Method of preparing benzofused n-heteropolycycles

Abstract

The present invention relates to a method for preparing a benzofused N-heteropolycyclic compound.

Description

Technology Field

[0001] The present invention relates to a method for preparing a benzofused N-heteropolycyclic compound. Background Technology

[0002] Benzofused N-heteropolycycles are major frameworks found in natural products and pharmaceuticals, and the development of efficient synthesis methods for them is an interesting field in medicinal chemistry and materials chemistry. These compounds include many biochemical substances essential for life. For example, nucleic acids, which are chemical substances that transmit genetic information, consist of long-chain heterocycle units linked by other types of substances. Compounds containing these heterocycles are utilized in pesticides, dyes, plastics, photoactive compounds, and conductive polymers.

[0003] In particular, benzofused N-heteropolycyclic compounds are key target molecules for pharmaceutical materials, and more than 90% of commercially available drugs and major pharmaceutical compounds possess a heterocyclic skeletal structure. These compounds exhibit diverse pharmacological activities depending on their molecular size and stereochemical structure. Therefore, methods for efficiently and selectively synthesizing heterocyclic skeletal structures are of great importance in the fields of organic chemistry and medicinal chemistry.

[0004] However, referring to the prior art 'Sahil Arora and Thomas R. Hoye, “Kobayashi Benzynes” as Hexadehydro-Diels-Alder Diynophiles”, Organic Letters 2021, 23(9), 3349-3353', there is a limitation in that the conventional method for preparing benzofused N-heteropolycyclic compounds was limited to compounds in which two alkynes are attached in succession as a heterocyclic structure containing oxygen as the starting material, and the benzyne formation initiation condition as an extension of the Kobayashi benzyne precursor was limited only to fluorine reagents. The problem to be solved

[0005] The present invention aims to provide a method for preparing a benzofused N-heteropolycyclic compound.

[0006] However, the problems that this invention seeks to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by a person skilled in the art from the description below. means of solving the problem

[0007] One aspect of the present invention is (a) a compound represented by the following chemical formula 1, comprising acetonitrile (MeCN) and potassium tert-butoxide (KO t A method for preparing a benzofused N-heteropolycyclic compound is provided, comprising: (a) reacting with Bu to obtain an intermediate product; and (b) reacting the intermediate product with tetra-n-butylammonium fluoride (TBAF) to obtain a benzofused N-heteropolycyclic compound represented by the following chemical formula 2:

[0008] [Chemical Formula 1]

[0009] ;

[0010] [Chemical Formula 2]

[0011] ;

[0012] In the above chemical formula 1 and the above chemical formula 2,

[0013] R is H, F, Cl, Br, I, a nitrile group, or an alkoxy group having 1 to 10 carbon atoms. Effects of the invention

[0014] Benzofused N-heteropolycyclic compounds prepared according to embodiments of the present invention can be utilized in various fields such as pharmaceuticals, pesticides, dyes, plastics, photoactive compounds, or conductive polymers.

[0015] The method for preparing a benzofused N-heteropolycyclic compound according to the embodiments of the present invention allows the reaction to proceed efficiently because the reaction conditions are mild and the reaction rate is fast.

[0016] Various aniline derivatives can be obtained through the method for preparing benzofused N-heteropolycyclic compounds according to the embodiments of the present invention.

[0017] The precursor used in the method for preparing benzofused N-heteropolycyclic compounds according to the embodiments of the present invention has a nitrogen-containing heterocyclic structure that has not been used conventionally, and only one alkyne ring is introduced, thereby enabling the effective synthesis of compound structures with a wider variety of pharmacological properties.

