KR101742377B1 - C-H -2- NOVEL INDOLE-2-CARBOXAMIDE DERIVATIVES PREPARED BY Rh-CATALYZED C-H AMIDATION AND PREPARING METHOD THEREOF - Google Patents

Abstract

The present invention relates to a novel indole-2-carboxamide derivative and a process for producing the same. More specifically, the present invention relates to a novel indole-2-carboxamide derivative which is produced through a coupling reaction of an indole derivative and an isocyanate derivative under a rhodium catalyst -2-carboxamide derivative and a process for producing the same.
The production of indole derivatives and isocyanate derivatives by rhodium catalysts according to the present invention is more simple and efficient than the conventional methods in that it induces the active CH bonds of indole and pyrrole, which are biologically important compounds, Lt; RTI ID = 0.0 > indole-2-carboxamide < / RTI > Therefore, the novel indole-2-carboxamide derivatives can be used as important motifs for major compounds such as drugs for the prevention or treatment of various diseases.

Description

CARBOXAMIDE DERIVATIVES PREPARED BY Rh (III) -CATALYZED C-H AMIDATION AND PREPARING METHOD THEREOF FIELD OF THE INVENTION The present invention relates to novel indole-2-carboxamide derivatives prepared by the C-

The present invention relates to a novel indole-2-carboxamide derivative and a process for preparing the same. More specifically, the present invention relates to a novel indole-2-carboxamide derivative which is produced through the reaction of an indole derivative with an isocyanate derivative under a rhodium catalyst, 2-carboxamide derivatives and a process for their preparation.

Indole and pyrrole are among the most interesting heterocycle compounds present in nature and are used as structural motifs in drug development. Accordingly, many methods for synthesizing and functionalizing the compound skeleton are known. In particular, the C2-amidated indole and the C2-amidated pyrrole are known as androgen receptor inhibitors, protein kinase inhibitors, DPP-4 inhibitors, DPP-4 inhibitors, allosteric modulators of cannabinoid receptors, and selective inhibitors of beta-amyloid.

However, although the C2-amidated indole and pyrrole are found in many molecules that act on living organisms, their synthesis methods involve the amidation of carboxylic acid derivatives with amines, dilithioindoles, A coupling reaction of an isocyanate with an isocyanate, a Beckmann rearrangement of an indole and an oxime group at a C2 position, and a C2-halogenated indole using an amine and carbon monoxide ) Palladium-catalyzed carbonylation. ≪ / RTI > In addition, the synthesis methods have inherent limitations such as chemical use of metallic reagents, use of harmful carbon monoxide gas, and strong reaction conditions. There is a need to develop efficient methods for the synthesis of indole-2-carboxamide and pyrrole-2-carboxamide, which can minimize the generation of waste and reduce the synthesis steps.

Over the past decade, a number of studies have been conducted for the coupling of various compounds and for the functionalization of inactive C-H bonds through transition metal catalysis. For example, the reaction of imidazole with aldehyde by iridium catalyst, the activation of arene CH bond by palladium catalyst, palladium addition of nitrile, and alkyne by rhenium catalyst The reaction of aromatic aldimines with isocyanates has been reported.

In recent years, studies on the imine insertion reaction of aryl C-H bonds by rhodium catalysts have been reported to obtain amine products, and direct addition of aldehyde C-H bonds by rhodium catalysts for ketone and alcohol formation has been reported. These methods present catalyst alternatives that can be exceeded by the classical Grignard reaction.

Through the discovery of this reactive mode, it has been found that a variety of directing groups can promote the arylation of polar C - N π-bonds of isocyanates. In this respect, it can be seen that acetanilide, phenylpyridine, oxime, and benzoic acid derivatives can be effectively combined with isocyanate to produce an ortho-aminated product under rhodium, rubidium, and rhenium catalysts.

The inventors of the present invention have found that the reaction of various indole derivatives and isocyanate derivatives under rhodium catalysts can produce C2-amidated indole optionally amidated with an inactive CH bond of an indole derivative , Thereby obtaining the novel indole-2-carboxamide derivatives, thereby completing the present invention.

Accordingly, it is an object of the present invention to provide a novel indole-2-carboxamide derivative.

It is another object of the present invention to provide a process for producing an indole-2-carboxamide derivative through a direct C2-addition reaction of an indole derivative and an isocyanate derivative under a rhodium catalyst.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

In order to accomplish the object of the present invention, the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In Formula 1,

, 또는

일 수 있고,R ₁ is

, or

Lt; / RTI >

R ₂ may be hydrogen, methoxy, nitrogen dioxide, a halogen element, or methyl,

R < ₃ > may be hydrogen or methyl,

,

,

,

,

,

, 또는

일 수 있다. R ₄ is C ₂ -C ₈ alkyl,

,

,

,

,

,

, or

Lt; / RTI >

In one embodiment of the invention, the compound represented by the above formula (I) is N - butyl-l- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N --1- (pyridin -2-yl) -1 H - indole-2-carboxamide; N - butyl-4-methoxy-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - butyl-4-nitro-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; 5-bromo - N - butyl-l- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - butyl-5-chloro-l- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - butyl-5-nitro-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - butyl-6-fluoro-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - butyl-7-methyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - butyl-3-methyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - ethyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - pentyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - hexyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - octyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - phenethyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - benzyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - Cyclopentyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - phenyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - (4- bromophenyl) -1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; 1- (pyrimidin -2-yl) - N - ( p- tolyl) -1 H - indole-2-carboxamide, and 1- (pyrimidin -2-yl) - N - ( 4- ( trifluoromethyl Romero butyl) phenyl) -1 H - may be selected from the group consisting of indole-2-carboxamide.

The present invention also relates to a process for the preparation of a compound of formula (I) which comprises reacting an indole derivative with an isocyanate derivative, wherein the reaction is carried out in the presence of a rhodium catalyst ([RhCp * Cl ₂ ] ₂ ), silver hexafluoroantimonate (AgSbF ₆ ) Carboxamide derivative of the general formula (I).

In one embodiment of the present invention, the indole derivative may be represented by the following general formula (2).

(2)

, 또는

일 수 있고,R ₁ is

, or

Lt; / RTI >

R ₂ may be hydrogen, methoxy, nitrogen dioxide, a halogen element, or methyl,

R ₃ may be hydrogen, or methyl.

