temp., ℃) hour
(Time, h) transference number
(Yield, %)[b] 1-1 - - 120 24 39 1-2 Ac ₂ O ^[c] DCM RT/reflux 24 NR 1-3 Acid or Base ^[d] - 120 24 NR 1-4 NH ₄ OAc - RT 24 43 1-5 NH ₄ OAc - 120 2 55 1-6 NH ₄ OAc DMSO 120 20min 97 1-7 NH ₄ OAc ^[c] DMSO 120 24 60 1-8 NH ₄ OAc ^[e] DMSO 120 2 80 1-9 NH ₄ OAc DMF 120 24 48 1-10 NH ₄ OAc Benzene 120 24 59 1-11 Other Acetates DMSO 120 3 52 to 60 1-12 NH ₄ Cl DMSO 120 24 14 1-13 (NH ₄ ) ₂ CO ₃ DMSO 120 3 95 1-14 Na ₂ CO ₃ DMSO 120 3 47 ^[a] Reaction conditions: 1i (0.2 mmol, 1.0 equiv), DMF-DMA (5.0 equiv), solvent (1.0M).
^[b] Calculated by GC using mesitylene as an internal standard.
^[c] 20 mol% of the additive was used.
^[d] acetic acid, NaOMe, DBU and K ₂ CO ₃
^[e] Additive 3.0 equivalents, RT = room temperature, NR = No Reaction

First, when the reaction was carried out without additives, the intermediate compound enaminonitrile (compounds 3 and 2i of Example 9) was not observed at room temperature, but 39% yield was obtained during the reaction at 120° C. for 24 hours (Experimental Example 1) -One). Next, Mcquade's reaction conditions (Ac ₂ O, DCM) were tried, but the desired product was not obtained (Experimental Example 1-2). Afterwards, an acid or a base was used as an additive to activate nitrile and/or DMF-DMA, but it was found to be ineffective (Experimental Examples 1-3). Upon reaction with ammonium acetate at room temperature in the absence of a solvent, the desired enamine (compounds 3 and 2i of Example 9) was obtained in 43% yield (Experimental Examples 1-4). It was hypothesized that the acetate ion could efficiently activate DMF-DMA to generate an active electrophile species (Fig. 3). After 2 hours, the yield was increased to 55% at 120° C. under neat conditions (Experimental Examples 1-5). The conversion condition from no solvent to DMSO solvent showed excellent performance improvement, and as the solubility of acetate in DMSO increased, the highest yield of 97% was observed even after only 20 minutes of reaction (Experimental Examples 1-6).

On the other hand, as a result of screening using various kinds of additives or other solvents, it was found that the intermediate production yield was very low and the reaction time was longer (Experimental Examples 1-7 to 1-10). For other acetate sources, the reaction did not show significant improvement in yield. For example, when _{CsOAc, NaOAc, KOAc, or LiOAc was used instead of NH 4} OAc, a yield of 52 to 60% (52 to 60%, Experimental Example 1-11) was shown. As a result of screening other ammonium additives, enamine compounds (compounds 3 and 2i of Example 9) were produced in a yield of 95% when ammonium carbonate was used, and when ammonium chloride or sodium carbonate was used, the yield was greatly reduced (Experimental Example 1- 12 to 1-14).

From these results, both ammonium and acetate ions are essential for the formation of enamine intermediates in the reaction of step 1, and in particular, _{when using NH 4} OAc, high yields of intermediate products (compounds 3 and 2i of Example 9) can be efficiently produced within the shortest reaction time. It was confirmed that it can be obtained.

In addition, an additional experiment was carried out for step 1 under optimal conditions by varying several conditions for 1i (compound 2 of Example 9), and the results are shown in FIG. 4 . First, _{when the reaction was performed using NaOMe instead of NH 4} OAc, the yield was reduced to 30%. This may be due to the lower stabilizing ability of NaOMe than _{NH 4 OAc.} In addition, as a result of confirming whether the reaction pathway was an ene-type or enolate-type reaction using _{D 2 O as a proton source, when D 2} O was used instead of DMF-DMA, an intermediate compound was not generated, _{When D 2} O and DMF were used instead of DMSO, the desired intermediate product 2i (compound 3 of Example 9) in 70% yield containing the product 1i-d in which the hydrogen of 1i (compound 2 of Example 9) was exchanged with deuterium ) to obtain a mixed mixture in a yield of 30%.