[0018] The method for preparing a benzofused N-heteropolycyclic compound according to embodiments of the present invention involves using not only a fluorine reagent but also NaH, KO t Benzoin can be formed using various bases such as Bu or TBAF. Brief explanation of the drawing

[0019] FIG. 1 is a reaction scheme of a method for preparing a benzofused N-heteropolycyclic compound according to one embodiment of the present invention. Specific details for implementing the invention

[0020] Hereinafter, embodiments and examples of the present invention are described in detail with reference to the attached drawings so that those skilled in the art can easily implement the present invention. However, the present invention may be implemented in various different forms and is not limited to the embodiments and examples described herein. Furthermore, in order to clearly explain the present invention in the drawings, parts unrelated to the explanation have been omitted, and similar parts throughout the specification have been given similar reference numerals.

[0021] Throughout this specification, when a part is described as being "connected" to another part, this includes not only cases where they are "directly connected," but also cases where they are "electrically connected" with other elements interposed between them.

[0022] Throughout this specification, when a component is described as being located "on" another component, this includes not only cases where a component is in contact with another component, but also cases where another component exists between the two components.

[0023] Throughout this specification, when a part is described as "comprising" a certain component, this means that, unless specifically stated otherwise, it does not exclude other components but may include additional components.

[0024] Terms of degree used in this specification, such as “about,” “substantially,” etc., are used to mean at or near the stated value when inherent manufacturing and material tolerances are presented in the stated meaning, and are used to prevent unscrupulous infringers from unfairly exploiting the disclosure in which precise or absolute values ​​are mentioned to aid in understanding the invention.

[0025] The terms “step of” or “step of” as used throughout this specification do not mean “step for”.

[0026] Throughout this specification, the term “combination(s) of these” included in the Markush-type expression means one or more mixtures or combinations selected from the group consisting of the components described in the Markush-type expression, and means including one or more selected from the group consisting of said components.

[0027] Throughout this specification, the description of "A and / or B" means "A or B, or A and B".

[0029] Embodiments of the present invention have been described in detail below, but the present invention may not be limited thereto.

[0031] One aspect of the present invention is (a) a compound represented by the following chemical formula 1, comprising acetonitrile (MeCN) and potassium tert-butoxide (KO t A method for preparing a benzofused N-heteropolycyclic compound is provided, comprising: (a) reacting with Bu to obtain an intermediate product; and (b) reacting the intermediate product with tetra-n-butylammonium fluoride (TBAF) to obtain a benzofused N-heteropolycyclic compound represented by the following chemical formula 2:

[0032] [Chemical Formula 1]

[0033] ;

[0034] [Chemical Formula 2]

[0035] ;

[0036] In the above chemical formula 1 and the above chemical formula 2,

[0037] R is H, F, Cl, Br, I, a nitrile group, or an alkoxy group having 1 to 10 carbon atoms.

[0038] In one embodiment of the present invention, the potassium tert-butoxide may be used in an amount of about 0.5 equivalents to about 2 equivalents, but is not limited thereto. In one embodiment of the present invention, the potassium tert-butoxide is about 0.5 to about 2 equivalents, about 0.5 to about 1.8 equivalents, about 0.5 to about 1.6 equivalents, about 0.5 to about 1.4 equivalents, about 0.7 to about 2 equivalents, about 0.7 to about 1.8 equivalents, about 0.7 to about 1.6 equivalents, about 0.7 to about 1.4 equivalents, about 0.9 to about 2 equivalents, about 0.9 to about 1.8 equivalents, about 0.9 to about 1.6 equivalents, about 0.9 to about 1.4 equivalents, about 1.1 to about 2 equivalents, about 1.1 to about 1.8 equivalents, about 1.1 to about 1.1 equivalents. It may be used in an amount of 1.6 equivalents, or about 1.1 to about 1.4 equivalents, but is not limited thereto. In one embodiment of the present invention, it may be most preferable to use the potassium tert-butoxide in an amount of about 1.2 equivalents.