In another embodiment of the present invention, the isocyanate derivative may be represented by the following general formula (3).

(3)

In Formula 3,

,

,

,

,

,

, 또는

일 수 있다.R is C ₂ -C ₈ alkyl,

,

,

,

,

,

, or

Lt; / RTI >

In another embodiment of the present invention, the organic solvent may be selected from the group consisting of dichloroethane, tetrahydrofuran, acetonitrile, and chlorobenzene.

In another embodiment, the production method of the present invention may be made from 80 ℃ to 120 ℃ in the presence of nitrogen gas (N _2).

The method of preparing the indium derivative and the C2-amidated indole of the isocyanate derivative by the rhodium catalyst according to the present invention is more simple and efficient than the conventional method, and activates the inactive CH bonds of the biologically important compounds indoles and pyrroles Lt; RTI ID = 0.0 > indole-2-carboxamide < / RTI > Therefore, the novel indole-2-carboxamide derivatives can be used as important motifs for major compounds such as drugs for the prevention or treatment of various diseases.

Fig. 1 shows reaction formulas, reaction products, and yields of indole derivatives (1a-1e) and n -butyl isocyanate (2a) in order to verify the reactivity of indole derivatives having various directing groups.
2 is a graph showing the relationship between the indole derivative (1f-1n) and the reaction formula of n -butyl isocyanate (2a), the product of the reaction, and ≪ / RTI >
Figure 3, in order to diversify the available isocyanate derivative in the amide C2- Chemistry indole-producing reaction of the present invention, 1- (pyrimidin -2-yl) -1 H - indole (1a) with an isocyanate derivative (2b-2m ), The product of the reaction, and the yield.
4 schematically shows the reaction formula of the C2-amidation reaction between the indole derivative and the isocyanate derivative of the present invention.
Fig. 5 is a schematic diagram showing the mechanism of the C2-amidated indole production reaction proposed in the present invention.

The present inventors have completed the present invention by obtaining various indole-2-carboxamide derivatives by reacting various indole derivatives and isocyanate derivatives under a rhodium catalyst.

Accordingly, the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

, 또는

일 수 있고,R ₁ is

, or

Lt; / RTI >

R ₂ may be hydrogen, methoxy, nitrogen dioxide, a halogen element, or methyl,

R < ₃ > may be hydrogen or methyl,

,

,

,

,

,

, 또는

일 수 있다.R ₄ is C ₂ -C ₈ alkyl,

,

,

,

,

,

, or

Lt; / RTI >

The compound represented by the above general formula (I) of the present invention is N - butyl-l- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N --1- (pyridin -2-yl) -1 H - indole-2-carboxamide; N - butyl-4-methoxy-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - butyl-4-nitro-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; 5-bromo - N - butyl-l- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - butyl-5-chloro-l- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - butyl-5-nitro-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - butyl-6-fluoro-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - butyl-7-methyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - butyl-3-methyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - ethyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - pentyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - hexyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - octyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - phenethyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - benzyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - Cyclopentyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - phenyl-1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; N - (4- bromophenyl) -1- (pyrimidin -2-yl) -1 H - indole-2-carboxamide; 1- (pyrimidin -2-yl) - N - ( p- tolyl) -1 H - indole-2-carboxamide, and 1- (pyrimidin -2-yl) - N - ( 4- ( trifluoromethyl Romero butyl) phenyl) -1 H - but it may be selected from the group consisting of indole-2-carboxamide, but is not limited to this.

The present invention also relates to a process for the preparation of a compound of formula (I) which comprises reacting an indole derivative with an isocyanate derivative, wherein the reaction is carried out in the presence of a rhodium catalyst ([RhCp * Cl ₂ ] ₂ ), silver hexafluoroantimonate (AgSbF ₆ ) Carboxamide derivative of the general formula (I).

, 또는

일 수 있고, R₂는 수소, 메톡시, 나이트로젠 디옥사이드, 할로겐 원소, 또는 메틸일 수 있으며, R₃는 수소, 또는 메틸일 수 있으나, 이것으로 제한되는 것은 아니다.The indole derivative of the present invention is represented by the following general formula (2), and preferably R ₁ in the general formula

, or

And R ₂ may be hydrogen, methoxy, nitrogenedioxide, halogen element, or methyl, and R ₃ may be hydrogen or methyl, but is not limited thereto.

(2)

,

,

,

,

,

, 또는

일 수 있으나, 이것으로 제한되는 것은 아니다. The isocyanate derivative of the present invention is represented by the following general formula (3), wherein R in the general formula (3) is C ₂ -C ₈ alkyl,

,

,

,

,

,

, or

But is not limited to this.

(3)

In one embodiment of the invention, to set the optimal conditions of the C2- amide-forming reaction of the present invention with isocyanate-indol-l- (pyrimidin -2-yl) -1 H for - indole (1a) and n-butyl isocyanate after reacting the (2a) under a variety of catalysts, additives, and solvent conditions N - butyl-l- (pyrimidin -2-yl) -1 H - indole-2-carboxamide of the yield was determined (example 1 Reference). Accordingly, the organic solvent may be selected from the group consisting of dichloroethane, tetrahydrofuran, acetonitrile, and chlorobenzene, preferably dichloroethane.

Further, the reaction is carried out in the presence of nitrogen gas at 80 to 120 ° C in the presence of nitrogen gas using the rhodium catalyst at a mole ratio of 2-10, the silver hexafluoroantimonate additive at a molar fraction of 10-30, and the dichloroethane solvent at 0.5-5 ml. , More preferably the reaction can be carried out at 100 ° C in the presence of nitrogen gas using a molar fraction of 5 for the rhodium catalyst, 20 molar fraction for the silver hexafluoroantimonate additive, and 1 ml of the dichloroethane solvent.

The C2-amidation reaction between the indole and the isocyanate of the present invention can be carried out according to the reaction conditions as described below. An indole derivative, a rhodium catalyst, a silver hexafluoroantimonate additive, and a dichloroethane solvent are added to a dried tube, and an isocyanate derivative is added and mixed. The mixed reaction product is stirred for 24 hours, cooled at room temperature, and the cooled reaction product is diluted with ethyl acetate (EtOAc), concentrated in vacuo, and purified by flash column chromatography to separate and purify the product.

