KR102292794B1 - Preparation method of 2-substituted 1,2,3,4-tetrahydroquinoline compound - Google Patents

Abstract

The present invention relates to a method for preparing a 2-substituted quinoline compound, and more particularly, to a hydroconversion reaction of a 2-substituted quinoline compound using a catalyst composition comprising an isothiouronium salt and a thioester to 2-substituted It relates to a method for preparing a 1,2,3,4-tetrahydroquinoline compound.
According to the present invention, a 2-substituted 1,2,3,4-tetrahydroquinoline compound can be prepared in high yield with improved reaction efficiency and reaction rate.

Description

Method for preparing a 2-substituted 1,2,3,4-tetrahydroquinoline compound {PREPARATION METHOD OF 2-SUBSTITUTED 1,2,3,4-TETRAHYDROQUINOLINE COMPOUND}

The present invention relates to a method for efficiently preparing 1,2,3,4-tetrahydroquinoline compounds widely present in biologically active natural products and pharmaceuticals, and more particularly, isothiouronium salt (Isothiouronium salt) ) and a 2-substituted quinoline (2-Substituted quinoline) compound using Hantzschester to hydrogenate the 2-substituted 1,2,3,4-tetrahydroquinoline (2-Substituted 1,2, 3,4-Tetrahydroquinoline) relates to a method for preparing a compound.

1,2,3,4-Tetrahydroquinoline-based backbones exist widely in biologically active natural products and pharmaceuticals. The 1,2,3,4-tetrahydroquinoline moiety is a very important structure used as a parent nucleus of various pharmaceuticals as illustrated below, and a new method for preparing it is continuously required.

Reduction of quinoline derivatives for tetrahydroquinoline synthesis is one of the most widespread approaches, and catalysts for conversion with hydrogen as a reducing agent have been developed. Although most of these transition metal catalysts exhibit high reactivity and selectivity in processes, they have problems such as contamination, toxicity, and danger of transition metals. In recent years, the development of sustainable synthesis methodologies has attracted much attention due to the increasing awareness of the risks of handling high-pressure hydrogen gas and the environmental impacts on chemical processes.

Organic catalysts of chemical transformation catalyzed by metal-free organic molecules are applied as a replacement for metals and biocatalysts. In this regard, a new paradigm has been created in the hydrogenation of unsaturated compounds such as imines and olefins and the reduction of organic compounds using organic catalysts. Hantzschester, one of the most widely used organic hydride sources, has been used as a bioreducing agent that mimics NAD(P)H (Nicotinamide Adenine Dinucleotide) in redox reactions since its appearance.

In 2006, researchers from the Rueping group developed the bronze acid-catalyzed reductive hydrogenation of quinolines using Hanchiesters as silver reducing agents. Similar to Bronsted acid catalysts, thiourea derivatives have been widely used as efficient catalysts in various chemical transformations.

The present inventors have discovered that the isothiouronium salt catalyst has a stronger hydrogen bonding ability than thiourea in the field of supramolecular chemistry for anion recognition. In order to efficiently prepare tetrahydroquinoline under mild reaction conditions, an isothiouronium salt catalyst having a structurally controlled and simple structure was applied to the hydrogenation conversion reaction of quinoline. As a result, 1,2,3,4- with fast reaction time and high yield. It was confirmed that tetrahydroquinoline was obtained and tried to complete the present invention.

Angew. Chem. Int. Ed. 2006, 45, 3683-3686

In order to provide high yield and improved reaction rate, the present invention uses a structurally controlled catalyst composition containing an isothiouronium salt and a thioester as an organic catalyst to provide 2-quinoline compounds as an important backbone of natural products or pharmaceuticals. An object of the present invention is to provide a method for efficiently preparing a substituted 1,2,3,4-tetrahydroquinoline compound.