From these results, it was confirmed that both DMF-DMA and NH ₄ OAc were very essential for the reaction of step 1. Without them, the deuterated product 1i- d is not obtained. Also, in the course of the reaction, DMF-DMA is initially dissociated into both alkoxyiminiumcation and methoxide ion, which acted as a base for extracting γ-hydrogen, and intermediate compound formation is mainly alkoxyiminiumcation. It was confirmed that it depends on the stabilization of iminium cations.

<Experimental Example 2> Optimization of reaction conditions in step 2 for generation of halopyridine

In order to check the optimal reaction conditions of step 2 for the formation of γ-enamine of the target compound, the intermediate enaminonitrile 2i prepared by the method of step 1 from the starting material 1i (compound 2 of Example 9) (execution) Compound 3 of Example 9, 0.28 mmol) as a reaction starting material, the type of additive (additive, 5-20 equivalents) and solvent (solvent, 0.5M), reaction temperature (Temp., ℃), and time (time, h ) to investigate intramolecular cyclization. The yield (yield, %) of the bromopyridine compound 3i (compound 1 of Example 9), which is the final compound produced through the reaction of step 2 and each reaction condition, is shown in Table 4 below.

Experimental example additive
(Additive,
equiv.) menstruum
(Solvent, 0.5M) Temperature
(Temp., ℃) hour
(Time, h) transference number
(Yield, %)[b] 2-1 HBr (6.3) ^[c] , AcOH (20) Toluene 55 24 57 2-2 AcBr (5) Toluene, H ₂ O (3:1) 55 24 39 2-3 AcBr (10) Toluene, H ₂ O (3:1) 55 6 81 2-4 AcBr (15) Toluene, H ₂ O (3:1) 55 6 62 2-5 AcBr (10) THF, H ₂ O (3:1) 55 24 Decompose 2-6 AcBr (10) DMF, H ₂ O (3:1) 55 24 Decompose 2-7 AcBr (10) EA, H ₂ O (3:1) 55 4 73 2-8 AcBr (10) EA, H ₂ O (3:1) RT 24 trace 2-9 AcBr (20) EA, H ₂ O (3:1) RT 4 84 2-10 AcBr (20) EA, H ₂ O (1:1) RT 24 60 2-11 AcBr (20) EA, H ₂ O (1:3) RT 24 40 ^[a] 2i was carried out under the reaction conditions of 0.28 mmol.
^[b] isolation yield
^[c] 48% HBr was used.
* THF=Anhydrous tetrahydrofuran, DCM=dichloromethane, EA=ethyl acetate, RT=room temperature

As a result of experiments under various conditions, using EA:H ₂ O (3:1) as a solvent and using 20 equivalents of acetyl bromide (AcBr) as a bromide source was not only the most effective in terms of yield (84 %), temperature and time, it was confirmed that the target compound 3i (compound 1 of Example 9) could be efficiently produced under mild conditions, and it was confirmed that the corresponding conditions were optimal conditions.

<Experimental Example 3> Comparison of halopyridine yields for each type of starting material under optimal reaction conditions

For the 4-aryl-2-halopyridine compounds of Examples 1 to 20 prepared under the optimal reaction conditions confirmed in Experimental Examples 1 and 2, the yield of the final product according to the substituent type of the starting material (Compound 2) was determined. compared.

As shown in Tables 1 and 2 above, substrates containing alkyl at the ortho, meta and para positions of the aromatic ring (Examples 2 to 4) and compounds containing methoxy substituents (Examples 5 and 6) are preferred It was converted into a bromopyridine derivative compound in yield. A compound having a methylenedioxy and methyl sulfide substituent was also prepared as a bromopyridine derivative compound in excellent yield (Examples 7 and 8). Next, as a result of preparing the target compound from the halogen-substituted acetophenone compound, very excellent yields were obtained (Examples 9 and 10). The compound containing the electron withdrawing functional group also obtained the target compound in excellent yield (Examples 11 to 13).