The C2-amidation reaction between indole and isocyanate by the rhodium catalyst of the present invention can be summarized by the reaction scheme shown in FIG. 4 and can be achieved by the following mechanism. For example, 1- (pyrimidin -2-yl) -1 H - indole (1a) and the case of reacting an isocyanate derivative as shown in Fig. 5, [RhCp * Cl _{2] 2} and AgSbF _6, due to the reaction of the cationic (RhCp * Cl ₂ ) ⁺ [SbF ₆ ] ^- , and the catalyst reversibly binds to the nitrogen atom of the pyrimidine group of the indole derivative to activate the 2-CH bond of the indole, (A) and induce the release of hydrogen. Subsequently, an intermediate (B) is formed by combining with an isocyanate derivative, and then rhodium is combined with a carbon atom of the isocyanate to form a complex (C) The rhodium (III) catalyst can be separated and reused in the reaction with the addition of hydrogen atoms back to the formed complex.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

[Example]

Example 1. Optimum reaction condition setting

In order to set the optimal conditions of the C2- indole amide Chemistry indole formation reaction by coupling of the isocyanate as shown in Scheme 1, 1- (pyrimidin -2-yl) -1 H - indole (1a) and n - butyl isocyanate in (2a) and then proceed with the catalyst and additives, and a solvent of the type and the response to the addition of different concentrations needed for coupling the reaction product of n - butyl-l- (pyrimidin -2-yl) -1 H (Yield (%)) of the indole-2-carboxamide (3a) was analyzed. As a common reaction conditions l- (pyrimidin -2-yl) -1 H - indole (1a) is 0.2 mmol, n - butyl isocyanate (2a) is 0.6 mmol, each solvent was added to 1 ㎖, in a reaction vessel The reaction was carried out in the presence of nitrogen gas (N ₂ ) at 100 ° C. for 24 hours. The types and concentrations of the catalyst, additives and solvents, and the yields of the products as a result of each reaction are shown in Table 1 below.

[Reaction Scheme 1]

Entry Catalyst (mol%) Additive (mol%) Solvent Yield (%) One _{[RhCp * Cl 2] 2 (} 2.5) AgSbF ₆ (10) DCE 60 2 [Ru ( p- Cy) Cl ₂ ] ₂ (2.5) AgSbF ₆ (10) DCE N.R. 3 [CoCp * (Co) I ₂ ] (2.5) AgSbF ₆ (10) DCE 12 4 _{[RhCp * Cl 2] 2 (} 2.5) DCE N.R. 5 AgSbF ₆ (10) DCE N.R. 6 _{[RhCp * Cl 2] 2 (} 2.5) AgSbF ₆ (10) THF 54 7 _{[RhCp * Cl 2] 2 (} 2.5) AgSbF ₆ (10) MeCN 50 8 _{[RhCp * Cl 2] 2 (} 2.5) AgSbF ₆ (10) DMSO N.R. 9 _{[RhCp * Cl 2] 2 (} 2.5) AgSbF ₆ (10) PhCl 35 10 _{[RhCp * Cl 2] 2 (} 2.5) AgNTf ₂ (10) DCE 52 11 _{[RhCp * Cl 2] 2 (} 2.5) AgBF ₄ (10) DCE 48 12 _{[RhCp * Cl 2] 2 (} 2.5) AgSbF ₆ (10) + NaOAc (30) DCE 51 13 _{[RhCp * Cl 2] 2 (} 2.5) AgSbF ₆ (10) + Cu (OAc) ₂ (30) DCE 24 14 [RhCp * Cl ₂ ] ₂ (5) AgSbF ₆ (20) DCE 81 15 _{[RhCp * Cl 2] 2 (} 5) AgSbF ₆ (20) DCE 64

As a result, it was found that the initial experiment (entry) in which the reaction was carried out according to the reaction conditions in the rhodium catalyst ([RhCp * Cl ₂ ] ₂ ) and silver hexafluoroantimonate (AgSbF ₆ ) additive and dichloroethane 1), the product was obtained with a yield of 60% (entry 1).

In order to determine the type of catalyst, the additive and solvent were the same as those of the entry 1, and the reaction was carried out after different kinds of catalysts. As a result, a cationic ruthenium catalyst other than rhodium catalyst ([Ru (p-Cy) Cl 2] 2) or cobalt catalyst ([CoCp * (Co) I 2]) or the product is not at all produced when using a very low yield (Entries 2 and 3). In addition, it was confirmed that if the catalyst and the additive were not present under the same condition as the entry 1, the reaction could not proceed properly (entries 4 and 5).

Next, tetrahydrofuran (THF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO) in the presence of a rhodium catalyst and a silver hexafluoroantimonate additive are added to determine the type of solvent. , Or chlorobenzene (phCl) solvent (entries 6 to 9). As a result, it was confirmed that the yield of the product was lower than that of dichloroethane of entry 1. It was therefore decided to use a dichloroethane solvent.

Finally, to determine the type of additive of the reaction, silver hexafluoroantimonate and other silver salts, namely silver bis (trifluoromethanesulfonyl) imide (AgNTf ₂ ) or silver tetrafluoro After the reaction was carried out using borate (AgBF ₄ ), the yields of the products were compared (entries 10 and 11). As a result, it was confirmed that the yield of the product was the highest when the additive used in the reaction of entry 1 was used. On the other hand, the addition of acetate (NaOAc or Cu (OAc) ₂ ) to the silver hexafluoroantimonate additive reduced the yield of the product (entries 12 and 13).

From the above results, it was found that the product yield was the highest in the case of using the rhodium catalyst, the silver hexafluoroantimonate additive, and the dichloroethane solvent (entry 1). In addition, the molar ratio (mol%) of the catalyst and the additive was doubled to increase the yield of the product from 60% to 81% (entry 14). On the other hand, when the concentration of n - butyl isocyanate (2a) was reduced to 0.4 mmol under the above reaction conditions, the yield of the product was found to decrease again (entry 15).

Example  2. The C2-C18 alkyl group of the indole derivative (1a-1n) and the isocyanate derivative (2a-2m) Amidation  Optimum conditions of reaction

The optimum conditions of the C2- was screen-indole amide formation reaction is determined by the above Example 1 are listed in the following, typically 1- (pyrimidin -2-yl) -1 H - indole (1a) and n - butyl isocyanate (2a ) Was described.