The present invention relates to a hydrogenation conversion reaction of a 2-substituted quinoline compound represented by the following formula (2) in the presence of an isothiouronium salt represented by the following formula (3) and a thioester represented by the following formula (4) to 2 represented by the following formula (1) Methods for preparing -substituted 1,2,3,4-tetrahydroquinoline compounds are provided:

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

(In Formulas 1 to 3,

R is C1-C10 alkyl, C3-C10 cycloalkyl, C6-C20 aryl or C3-C20 heteroaryl, wherein aryl and heteroaryl of R are halogen, nitro, C1-C10 alkyl, C1-C10 alkylcarbonyl, C1 which may be further substituted with one or more substituents selected from -C10 alkoxy, C3-C10 cycloalkyl, hydroxy, C6-C20 aryl and C3-C20 heteroaryl;

R ¹ is hydrogen, C1-C10 alkyl, C6-C20 arylC1-C10 alkyl, C6-C20 aryl or C3-C20 heteroaryl;

R ² and R ³ are each independently halogen, nitro or haloC1-C10 alkyl;

a and b are each independently an integer from 0 to 5;

X ^- is a halogen anion, BPh ₄ ^- , BF ₄ ^- , PF ₆ ^- , R ⁴ CO ₂ ^- , R ⁵ SO ₃ ^- or (R ⁵ ) ₂ PO ₂ ^- ;

R ⁴ is hydrogen, C1-C10 alkyl, haloC1-C10 alkyl, C6-C20 aryl or C3-C20 heteroaryl;

R ⁵ is hydrogen, C1-C10 alkyl, C6-C20 aryl or C3-C20 heteroaryl;

The heteroaryl includes one or more heteroatoms selected from N, O and S.)

The method for preparing a 2-substituted 1,2,3,4-tetrahydroquinoline compound according to the present invention provides a structurally controlled N,N'-diphenylisothiouronium salt and hydrogen supply to significantly improve the reaction rate By using the causative ester, the 2-substituted quinoline compound is subjected to a hydrogenation conversion reaction under a mild reaction temperature to produce a 1,2,3,4-tetrahydroquinoline compound having various substituents introduced at the 2nd position within a short reaction time in high yield and It can be produced efficiently with selectivity.

In addition, the method for producing a 2-substituted 1,2,3,4-tetrahydroquinoline compound according to the present invention is a 1,2,3,4-tetrahydroquinoline widely present in biologically active natural products and pharmaceuticals. Since the compound is efficiently manufactured, it can be said that the industrial use value is very high for the production of pharmaceutical products such as cholesterol lowering agents, antibiotics and arrhythmias.

Hereinafter, the present invention will be described in detail. At this time, if there is no other definition in the technical terms and scientific terms used, those of ordinary skill in the art to which this invention belongs have the meanings commonly understood. In addition, repeated description of the same technical configuration and operation as in the prior art will be omitted. In addition, although preferred methods and samples are described herein, similar or equivalent ones are also included in the scope of the present invention.

Throughout this specification, unless the context requires otherwise, the terms "comprises" and "comprising" include the steps or elements presented, or groups of steps or elements, but any other step or element, or It is to be understood that a step or group of elements is not excluded.

As used herein, the terms “substituent”, “radical”, “group”, “moiety”, and “fragment” may be used interchangeably.

The term "C _A -C _B " as used herein means "the number of carbon atoms is greater than or equal to A and less than or equal to B".

As used herein, the term “alkyl” refers to a monovalent straight-chain or branched saturated hydrocarbon radical composed only of carbon and hydrogen atoms. The alkyl may have 1 to 10 carbon atoms, 1 to 7 carbon atoms, 1 to 5 carbon atoms, or 1 to 4 carbon atoms. The alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethylhexyl, and the like.

As used herein, the term “cycloalkyl” is a monovalent saturated or unsaturated carbocyclic radical composed of one or more rings, and is not aromatic. The cycloalkyl may be monocyclic or may be a fused, spiro, or bridged bicyclic ring system. The cycloalkyl may have 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 7 carbon atoms. Specifically, monocyclic cycloalkyl rings contain 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, in the ring. Bicyclic cycloalkyl rings contain 6 to 10 carbon atoms, preferably 7 to 9 carbon atoms, in the ring. Preferred bicyclic cycloalkyl rings include 5-, or 6-membered rings fused to 4-, 5- or 6-membered rings. Specific examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

As used herein, the term "aryl" is an aromatic ring monovalent organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, suitably containing 4 to 7, preferably 5 or 6 ring atoms in each ring. It includes a single or fused ring system, and includes a form in which a plurality of aryls are connected by a single bond. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like.