[0039] In one embodiment of the present invention, the tetra-n-butylammonium fluoride may be used in an amount of about 1 equivalent to about 5 equivalents, but is not limited thereto. In one embodiment of the present invention, the tetra-n-butylammonium fluoride is about 1 equivalent to about 5 equivalents, about 1 equivalent to about 4.5 equivalents, about 1 equivalent to about 4 equivalents, about 1 equivalent to about 3.5 equivalents, about 1.5 equivalents to about 5 equivalents, about 1.5 equivalents to about 4.5 equivalents, about 1.5 equivalents to about 4 equivalents, about 1.5 equivalents to about 3.5 equivalents, about 2 equivalents to about 5 equivalents, about 2 equivalents to about 4.5 equivalents, about 2 equivalents to about 4 equivalents, about 2 equivalents to about 3.5 equivalents, about 2.5 equivalents to about 5 equivalents, about 2.5 equivalents to about 4.5 equivalents, about 2.5 equivalents to about 4 equivalents, or about 2.5 equivalents to about 3.5 equivalents. It may be used in equivalent amounts, but is not limited thereto. In one embodiment of the present invention, it may be most preferable to use the tetra-n-butylammonium fluoride in an amount of about 3 equivalents.

[0040] In one embodiment of the present invention, (a) may be performed at about -70°C to about -30°C, but is not limited thereto. In one embodiment of the present invention, (a) may be performed at about -70°C to about -30°C, about -70°C to about -35°C, about -70°C to about -40°C, about -70°C to about -45°C, about -65°C to about -30°C, about -65°C to about -35°C, about -65°C to about -40°C, about -65°C to about -45°C, about -60°C to about -30°C, about -60°C to about -35°C, about -60°C to about -40°C, about -60°C to about -45°C, about -55°C to about -30°C, about -55°C to about -35°C, about -55°C to about -40°C, or about -55°C to about -40°C, but is not limited thereto. In one embodiment of the present invention, the above (a) may most preferably be performed at about -50°C.

[0041] In one embodiment of the present invention, (b) may be performed at room temperature, but is not limited thereto. Here, room temperature may be about 10°C to about 35°C, about 10°C to about 30°C, about 10°C to about 25°C, about 15°C to about 35°C, about 15°C to about 30°C, or about 15°C to about 25°C.

[0042] In one embodiment of the present invention, the reaction times of (a) and (b) may each independently be greater than 0 hours to about 2 hours, but are not limited thereto. In one embodiment of the present invention, the reaction time of (a) may be greater than 0 hours to about 2 hours, greater than 0 hours to about 1 hour 30 minutes, or greater than 0 hours to about 1 hour, but is not limited thereto. In one embodiment of the present invention, the reaction time of (b) may be greater than 0 hours to about 2 hours, greater than 0 hours to about 1 hour 30 minutes, about 30 minutes to about 2 hours, or about 30 minutes to about 1 hour 30 minutes, but is not limited thereto.

[0043] In one embodiment of the present invention, the method for preparing the benzofused N-heteropolycyclic compound comprises a fluorine reagent, NaH, and KO. t Benzoin can be formed using various bases such as Bu or TBAF.

[0044] In one embodiment of the present invention, various aniline derivatives can be obtained through the method for preparing the benzofused N-heteropolycyclic compound.

[0045] In one embodiment of the present invention, the method for preparing the benzofused N-heteropolycyclic compound may form a benzine intermediate by a 1,3-Aza-Brook rearrangement reaction of the compound represented by Chemical Formula 1.

[0046] In one embodiment of the present invention, the method for preparing the benzofused N-heteropolycyclic compound may involve performing an intramolecular [4+2] cyclization addition reaction, an ene reaction, and a hexadehydro-Diels-Alder (HDDA) reaction.

[0047] In one embodiment of the present invention, the yield of the benzofused N-heteropolycyclic compound may be about 50% or more, about 60% or more, about 70% or more, or about 80% or more.

[0049] The present invention will be explained in more detail below using examples, but the following examples are merely illustrative to aid in understanding the present invention, and the content of the present invention is not limited to the following examples.