A drying tube 1- (pyrimidin -2-yl) -1 H - indole (1a) (39.1 mg, 0.2 mmol, 100 mol%), rhodium catalysts _{([RhCp * Cl 2] 2} ) (6.2 mg, 0.01 mmol, 5 mol%), with silver hexafluoroantimonate additives _{(AgSbF 6) (13.7 mg,} 0.04 mmol, 20 mol%), and dichloroethane (1 ㎖), insert the solvents n under a nitrogen gas condition-butyl isocyanate (2a) were added and mixed. The mixed reaction product was stirred at 100 DEG C for 24 hours and then cooled at room temperature. The cooled reaction was diluted with ethyl acetate (EtOAc) (3 mL), concentrated in vacuo and the product isolated and purified by flash column chromatography and the yield was determined.

Example 3. Directed penis screening

As shown in Reaction Scheme 2, C2-amidated indole-forming reaction of indole derivatives (1a-1e) and n -butyl isocyanate (2a) having various directing groups (DG) (3a-3e) and yields according to the directing group are shown in Fig. The reaction conditions were the same as those described in Example 2 above.

[Reaction Scheme 2]

As a result, the, pyridinyl (pyridinyl) orientation of an indole derivative (1b) having n as shown in FIG. 1-butyl isocyanate (2a) and in which case the reaction product, N-butyl-1- (pyridin -2-yl) -1 H -indole-2-carboxamide (3b) was obtained in a yield of 48%. On the other hand, when pivaloyl, benzoyl, or an indole derivative (1c-1e) having a directing group of N, N-dimethylcarbamoyl were respectively reacted, no product was obtained . Example 1 of an indole derivative (1a) having a pyrimidinyl (pyrimidinyl) directivity in n-butyl isocyanate (2a) and when reacted N-butyl-1- (pyrimidin -2-yl) -1 H - indole - It has been confirmed that 2-carboxamide (3a) can be obtained at a yield of 81%. Thus, the nitrogen-containing heterocyclic directing group containing nitrogen can be obtained by C2-amidation of indole and isocyanate And it is very important for the progress of the indole formation reaction.

Example 4. Screening of Indole Derivatives

In order to evaluate the possible ranges and limitations of the C2-amidated indole formation reaction of indole and isocyanate according to this example, various indole derivatives (1f-1n) were synthesized by the method and conditions of Example 2 Reacted with n -butyl isocyanate (2a) according to the method described above and the yield and yield of the product were analyzed.

[Reaction Scheme 3]

As a result, methoxy (OMe) a C4-, C5-, C6- or position as shown in Figure 2, the nitro halogen dioxide (NO _2), bromine (Br), chlorine (Cl), or fluorine (F) (1f-1k), various products were obtained with an overall yield of 40 to 60% on average. In the case of the products (3h and 3i) obtained by reacting the indole derivatives (1h and 1i) bonded with bromine or chlorine, other conventional cross coupling reactions were performed to further change them.

However, when the indole derivative (1 l) having a methyl group bonded to the 7th carbon position was reacted, the yield of the product (3l) was somewhat low, indicating that the reactivity was low. Further, when indole derivatives (1m and 1n) were reacted, the products (3m and 3n) were obtained in a proper yield ratio.

Example 5. Screening of Isocyanate Derivatives

In order to verify and screen the reactivity of various isocyanate derivatives for the C2-amidated indole production reaction of the present invention, as shown in the following reaction formula (4), alkyl-, aryl-, or arylsulfonyl arylsulfonyl) an isocyanate derivative (2b-2m) 1-binding group (pyrimidin -2-yl) -1 H - indole was reacted according to (1a) as in method and conditions of example 2, the yield of the reactive product, and Respectively.

[Reaction Scheme 4]

As a result, as shown in Fig. 3, when the alkyl group-bonded isocyanate derivative (2b-2f) was reacted, the C2-amidated indole product (4b-4f) was obtained with high yield. On the other hand, when the benzyl group-bonded isocyanate derivative (2g) and the cyclopentyl group-bonded isocyanate derivative (2h) were reacted, the reactivity was slightly lower and the yields of the products (4g and 4h) were somewhat low. (4i-4l) was obtained when phenyl, bromophenyl, toluene, or an isocyanate derivative (2i-2l) having trifluoromethylphenyl bonded thereto was reacted, phenylsulfonylisocyanate (2m ), It was found that the reaction did not proceed properly.

The results of the above examples demonstrate the selective C2-amidated indole formation of indole and isocyanate under rhodium catalysts. When the reaction was carried out using a reactant to which various functional groups were bonded during the reaction, various products could be obtained at relatively high yields.

Example 6. Structural Analysis of New Compounds by NMR Analysis

(NMR), infrared spectrometry (IR), and infrared spectroscopy (IR) to identify the structures of the novel compounds formed through the C2-amidated indole formation reaction of indoles and isocyanates of Examples 3 to 5, And mass spectrometry were performed, and the results are shown below in order.

6-1. N Butyl-1- (pyrimidin-2-yl) -1 H -Indole-2-carboxamide (3a)

48.0 mg (81%); Brown solid; mp = 241.7-244.6 DEG C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.69 (d, J = 4.2 Hz, 2H), 8.26 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.34 (t 1H, J = 8.4 Hz, 1H), 7.21 (t, J = 7.0 Hz, 1H), 7.10 (t, J = 4.9 Hz, 1H), 6.89 , J = 7.0 Hz, 2H), 1.57-1.55 (m, 2H), 1.42-1.38 (m, 2H), 0.94 (t, J = 7.7 Hz, 3H); ¹³ C NMR (175 MHz, CDCl ₃ ) δ 162.8, 157.9, 157.2, 137.5, 134.7, 127.8, 125.2, 122.3, 121.5, 117.5, 113.8, 109.1, 39.4, 31.5, 19.9, 13.7; IR (KBr) ν 3249, 2927, 2870, 1637, 1556, 1417, 1344, 1286, 1233, 1192, 1145, 1058, 977, 817, 742 cm @ -1; HRMS (quadrupole, EI) calcd for C 17 H 18 N 4 O [M] + 294.1481, found 294.1479.