As used herein, the term "heteroaryl" refers to an aryl group containing 1 to 4 heteroatoms selected from N, O and S as an aromatic ring skeleton atom, and the remaining aromatic ring skeleton atoms are carbon, and 5 to 6 membered. monocyclic heteroaryl, and polycyclic heteroaryl condensed with one or more benzene rings. In addition, heteroaryl in the present invention includes a form in which one or more heteroaryls are connected by a single bond. Specific examples include furyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, monocyclic heteroaryl such as pyridyl, benzofuranyl, dibenzofuranyl, di Polycyclic heterocycles such as benzothiophenyl, benzothiophenyl, isobenzofuranyl, benzoimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, quinolyl, isoquinolyl, and carbazolyl aryl and the like.

As used herein, the term "halo" or "halogen" refers to a halogen element and includes, for example, fluoro, chloro, bromo and iodo.

As used herein, the term "nitro" refers to -NO ₂ , and "hydroxy" refers to -OH.

As used herein, the term "alkylcarbonyl" refers to a -C(=O)alkyl radical, where 'alkyl' is as defined above. Examples of such alkylcarbonyl radicals include, but are not limited to, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, propylcarbonyl, butylcarbonyl, isobutylcarbonyl, t-butylcarbonyl, and the like.

As used herein, the term "alkoxy" refers to an -O-alkyl radical, where 'alkyl' is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and the like.

As used herein, the term "arylalkyl" refers to an alkyl radical substituted with at least one aryl, where 'alkyl' is as defined above. Examples of such arylalkyl radicals include, but are not limited to, benzyl and the like.

As used herein, the term “haloalkyl” refers to an alkyl radical substituted with at least one halogen, where “alkyl” is as defined above. Examples of such haloalkyl radicals include, but are not limited to, fluoromethyl, trifluoromethyl, bromomethyl, perfluoroethyl, and the like.

The present invention relates to a method for preparing various 1,2,3,4-tetrahydroquinoline compounds using a catalyst composition containing an isothiouronium salt and an organic catalyst capable of providing high yield and improved reaction rate. , more specifically, a hydrogenation conversion reaction of a 2-substituted quinoline compound represented by the following formula (2) in the presence of an isothiouronium salt represented by the following formula (3) and a thioester represented by the following formula (4) to be represented by the following formula (1) A method for preparing a 2-substituted 1,2,3,4-tetrahydroquinoline compound is provided:

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

(In Formulas 1 to 3,

R is C1-C10 alkyl, C3-C10 cycloalkyl, C6-C20 aryl or C3-C20 heteroaryl, wherein aryl and heteroaryl of R are halogen, nitro, C1-C10 alkyl, C1-C10 alkylcarbonyl, C1 which may be further substituted with one or more substituents selected from -C10 alkoxy, C3-C10 cycloalkyl, hydroxy, C6-C20 aryl and C3-C20 heteroaryl;

R ¹ is hydrogen, C1-C10 alkyl, C6-C20 arylC1-C10 alkyl, C6-C20 aryl or C3-C20 heteroaryl;

R ² and R ³ are each independently halogen, nitro or haloC1-C10 alkyl;

a and b are each independently an integer from 0 to 5;

X ^- is a halogen anion, BPh ₄ ^- , BF ₄ ^- , PF ₆ ^- , R ⁴ CO ₂ ^- , R ⁵ SO ₃ ^- or (R ⁵ ) ₂ PO ₂ ^- ;

R ⁴ is hydrogen, C1-C10 alkyl, haloC1-C10 alkyl, C6-C20 aryl or C3-C20 heteroaryl;

R ⁵ is hydrogen, C1-C10 alkyl, C6-C20 aryl or C3-C20 heteroaryl;

The heteroaryl includes one or more heteroatoms selected from N, O and S.)