[0051] [실시예]

[0052] After dissolving an aminobenzine precursor (1.0 equivalent) in an acetonitrile (MeCN) solution (0.03 M), KO at -50℃ t Bu (1.2 equivalents) was added gradually. The reaction mixture was stirred at the same temperature for 30 minutes, after which tetra-n-butylammonium fluoride (TBAF) (3.0 equivalents; 1.0 M solution in THF) was added and stirred at room temperature. After monitoring the completion of the reaction using thin layer chromatography (TLC), the reaction mixture was evaporated with NH4Cl (sat.) and extracted three times with 10 mL of diethyl ether. The organic components were collected, dried using anhydrous magnesium sulfur (MgSO4), filtered, and concentrated under vacuum. Purification was performed using flash column chromatography with silica gel to obtain products represented by compounds 1 to 4 below (see Fig. 1):

[0053] [Compound 1]

[0054]

[0055] 1 H NMR (300 MHz, CDCl 3 ) δ 8.28 (d, J= 2.3 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.52-7.40 (m, 2H), 7.32 (s, 1H), 7.10 (s, 1H), 4.80 (s, 2H), 4.28 (d, J = 2.8 Hz, 1H).

[0056] Yield: 75%

[0057] [Compound 2]

[0058]

[0059] 1 H NMR (300 MHz, CDCl 3 ) δ 8.04 (s, 1H), 7.60 (s, 1H), 7.52 (d, J = 12.2 Hz, 2H), 7.48 (t, J = 9.2 Hz, 2H), 7.45-7.35 (m, 2H), 4.98 (s, 1H), 4.15 (s, 1H), 2.31 (s, 3H).

[0060] Yield: 80%

[0061] [Compound 3]

[0062]

[0063] 1 H NMR (300 MHz, CDCl 3 ) δ 8.44 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.50-7.43 (m, 2H), 7.36 (s, 1H), 7.17 (s, 1H), 4.89 (s, 2H), 4.34 (d, J = 2.8 Hz, 1H).

[0064] Yield: 67%

[0065] [Compound 4]

[0066]

[0067] 1 H NMR (300 MHz, CDCl 3 ) δ 8.84 (s, 1H), 7.90 (s, 1H), 7.77 (d, J = 12.2 Hz, 2H), 7.57 (t, J = 9.2 Hz, 2H), 7.43-7.31 (m, 2H), 4.98 (s, 2H), 4.15 (s, 1H).

[0068] Yield: 61%

[0070] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical concept or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. For example, each component described as a single unit may be implemented in a distributed manner, and components described as distributed may likewise be implemented in a combined form.

Claims

Claim 1 (a) A compound represented by the following chemical formula 1 is prepared in an acetonitrile (MeCN) solution of potassium tert-butoxide (KO t A method for preparing a benzofused N-heteropolycyclic compound, comprising: (a) reacting with (Bu) to obtain an intermediate product; and (b) reacting the intermediate product with tetra-n-butylammonium fluoride (TBAF) to obtain a benzofused N-heteropolycyclic compound represented by the following formula 2, wherein the potassium tert-butoxide is used in an amount of 1.2 equivalents relative to the compound represented by the following formula 1, and (a) is performed at -55°C to -30°C: [Formula 1] ;[Chemical Formula 2] ;In the above chemical formula 1 and the above chemical formula 2, R is H, F, Cl, Br, I, a nitrile group, or an alkoxy group having 1 to 10 carbon atoms. Claim 2 delete Claim 3 A method for preparing a benzofused N-heteropolycyclic compound according to claim 1, wherein the tetra-n-butylammonium fluoride is used in an amount of 1 to 5 equivalents. Claim 4 delete Claim 5 A method for preparing a benzofused N-heteropolycyclic compound according to claim 1, wherein (b) is performed at room temperature. Claim 6 A method for preparing a benzofused N-heteropolycyclic compound according to claim 1, wherein the reaction times of (a) and (b) are each independently greater than 0 hours and up to 2 hours.

Images