6-2. N Butyl-1- (pyridin-2-yl) -1 H - indole-2-carboxamide (3b)

28.2 mg (48%); White solid; mp = 96.5-99.4 < 0 >C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.59 (d, J = 4.2 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.43 (d J = 7.7 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 6.3 Hz, 1H), 7.27 J = 7.0 Hz, 2H), 1.52-1.50 (m, 2H), 1.36-1.32 (m, 2H), 0.92 (t, J = 7.7 Hz, 3H); ^{13 C NMR (175 MHz, CDCl} 3) δ 161.7, 151.5, 149.1, 138.5, 138.2, 134.0, 127.0, 124.8, 122.5, 121.9, 121.6, 121.3, 111.1, 107.4, 39.3, 31.5, 20.0, 13.7; IR (KBr) ν 3284, 3054, 2924, 2855, 1641, 1546, 1467, 1447, 1387, 1350, 1273, 1225, 1148, 809, 739 cm @ -1; HRMS (quadrupole, EI) calcd for C 18 H 19 N 3 O [M] + 293.1528, found 293.1522.

6-3. N Butyl-4-methoxy-1- (pyrimidin-2-yl) -1 H - indole-2-carboxamide (3f)

39.6 mg (61%); Light yellow solid; mp = 142.5-147.5 [deg.] C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.74 (d, J = 4.2 Hz, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.16 (t 1H, J = 4.9 Hz, 1H), 7.07 (s, 1H), 6.64 (d, J = 8.4 Hz, 1H) , 1.62-1.59 (m, 2H), 1.45-1.42 (m, 2H), 0.96 (t, J = 7.7 Hz, 3H); ^{13 C NMR (175 MHz, CDCl} 3) δ 162.6, 158.0, 157.5, 153.6, 139.0, 133.3, 126.3, 118.4, 117.8, 106.6, 106.4, 102.2, 55.4, 39.4, 31.6, 20.2, 13.8; IR (KBr) ν 3297, 2923, 2854, 1637, 1541, 1432, 1360, 1296, 1255, 1227, 1183, 1109, 1080, 985, 853, 822, 757, 722, cm -1; HRMS (quadrupole, EI) calcd for C 18 H 20 N 4 O 2 [M] + 324.1586, found 324.1586.

6-4. N -Butyl-4-nitro-1- (pyrimidin-2-yl) -1 H -Indole-2-carboxamide (3 g)

35.3 mg (52%); Dark brown solid; mp = 160.5-164.2 DEG C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.79 (d, J = 4.2 Hz, 2H), 8.52 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.60 (s J = 7.7 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.27 (m, 2H), 1.48 - 1.45 (m, 2H), 0.99 (t, J = 7.7 Hz, 3H); ^{13 C NMR (175 MHz, CDCl} 3) δ 161.7, 158.3, 156.7, 140.8, 138.9, 138.3, 124.2, 122.1, 120.6, 119.6, 118.8, 107.5, 39.7, 31.6, 20.0, 13.7; IR (KBr) ν 3291, 2928, 1644, 1549, 1505, 1420, 1333, 1286, 1226, 991, 824, 760, 733 cm @ -1; HRMS (quadrupole, EI) calcd for C 17 H 17 N 5 O 3 [M] + 339.1331, found 339.1326.

6-5. 5-Bromo- N Butyl-1- (pyrimidin-2-yl) -1 H -Indole-2-carboxamide (3h)

38.1 mg (51%); Light yellow solid; mp = 180.0-182.5 C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.72 (d, J = 3.5 Hz, 2H), 8.18 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.41 (d, J = 9.1 Hz 2H), 1.63-1.59 (m, 2H), 7.17 (t, J = 3.5 Hz, 1H), 6.82 (s, , 1.46-1.42 (m, 2H), 0.97 (t, J = 6.3 Hz, 3H); ^{13 C NMR (175 MHz, CDCl} 3) δ 162.5, 158.0, 157.0, 136.1, 135.8, 129.6, 128.1, 124.0, 117.9, 115.6, 115.5, 108.1, 39.5, 31.5, 20.0, 13.8; IR (KBr) v 3265, 2921, 2852, 1637, 1554, 1426, 1378, 1333, 1290, 1210, 1051, 863, 801, 754, 717 cm @ -1; HRMS (quadrupole, EI) calcd for C 17 H 17 BrN 4 O [M] + 372.0586, found 372.0580.

6-6. N Butyl-5-chloro-1- (pyrimidin-2-yl) -1 H -Indole-2-carboxamide (3i)

40.1 mg (61%); Light yellow solid; mp = 167.4-171.8 [deg.] C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.72 (d, J = 4.9 Hz, 2H), 8.23 (d, J = 9.1 Hz, 1H), 7.54 (s, 1H), 7.28 (dd, J = 8.4, J = 7.0 Hz, 2H), 1.63-1.59 (m, 2H), 7.16 (t, J = 4.9 Hz, 1H), 6.82 (s, 2H), 1.46-1.41 (m, 2H), 0.97 (t, J = 7.7 Hz, 3H); ^{13 C NMR (175 MHz, CDCl} 3) δ 162.6, 158.0, 157.0, 136.0, 135.8, 129.0, 127.9, 125.5, 120.9, 117.8, 115.2, 108.2, 39.5, 31.5, 20.0, 13.8; IR (KBr) v 3276, 2927, 2871, 1642, 1556, 1425, 1335, 1290, 1229, 1067, 879, 804, 713, 656 cm @ -1; HRMS (quadrupole, EI) calcd for C 17 H 17 ClN 4 O [M] + 328.1091, found 328.1092.

6-7. N Butyl-5-nitro-1- (pyrimidin-2-yl) -1 H -Indole-2-carboxamide (3j)

30.5 mg (45%); Light brown solid; mp = 205.0-206.8 [deg.] C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.77 (d, J = 4.9 Hz, 2H), 8.50 (s, 1H), 8.31 (d, J = 9.1 Hz, 1H), 8.18 (d, J = 9.1 Hz 2H), 1.65-1.63 (m, 2H), 7.26 (t, J = 4.9 Hz, , 1.48 - 1.44 (m, 2H), 0.98 (t, J = 7.0 Hz, 3H); ^{13 C NMR (175 MHz, CDCl} 3) δ 161.9, 158.2, 156.6, 143.5, 140.0, 137.8, 127.5, 120.3, 118.7, 118.2, 114.3, 109.2, 39.7, 31.5, 20.0, 13.7; IR (KBr) v 3271, 2926, 1642, 1565, 1511, 1422, 1332, 1296, 1280, 1072, 896, 812, 731, 655 cm @ -1; HRMS (quadrupole, EI) calcd for C 17 H 17 N 5 O 3 [M] + 339.1331, found 339.1333.