2-Acetylnaphthalene gave the desired product (Example 14) in high yield. Acetyl thiophene was also reacted under the same conditions to give the desired product (Example 15) in 66% yield. A 2-bromonicotino nitrile derivative was synthesized by modification of SM(2-(1-Phenylethylidene)malononitrile). After three consecutive reactions, 1-cyanoacetophenone (1-cyanoacetophenone) provided the desired product of Example 16 in a yield of 74%. In the substrate having active methylidene, the reaction proceeded effectively under the above conditions to obtain the desired product (Examples 16, 17 and 19) in good yield. The intermediate dinitrile obtained as a result of using α-tetralone in the same manner was successfully converted to the desired product (Example 18) in 53% yield.

On the other hand, in the case of Examples 16, 17 and 19, as a result of carrying out step 1 using DCM instead of DMSO at room temperature, the target compound was produced in good yield, but showed a lower yield than DMSO, and alkyl and aryl substrates at the γ position Compounds with For example, propiophenone did not provide the desired enamine product, whereas 2-phenylacetophenone produced the desired enamine in a very low yield of less than 20%. provided.

In addition, in Step 1, the same reaction as in Example 9 was performed, and as a result of using acetyl chloride (AcCl) instead of acetyl bromide (AcBr) in the intramolecular cyclization reaction of Step 2, the 2-chloropyridine compound of Example 20 ( 10) was confirmed to be produced in high yield.

Therefore, it was confirmed that the 4-aryl-2-halopyridine derivative compound could be prepared in high yield under the optimal conditions of Step 1 and Step 2 of the present invention.

<Experimental Example 4> Confirmation of the mechanism of the preparation step of the 4-aryl-2-halopyridine derivative

Based on the results of the above experimental example, the mechanism for the optimal preparation method of the 4-aryl-2-halopyridine compound of the present invention is shown in FIG. 3 .

In reaction pathway A, the nitrile group can be activated by the ammonium ion of A and the methoxide produced from DMF-DMA initiates base-catalyzed isomerization to ene isomer B and iminium (iminium) provided the ion C. Many of the reactive isomers B are converted to D by reaction with C, and intermediate D is then methanol removed to give enaminonitrile E. Then, intramolecular Pinner cyclization with HBr gave the final 2-bromopyridine F.

In reaction pathway B, extended conjugated enolate B' was induced by methoxide generated from DMF-DMA. B' then attacks the iminium ion C to form D.

In order to confirm the feasibility of this reaction condition, it was confirmed that when the starting material (8) in which t-butyl ester was introduced into EWG instead of CN was used, it was converted to α-pyrone (9) in good yield.

<Example 21> Preparation of 4-aryl-2-halopyridine derivatives

Toluene (1 mL), ethanol (0.21 mL) and H ₂ O (1 mL) 2- bromo -4- (m- tolyl) of Example 3 (3c) in a solvent mixture in 50mL 2-neck flask under argon and pyridine ( To a solution of 72 mg, 0.3 mmol) was added Na ₂ CO ₃ (227 mg), then 3 mol% of Pd(PPh ₃ ) ₄ (10 mg, 0.008 mmol) and 3,4-dimethoxyphenylboron Acid (0.38 mmol) was added. The reaction mixture was refluxed for 12 hours and then cooled to room temperature. To the reaction mixture was _{added aqueous NH 4} Cl (15 mL), extracted 3 times with EtOAc, _{dried over MgSO 4} and evaporated in vacuo to give the crude product, which was flashed on silica gel using n-hexane/EtOAc Further purification via chromatography.

As a result, from the 2-bromopyridine compound according to the present invention, 2-(3,4-dimethoxyphenyl)-4-(m-tolyl)pyridine (2-(3,4-Dimethoxyphenyl)-4-(m) -tolyl)pyridine;12) was obtained in a high yield of 95%, and it was confirmed that the Suzuki-Miyaura coupling was successfully performed.

The Suzuki-Miyaura coupling reaction from the compounds of Examples 1 to 20 according to the present invention is shown in Scheme 2 below through the preparation of the pyridine-based compound (Compound 4).