In the preparation method according to the present invention, the isothiouronium salt of Formula 3 used as a catalyst has a stronger hydrogen bonding ability than a thiourea catalyst conventionally known in the field of supramolecular chemistry for anion recognition, and also hydrogen Since it has a structurally controlled structure by introducing a phenyl group to each nitrogen atom for a significant increase in bonding, 1,2,3,4-tetrahydrogen in a high yield within a significantly shortened reaction time in the hydrogenation conversion reaction of quinoline Quinoline compounds can be efficiently prepared.

That is, in the isothiouronium salt of Chemical Formula 3, the acidity of N-H hydrogen is increased due to the phenyl group substituted for the nitrogen atom, and thus a stronger hydrogen bonding interaction can occur. As shown in Scheme 1 below, the isothiouronium salt of Formula 3 strongly hydrogen bonds to the 2-substituted quinoline compound of Formula 2 and activates it so that the Hanchiester of Formula 4 can easily supply hydrogen, resulting in a short reaction time The 2-substituted 1,2,3,4-tetrahydroquinoline compound of Formula 1 can be prepared in high yield.

In one embodiment according to the present invention, the isothiouronium salt of Chemical Formula 3 may be at least one selected from the following Chemical Formulas 3-1 to 3-4:

[Formula 3-1]

[Formula 3-2]

[Formula 3-3]

[Formula 3-4]

(In Formulas 3-1 to 3-4,

R ¹ is C1-C7 alkyl, C6-C12 aryl or C3-C12 heteroaryl;

X ^- is Cl ^- , Br ^- , I ^- , BPh ₄ ^- , BF ₄ ^- , PF ₆ ^- , R ⁴ CO ₂ ^- , R ⁵ SO ₃ ^- or (R ⁵ ) ₂ PO ₂ ^- ;

R ⁴ is hydrogen, C1-C7 alkyl, haloC1-C7 alkyl, C6-C12 aryl or C3-C12 heteroaryl;

R ⁵ is hydrogen, C1-C7 alkyl, C6-C12 aryl or C3-C12 heteroaryl;

R' and R'' are each independently hydrogen, halogen, nitro or haloC1-C7 alkyl;

Y is halogen.)

In one embodiment, the X ^- may be Cl ^- , Br ^- or I ^- .

In one embodiment, the isothiouronium salt may be of Formula 3-1, wherein R ¹ may be C1-C4 alkyl, and X ^- may be Cl ^- , Br ^- or I ^- . In terms of having a better reactivity, X ^- may be I ^-.

The isothiouronium salt according to an embodiment may be represented by the following structure.

In one embodiment, the isothiouronium salt may be of Formula 3-2, Formula 3-3, or Formula 3-4, wherein X ^- may be Cl ^- , Br ^- or I ^- , and R' and R'' are each independently haloC1-C4alkyl, and Y may be halogen. Preferably, in terms of better reactivity and yield, the isothiouronium salt may be of Formula 3-3, wherein X ^- may be I ^-.

The isothiouronium salt according to an embodiment may be represented by the following structure.

In one embodiment, the isothiouronium salt of Formula 3 may be used in the range of 0.01 to 0.1 mol, preferably in the range of 0.05 to 0.1 mol, based on 1 mol of the 2-substituted quinoline compound of Formula 2 Within this range, it is more preferable in terms of reactivity and yield.

In one embodiment, the Hanchi ester of Formula 4 may be used in the range of 2 to 3 moles, preferably in the range of 2.5 to 3 moles, based on 1 mole of the 2-substituted quinoline compound of Formula 2, within the above range It is more preferable in terms of reactivity and yield.

In one embodiment, the reaction may be carried out in a conventional organic solvent, and as long as it can dissolve the 2-quinoline compound of Formula 2, the isothiouronium salt of Formula 3, and the Hanchi ester of Formula 4, the reaction may be performed in an organic solvent. There is no need to limit Specifically, the organic solvent may be one or two or more selected from the group consisting of chloroform, dichloromethane, dichloroethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile and dimethylformamide. and chloroform, dichloromethane, tetrahydrofuran, methanol or acetonitrile may be used in consideration of the solubility of the reactant and the ease of removal.