6-8. N -Butyl-6-fluoro-1- (pyrimidin-2-yl) -1 H - indole-2-carboxamide (3k)

34.4 mg (55%); Light yellow solid; mp = 146.3-148.1 [deg.] C; _{^{1 H NMR (700MHz, CDCl 3}} ) δ8.73 (d, J = 4.9 Hz, 2H), 8.05 (d, J = 10.5 Hz, 1H), 7.53 (t, J = 8.4 Hz, 1H), 7.17 (t J = 4.2 Hz, 1H), 6.99 (td, J = 9.8, 2.1 Hz, 1H), 6.89 (s, -1.59 (m, 2H), 1.46 - 1.43 (m, 2H), 0.97 (t, J = 7.0 Hz, 3H); _{^{13 C NMR (175MHz, CDCl 3}} ) δ162.6, 161.5 (d, JC-F = 239.4Hz), 158.0, 157.1, 137.9, 135.3 (d, JC-F = 4.2Hz), 124.2, 122.4 (d, JC IR (KBr) υ 3272, IR (KBr) δ 32.272, dH, J = 2927, 2869, 1644, 1617, 1552, 1473, 1423, 1357, 1291, 1234, 1211, 1134, 977, 858, 834, 736, 673 cm -1; HRMS (quadrupole, EI) calcd for C ₁₇ H ₁₇ FN ₄ O [M] + 312.1386, found 312.1383.

6-9. N -Butyl-7-methyl-1- (pyrimidin-2-yl) -1 H -Indole-2-carboxamide (3l)

16.1 mg (26%); Light yellow solid; mp = 130.2-131.6 [deg.] C; ^{1 H NMR (700 MHz, CDCl} 3) δ 9.11 (d, J = 4.9 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.66 (t, J = 4.9 Hz, 1H), 7.52 (s J = 7.0 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.28 , 3H), 1.80-1.78 (m, 2H), 1.64-1.60 (m, 2H), 1.18 (t, J = 7.7 Hz, 3H); ^{13 C NMR (175 MHz, CDCl} 3) δ 161.4, 159.8, 158.0, 137.5, 133.5, 127.4, 127.3, 122.3, 121.6, 120.2, 119.9, 106.2, 39.3, 31.6, 20.0, 19.1, 13.7; IR (KBr) .nu. 3327, 2924, 1636, 1549, 1421, 1282, 1243, 911, 829, 772, 728, cm @ -1; HRMS (quadrupole, EI) calcd for C 18 H 20 N 4 O [M] + 308.1637, found 308.1632.

6-10. N -Butyl-3-methyl-1- (pyrimidin-2-yl) -1 H -Indole-2-carboxamide (3m)

33.4 mg (54%); Yellow solid; mp = 176.4-181.3 [deg.] C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.68 (d, J = 4.9 Hz, 2H), 8.45 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.35 (t J = 7.0 Hz, 1H), 7.26 (t, J = 9.1 Hz, 1H), 7.06 (t, J = 4.9 Hz, 1H), 5.84 ), 2.44 (s, 3H), 1.63-1.60 (m, 2H), 1.45-1.41 (m, 2H), 0.97 (t, J = 7.7 Hz, 3H); ^{13 C NMR (175 MHz, CDCl} 3) δ 163.7, 157.8, 157.5, 136.6, 131.3, 129.9, 125.4, 122.2, 119.6, 117.7, 116.7, 114.6, 39.6, 31.6, 20.1, 13.8, 9.3; IR (KBr) υ 3285, 2926, 2868, 2363, 1698, 1623, 1558, 1424, 1348, 1280, 1224, 1159, 1074, 947, 759, 744, 700 cm @ -1; HRMS (quadrupole, EI) calcd for C 18 H 20 N 4 O [M] + 308.1637, found 308.1642.

6-11. N -Butyl-4-oxo-1- (pyrimidin-2- yl ) -4,5,6,7- Tetrahydro -One H -Indole-2-carboxamide (3n)

28.2 mg (45%); Yellow oil; ¹ H NMR (700 MHz, CDCl ₃ )? 8.79 (d, J = 4.9 Hz, 2H), 7.34 (t, J = 4.9 Hz, 1 H), 6.98 (t, J = 7.3 Hz, 2H), 2.87 (t, J = 5.6 Hz, 2H), 2.52 (m, 2H), 1.39 - 1.35 (m, 2H), 0.92 (t, J = 7.7 Hz, 3H); ^{13 C NMR (175 MHz, CDCl} 3) δ 194.6, 160.8, 158.4, 156.8, 147.7, 130.0, 120.9, 120.0, 109.1, 39.2, 37.8, 31.6, 23.3, 22.9, 20.0, 13.7; IR (KBr) v 3298, 2923, 2854, 2139, 1640, 1554, 1416, 1296, 1223, 1129, 1087, 997, 898, 817, 751, 718 cm @ -1; HRMS (quadrupole, EI) calcd for C 17 H 20 N 4 O 2 [M] + 312.1586, found 312.1585.

6-12. N -Ethyl-1- (pyrimidin-2-yl) -1 H - indole-2-carboxamide (4b)

41.0 mg (77%); Yellow sticky solid; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.76 (br s, 2H), 8.28 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.0 Hz, 1H), 7.36 (t, J = 7.0 1H), 7.26-7.23 (m, 1H), 7.17 (s, 1H), 6.94 (s, 1H), 6.20 (s, 1H), 3.47 (s, 2H), 1.26 ^{13 C NMR (175 MHz, CDCl} 3) δ 162.8, 157.9, 157.3, 137.6, 134.7, 127.9, 125.3, 122.4, 121.6, 117.7, 113.9, 109.3, 34.7, 14.7; IR (KBr) v 3283, 2924, 1642, 1556, 1419, 1345, 1284, 1231, 1148, 931, 810, 741, 657 cm @ -1; HRMS (quadrupole, EI) calcd for C 15 H 14 N 4 O [M] + 266.1168, found 266.1174.