[Scheme 2]

So far, the present invention has been looked at with respect to preferred embodiments thereof. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than in the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims (13)

As shown in Scheme 1 below,
preparing a compound represented by Formula 3 by dissolving a compound represented by Formula 2 and an ammonium compound in an organic solvent, and then adding and heating N,N-Dimethylformamide dimethyl acetal (DMF-DMA) to prepare a compound represented by Formula 3 (step 1); and
preparing a compound represented by Formula 1 by dissolving the compound represented by Formula 3 in a mixed solvent of ethyl acetate (EA) and water (H ₂ O) and adding acetyl halogen (AcX) dropwise (step 2);
including,
The ammonium compound of step 1 is ammonium acetate (NH ₄ OAc) and ammonium carbonate ((NH ₄ ) ₂ CO ₃ ) Preparation of a 4-aryl-2-halopyridine derivative, characterized in that at least one selected from the group consisting of Way:
[Scheme 1]

(In Scheme 1,
R ¹ and R ³ are independently H, nitrile, or C _6-8 arylcarbonyl;
R ² is C _6-8 aryl, 5-6 membered heteroaryl containing at least one hetero atom selected from the group consisting of N, O and S, naphthalene, or 1,3-benzodioxole, wherein the C _{6- 8} aryl includes C _1-5 straight or branched chain alkyl, C _1-3 straight or branched alkoxy, C _1-3 alkylsulfinyl, halogen, C _1-3 alkyl halide, nitro and nitrile One or more substituents selected from may be substituted;
said R ² and R ³ together with the carbon atom to which they are connected may form dihydronaphthalene;
X is halogen).
According to claim 1,
wherein R ¹ is H, nitrile, or benzoyl;
R ² is phenyl, 5-membered heteroaryl containing one S atom, naphthalene or 1,3-benzodioxole, wherein the phenyl is C _1-3 straight-chain alkyl, methoxy, methylthio, halogen, trifluoro One or more substituents selected from the group consisting of romethyl, nitro and nitrile may be substituted;
R ³ is H or nitrile;
said R ² and R ³ together with the carbon atom to which they are connected may form dihydronaphthalene;
X is Br or Cl.
delete According to claim 1,
The organic solvent of step 1 is dimethyl sulfoxide (DMSO), dimethylformamide (DMF), benzene, toluene, acetic acid (AcOH), glacial acetic acid, 1,4-dioxane, acetonitrile (MeCN), ethanol ( EtOH), tetrahydrofuran (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylacetamide (DMA), dichloromethane (DCM), chlorobenzene, acetone, carbon tetrachloride ( CCl ₄ ) and chloroform (CHCl ₃ ) A manufacturing method, characterized in that at least one selected from the group consisting of.
5. The method of claim 4,
The organic solvent of step 1 is a manufacturing method, characterized in that at least one selected from the group consisting of dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and benzene.
6. The method of claim 5,
The organic solvent of step 1 is a manufacturing method, characterized in that dimethyl sulfoxide (DMSO).
According to claim 1,
The step 1 is a manufacturing method, characterized in that the heating for 10 to 30 minutes at a temperature of 110 to 130 ℃.
8. The method of claim 7,
Step 1 is a manufacturing method, characterized in that heating for 15 to 25 minutes at a temperature of 115 to 125 ℃.
According to claim 1,
The mixed solvent of step 2 is a manufacturing method, characterized in that ethyl acetate (EA) and water (H ₂ O) are mixed in a volume ratio of 4:1 to 1:4.
10. The method of claim 9,
The mixed solvent of step 2 is a manufacturing method characterized in that ethyl acetate (EA) and water (H ₂ O) are mixed in a volume ratio of 3:0.8 to 1:3.
11. The method of claim 10,
In the mixed solvent of step 2, ethyl acetate (EA) and water (H ₂ O) are mixed in a volume ratio of 3:0.8 to 3:1.2.
11. The method of claim 10,
The mixed solvent of step 2 is a manufacturing method characterized in that ethyl acetate (EA) and water (H ₂ O) are mixed in a volume ratio of 3:0.9 to 3:1.1.
According to claim 1,
The acetyl halogen in step 2 is AcBr or AcCl.

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