In one embodiment, the reaction may be carried out at a mild reaction temperature of 20 to 70 ° C, preferably 25 to 60 ° C, and the reaction time may vary depending on the reactant, the type of the solvent and the amount of the solvent, The reaction is completed after confirming that the 2-quinoline compound of Formula 2 as the starting material is consumed and the product is produced through TLC or the like. After the reaction is completed, the solvent is distilled under reduced pressure, and then the target substance can be separated and purified through a conventional method such as column chromatography.

이고;In one embodiment, in Formulas 1 and 2, R is C1-C7 alkyl or

ego;

R ¹¹ to R ¹⁵ may each independently be hydrogen, halogen, nitro, C1-C7 alkyl, C3-C7 cycloalkyl, hydroxy or C6-C12 aryl.

In one embodiment, the 2-substituted 1,2,3,4-tetrahydroquinoline compound may be more specifically selected from the following compounds, but is not limited thereto.

The 2-substituted 1,2,3,4-tetrahydroquinoline compound of Formula 1 prepared by the manufacturing method according to the present invention has a physiologically active natural product and a core structure in the pharmaceutical field, and is an important raw material or It can be used widely and usefully as an intermediate.

Hereinafter, the configuration of the present invention will be described in more detail through examples, but the following examples are provided to help the understanding of the present invention, and the scope of the present invention is not limited thereto.

[Preparation Example 1] Preparation of S-benzyl-N,N'-diphenylisothiouronium iodide (S-Benzyl-N,N'-diphenylisothiouronium iodide)

Step 1: Preparation of 1,3-diphenylthiourea (1,3-Diphenylthiourea)

Phenyl isothiocyanate (phenyl isothiocyanate, 1.0 mL, 1.1 mmol) and aniline (aniline, 1.6 mL, 1.3 mmol) were dissolved in dry DCM (dry dichloromethane, 10 mL) at room temperature, followed by reaction for 24 hours. After completion of the reaction, the solvent was removed and filtered with a solution (100 mL) in which chloroform and n-hexane were mixed in a volume ratio of 2:8 to obtain 1,3-diphenylthiourea as a white solid (2.1 g, yield). 84%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.111 (br, 2H), 7.242-7.432 (m, 10H).

Step 2: Preparation of S-benzyl-N,N'-diphenylisothiouronium iodide (S-Benzyl-N,N'-diphenylisothiouronium iodide)

1,3-diphenylthiourea (1.0 g, 4.4 mmol) and benzyl iodide (2.80 mL, 13.2 mmol) were dissolved in dry DCM (10 mL) at room temperature, followed by reaction for 24 hours. After completion of the reaction, the precipitated solid was washed with DCM, and then recrystallized with methanol to obtain S-benzyl-N,N'-diphenylisothiouronium iodide as a yellow transparent solid (1.1 g, yield 58%). ).

¹ H NMR (300 MHz, DMSO): δ 7.207-7.387 (m, 15H), 4.445 (s, 2H).

[Preparation Example 2] Preparation of S-methyl-N,N'-diphenylisothiouronium iodide (S-Methyl-N,N'-diphenylisothiouronium iodide)

1,3-diphenylthiourea (1.4 g, 6.1 mmol) and methyl iodide (18.3 mmol) were dissolved in dry DCM (10 mL) at room temperature, followed by reaction for 24 hours. After completion of the reaction, the precipitated solid was washed with DCM, and then recrystallized with methanol to obtain S-methyl-N,N'-diphenylisothiouronium iodide as a yellow solid (1.8 g, yield 80%). .

¹ H NMR (300 MHz, DMSO): δ 7.4392-7.2799 (m, 10H), 2.6146 (s, 3H).

Example I: Preparation of 2-substituted 1,2,3,4-tetrahydroquinoline compound (1) using isothiouronium salt and Hanchiester

2-substituted quinoline compound (2) (0.30 mmol, 1 equiv.), S-benzyl-N,N'-diphenylisothiouronium iodide (5 mol%), and Hantzsch ester, 2.5 equiv.) was dissolved in dry chloroform (5 mL), and then reacted at room temperature (25° C.) or 60° C. for 10 to 180 minutes. After completion of the reaction, the solvent was removed under reduced pressure and purified by silica gel column chromatography (eluent: n-Hexane/EtOAc = 20/1 (v/v)), and the target compound, 1,2,3,4-tetrahydroquinoline compound (1 ) was obtained.