6-13. N -Pentyl-1- (pyrimidin-2-yl) -1 H - indole-2-carboxamide (4c)

37.6 mg (61%); Yellow oil; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.74 (d, J = 4.2 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.34 (t J = 7.0 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.16 (t, J = 4.9 Hz, 1H), 6.94 , J = 7.0 Hz, 2H), 1.64-1.62 (m, 2H), 1.40-1.37 (m, 4H), 0.93 (t, J = 7.0 Hz, 3H); ^{13 C NMR (175 MHz, CDCl} 3) δ 162.9, 158.0, 157.4, 137.6, 134.8, 127.9, 125.3, 122.4, 121.6, 117.6, 113.9, 109.2, 39.8, 29.2, 29.0, 22.4, 14.0; IR (KBr) v 3272, 2925, 2856, 1639, 1548, 1146, 1426, 1348, 1290, 1266, 1233, 1149, 1026, 817, 739, 708 cm < -1 >; HRMS (quadrupole, EI) calcd for C 18 H 20 N 4 O [M] + 308.1637, found 308.1638.

6-14. N -Hexyl-1- (pyrimidin-2-yl) -1 H -Indole-2-carboxamide (4d)

47.7 mg (74%); Yellow solid; mp = 117.6-120.4 [deg.] C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.73 (d, J = 4.9 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.35 (t 1H, J = 7.7 Hz, 1H), 7.23 (t, J = 7.0 Hz, 1H), 7.15 (t, J = 4.9 Hz, 1H), 6.93 J = 6.3 Hz, 2H), 1.64-1.62 (m, 2H), 1.42-1.40 (m, 2H), 1.34-1.33 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H); ^{13 C NMR (175 MHz, CDCl} 3) δ 162.9, 158.0, 157.4, 137.7, 134.9, 128.0, 125.3, 122.5, 121.6, 117.6, 113.9, 109.2, 39.8, 31.5, 29.5, 26.6, 22.6, 14.0; IR (KBr) v 3274, 2924, 2855, 1643, 1558, 1419, 1347, 1287, 1233, 1149, 807, 744, 657 cm @ -1; HRMS (quadrupole, EI) calcd for C 19 H 22 N 4 O [M] + 322.1794, found 322.1795.

6-15. N -Octyl-1- (pyrimidin-2-yl) -1 H - indole-2-carboxamide (4e)

36.4 mg (52%); Yellow solid; mp = 103.3-105.4 [deg.] C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.74 (d, J = 4.9 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.35 (t 1H, J = 7.7 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.15 (t, J = 4.9 Hz, 1H), 6.94 J = 7.0 Hz, 2H), 1.64-1.61 (m, 2H), 1.42-1.38 (m, 2H), 1.35-1.27 (m, 8H), 0.89 (t, J = 7.0 Hz, 3H); ^{13 C NMR (175 MHz, CDCl} 3) δ 162.9, 158.0, 157.5, 137.7, 134.9, 128.0, 125.3, 122.5, 121.6, 117.6, 113.9, 109.2, 39.9, 31.8, 29.7, 29.6, 29.2, 26.9, 22.6, 14.0 ; IR (KBr) ν 3273, 2921, 2851, 1644, 1557, 1420, 1347, 1288, 1234, 1213, 1150, 804, 744, 720 cm @ -1; HRMS (quadrupole, EI) calcd for C 21 H 26 N 4 O [M] + 350.2107, found 350.2106.

6-16. N -Phenethyl-1- (pyrimidin-2-yl) -1 H -Indole-2-carboxamide (4f)

47.9 mg (70%); Yellow oil; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.73 (d, J = 4.9 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.37-7.32 (m, 3H), 7.28 (d, J = 7.0 Hz, 2H), 7.26-7.22 (m, 2H), 7.15 (t, J = 4.9 Hz, 1H), 3.69 (q, J = 6.3 Hz, 2H), 2.95 (t, J = 7.0 Hz, 2H); ^{13 C NMR (175 MHz, CDCl} 3) δ 162.8, 158.0, 157.3, 139.0, 137.6, 134.6, 128.9, 128.6, 127.8, 126.5, 125.4, 122.5, 121.6, 117.6, 113.9, 109.4, 41.0, 35.5; IR (KBr) v 3285, 2923, 2854, 1642, 1556, 1421, 1346, 1284, 1231, 1151, 809, 742, 697 cm @ -1; HRMS (quadrupole, EI) calcd for C 21 H 18 N 4 O [M] + 342.1481, found 342.1485.

6-17. N -Benzyl-1- (pyrimidin-2-yl) -1 H -Indole-2-carboxamide (4 g)

24.9 mg (38%); Light yellow solid; mp = 175.2-176.9 [deg.] C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.70 (d, J = 4.9 Hz, 2H), 8.31 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.43 (d J = 7.7 Hz, 2H), 7.38-7.35 (m, 3H), 7.31 (t, J = 6.3 Hz, 1H), 7.24 4.9 Hz, 1 H), 6.98 (s, 1 H), 6.52 (s, 1 H), 4.64 (d, J = 5.6 Hz, 2 H); ^{13 C NMR (175 MHz, CDCl} 3) δ 162.8, 158.0, 157.3, 138.2, 137.7, 134.4, 128.6, 127.9, 127.8, 127.5, 125.5, 122.5, 121.7, 117.6, 114.0, 109.6, 43.7; IR (KBr) v 3315, 2919, 1649, 1552, 1421, 1338, 1240, 1078, 975, 836, 754, 695 cm @ -1; HRMS (quadrupole, EI) calcd for C 20 H 16 N 4 O [M] + 328.1324, found 328.1319.

6-18. N -Cyclopentyl-l- (pyrimidin-2-yl) -1 H - indole-2-carboxamide (4h)

18.3 mg (30%); Light yellow solid; mp = 185.0-190.0 [deg.] C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.75 (d, J = 4.9 Hz, 2H), 8.29 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.35 (t J = 8.4 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.16 (m, 1H), 2.09-2.04 (m, 2H), 1.73-1.70 (m, 2H), 1.68-1.64 (m, 2H), 1.58-1.57 (m, 2H); ^{13 C NMR (175 MHz, CDCl} 3) δ 162.6, 158.0, 157.4, 137.5, 134.9, 128.0, 125.3, 122.5, 121.6, 117.6, 113.9, 109.1, 51.6, 32.9, 23.7; IR (KBr) v 3319, 3046, 2953, 2865, 1626, 1557, 1425, 1350, 1295, 1150, 1079, 823, 803, 740, 664 cm @ -1; HRMS (quadrupole, EI) calcd for C 18 H 18 N 4 O [M] + 306.1481, found 306.1476.

6-19. N -Phenyl-1- (pyrimidin-2-yl) -1 H -Indole-2-carboxamide (4i)

32.1 mg (51%); Light yellow solid; mp = 173.9-176.0 [deg.] C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.74 (d, J = 4.9 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H), 8.11 (br s, 1H), 7.61-7.59 (m, 3H ), 7.38 (t, J = 8.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 2H), 7.24-7.23 , J = 7.0 Hz, 1 H), 7.08 (s, 1 H); ¹³ C NMR (175 MHz, CDCl ₃ )? 160.5, 158.1, 157.3, 138.0, 137.9, 134.4, 129.0, 127.7, 125.8, 124.4, 122.7, 121.9, 119.9, 117.8, 113.9, 110.3; IR (KBr) v 3016, 1653, 1600, 1564, 1538, 1444, 1425, 1353, 1310, 1236, 1191, 1150, 819, 744, 690 cm @ -1; HRMS (quadrupole, EI) calcd for C 19 H 14 N 4 O [M] + 314.1168, found 314.1173.

6-20. N - (4-bromophenyl) -1- (pyrimidin-2-yl) -1 H -Indole-2-carboxamide (4j)

34.6 mg (44%); Light yellow solid; mp = 223.3-225.9 [deg.] C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.74 (d, J = 4.9 Hz, 2H), 8.29 (d, J = 8.4 Hz, 1H), 8.10 (br s, 1H), 7.60 (d, J = 7.7 (M, 2H), 7.43 (d, J = 9.1 Hz, 2H), 7.39 (t, J = 8.4 Hz, 1H), 7.26-7.24 , J = 4.9 Hz, 1 H), 7.08 (s, 1 H); ¹³ C NMR (175 MHz, CDCl ₃ )? 160.5, 158.2, 157.2, 137.9, 137.0, 134.0, 132.0, 127.6, 126.0, 122.8, 121.9, 121.4, 117.8, 117.0, 113.9, 110.5; IR (KBr) ν 3292, 2920, 2850, 1659, 1588, 1538, 1184, 1424, 1396, 1305, 1239, 1194, 1069, 938, 819, 737, 655 cm -1; HRMS (quadrupole, EI) calcd for C 19 H 13 BrN 4 O [M] + 392.0273, found 392.0269.

6-21. 1- (Pyrimidin-2-yl) - N - (p-tolyl) -1 H -Indole-2-carboxamide (4k)

20.3 mg (31%); Colorless oil; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.75 (d, J = 4.9 Hz, 2H), 8.31 (d, J = 8.4 Hz, 1H), 7.96 (br s, 1H), 7.64 (d, J = 7.7 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.28-7.26 (m, 2H), 7.16-7.15 2.35 (s, 3 H); ^{13 C NMR (175 MHz, CDCl} 3) δ 158.1, 157.4, 137.9, 135.5, 134.7, 134.1, 129.5, 127.9, 125.7, 122.7, 121.8, 120.0, 117.7, 114.0, 110.1, 20.8; IR (KBr) v 3256, 2921, 1660, 1602, 1564, 1534, 1422, 1348, 1313, 1240, 1191, 1149, 814, 734 cm @ -1; HRMS (quadrupole, EI) calcd for C 20 H 16 N 4 O [M] + 328.1324, found 328.1328.

6-22. 1- (Pyrimidin-2- yl ) - N -(4-( Trifluoromethyl ) Phenyl) -1 H - indole-2- Carboxamide  (4l)

32.9 mg (43%); Light yellow solid; mp = 241.7-244.6 DEG C; ^{1 H NMR (700 MHz, CDCl} 3) δ 8.75 (d, J = 4.2 Hz, 2H), 8.30 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 7.70 (d, J = 7.7 Hz J = 7.7, 1.4 Hz, 1 H), 7.27 - 7.25 (m, 1 H), 7.62 (d, J = 8.4 Hz, , 7.18 (t, J = 4.9 Hz, 1 H), 7.12 (s, 1 H); ^{13 C NMR (175 MHz, CDCl} 3) δ 160.7, 158.2, 157.2, 141.0, 138.0, 133.8, 127.6, 126.4 (q, JC-F = 2.6 Hz), 126.3 (q, JC-F = 32.2 Hz), 126.2 , 124.0 (q, Jc-F = 269.3 Hz), 122.9, 122.0, 119.5, 117.9, 114.0, 110.8; IR (KBr) v 3261, 2918, 2359, 1666, 1602, 1542, 1423, 1315, 1249, 1158, 1107, 1065, 937, 835, 739 cm @ -1; HRMS (quadrupole, EI) calcd for C 20 H 13 F 3 N 4 O [M] + 382.1041, found 382.1039.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the invention. There will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

Claims (7)

delete delete A process for preparing an indole-2-carboxamide derivative represented by the following general formula (1), comprising the step of reacting an indole derivative represented by the following general formula (2) with an isocyanate derivative represented by the following general formula
The process is carried out in the presence of a rhodium catalyst ([RhCp * Cl ₂ ] ₂ ), silver hexafluoroantimonate (AgSbF ₆ ) additive and an organic solvent,
Wherein the organic solvent is selected from the group consisting of dichloroethane, tetrahydrofuran, acetonitrile, and chlorobenzene.
[Chemical Formula 1]

(2)

(3)

(Wherein,
R ₁ is

or

ego,
R ₂ is hydrogen, methoxy, nitrogene dioxide, a halogen element, or methyl,
R < ₃ > is hydrogen or methyl,
R and R ₄ are each independently alkyl of C ₂ -C _8,

,

,

,

,

, or

to be.)
delete delete delete The method of claim 3,
The manufacturing method is characterized in that formed at 80 ℃ to 120 ℃ in the presence of nitrogen gas (N _2), method.

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