Using the method described above, various 1,2,3,4-tetrahydroquinoline compounds (1) were obtained as shown in Table 1 below.

Example R reaction
Temperature
(℃) reaction
hour
(minute) transference number
(%) ¹ H NMR One

25 60 98 δ 7.33-7.13 (m, 5H), 6.97-6.88 (m, 2H), 6.56 (t, J= 7.4 Hz, 1H), 6.45 (d, J= 7.5 Hz, 1H), 4.35 (dd, J= 9 ,3-3.3 Hz, 1H), 3.94 (brs, 1H), 2.44 (ddd, J= 16.2, 10.6, 5.5 Hz, 1H), 2.65 (dt, J= 16.3, 4.8 Hz, 1H), 2.10-1.97 ( m, 1H), 1.96-1.83 (m, 1H) 2

25 60 97 δ 7.19 (t, J= 8.0 Hz, 2H), 7.08 (d, J= 7.8 Hz, 2H), 6.92 (t, J= 7.0 Hz, 2H), 6.56 (t, J= 7.4 Hz, 1H), 6.45 (d, J= 9.6 Hz, 1H), 4.43 (dd, J= 9.4, 3.2 Hz, 1H), 2.84 (ddd, J= 16.3, 10.8, 5.5 Hz, 1H), 2.66 (dt, J= 16.3, 4.7) Hz, 1H), 2.27 (s, 3H), 2.08-1.97 (m, 1H), 1.96-1.82 (m, 1H) 3

60 60 70 δ 7.31 (d, J= 7.8 Hz, 1H), 6.97-6.87 (m, 4H), 6.57 (t, J= 7.9 Hz, 1H), 6.46 (d, J= 9.3 Hz, 1H), 4.64 (dd, J= 9.2, 3.2 Hz, 1H), 3.83 (brs, 1H), 2.84 (dd, J= 10.8, 5.5, 5.4 Hz, 1H), 2.69 (dt, J= 16.3, 4.6 Hz, 1H), 2.27 (s) , 3H), 2.23 (s, 3H), 2.05-1.96 (m, 1H), 1.89-1.77 (m, 1H) 4

25 180 92 δ 7.24 (d, J= 8.1 Hz, 2H), 7.19-7.06 (m, 2H), 6.92 (t, J= 6.8 Hz, 2H), 6.56 (t, J= 7.4 Hz, 1H), 6.44 (d, J= 8.4 Hz, 1H), 4.33 (dd, J= 9.5, 3.2 Hz, 1H), 2.94-2.79 (m, 2H), 2.67 (dt, J= 16.3, 4.6 Hz, 1H), 2.10-1.98 (m) , 1H), 1.98-1.82 (m, 1H), 1.18 (d, J= 6.9 Hz, 6H) 5

60 20 98 δ 7.22 (d, J= 68.5 Hz, 2H), 6.91 (t, J= 6.6 Hz, 2H), 6.80 (d, J= 8.7 Hz, 2H), 6.55 (t, J= 7.4 Hz, 1H), 6.43 (d, J= 9.5 Hz, 1H), 4.29 (dd, J= 9.5, 3.2 Hz, 1H), 3.86 (brs, 1H), 3.72 (s, 3H), 2.83 (ddd, J= 16.4, 10.9, 5.5 Hz, 1H), 2.65 (dt, J= 16.4, 4.6 Hz, 1H), 2.07-1.95 (m, 1H), 1.93-1.77 (m, 1H) 6

25 60 90 δ 7.56-7.46 (m, 4H), 7.44-7.32 (m, 4H), 7.31-7.23 (m, 1H), 6.95 (t, J = 7.2 Hz, 2 H), 6.59 (t, J = 6.1 Hz, 1 H), 6.49 (d, J = 7.3 Hz, 1 H), 4.42 (dd, J = 9.3, 3.3 Hz, 1 H), 3.99 (br s, 1 H), 2.87 (ddd, J = 16.1, 10.6) , 5.4 Hz, 1 H), 2.69 (dt, J= 16.4, 4.8 Hz, 1 H), 2.16-2.04 (m, 1 H), 2.03-1.86 (m, 1 H) 7

60 30 85 δ 7.39 (t, J= 7.6 Hz, 1H), 7.21-7.11 (m, 1H), 7.09-6.85 (m, 4H), 6.58 (t, J= 7.4 Hz, 1H), 6.48 (d, J= 7.9) Hz, 1H), 4.77 (dd, J= 8.1, 3.5 Hz, 1H), 3.90 (brs, 1H), 2.92-2.71 (m, 1H), 2.61 (dt, J= 16.3, 5.5 Hz, 1H), 2.17 -2.01 (m, 1H), 2.00-1.80 (m, 1H) 8

60 20 87 δ 7.28-7.20 (m, 4H), 7.01-6.86 (m, 2H), 6.58 (t, J= 7.9 Hz, 1H), 6.47 (d, J= 7.9 Hz, 1H), 4.35 (dd, J= 9.1 , 3.3 Hz, 1H), 3.93 (brs, 1H), 2.83 (ddd, J= 16.1, 10.4, 5.4 Hz, 1H), 2.63 (dt, J= 16.4, 4.9 Hz, 1H), 2.07-1.96 (m, 1H), 1.93-1.76 (m, 1H) 9

60 30 91 δ 7.44-7.32 (m, 2H), 7.26-7.11 (m, 2H), 7.01-6.85 (m, 2H), 6.58 (t, J= 7.4 Hz, 1H), 6.46 (d, J= 7.9 Hz, 1H) ), 4.32 (dd, J= 9.1, 3.3 Hz, 1H), 3.92 (brs, 1H), 2.82 (ddd, J= 16.0, 10.4, 5.4 Hz, 1H), 2.62 (dt, J= 16.4, 4.9 Hz, 1H), 2.09-1.94 (m, 1H), 1.94-1.76 (m, 1H) 10

60 45 95 δ 6.98-6.79 (m, 2H), 6.52 (t, J= 7.4 Hz, 1H), 6.40 (d, J= 8.4 Hz, 1H), 3.69 (brs, 1H), 3.25-3.05 (m, 1H), 2.84-2.50 (m, 2H), 1.89 (dddd, J= 12.7, 5.6, 4.0, 3.0 Hz, 1H), 1.56-1.41 (m, 3H), 1.36-1.23 (m, 4H), 0.86 (t, J = 7.1 Hz, 3H) 11

60 30 90 δ 6.88 (t, J= 6.7 Hz, 1H), 6.52 (t, J= 7.4 Hz, 1H), 6.40 (d, J= 7.3 Hz, 1H), 3.68 (brs, 1H), 3.32-3.17 (m, 1H), 2.82-2.59 (m, 2H), 1.94-1.80 (m, 1H), 1.77-1.62 (m, 1H), 1.58-1.41 (m, 2H), 1.39-1.21 (m, 1H), 0.88 ( d, J = 6.6 Hz, 6H)

[Examples 12 to 22 and Comparative Examples 1 to 3]

In order to determine whether the 1,2,3,4-tetrahydroquinoline compound was prepared according to the reaction conditions, an experiment was performed as follows.

2-phenylquinoline (0.30 mmol, 1 equiv.), catalyst (S-benzyl-N,N'-diphenylisothiouronium iodide (Preparation Example 1) or S-methyl-N,N'-diphenyl Isothiouronium iodide (Preparation Example 2)) and Hantzsch ester were dissolved in a solvent (5 mL), and then reacted at room temperature (25°C), 40°C or 60°C. After completion of the reaction, the solvent was removed under reduced pressure and purified by silica gel column chromatography (eluent: n-Hexane/EtOAc = 20/1 (v/v)) to 1,2,3,4-tetrahydro-2-phenyl as the target compound Quinoline was obtained.

Table 2 below shows the reaction results according to the amount of catalyst and cold ester used, the type of solvent, and the reaction temperature and time.

catalyst Hanchiester
(equiv.) menstruum reaction temperature
(℃) reaction
hour transference number
(%) Kinds usage
(mol%) Example
12 S-benzyl-N,N'-diphenylisothiouronium iodide 10 3.0 CHCl ₃ 60 10 minutes 98 Example 13 S-benzyl-N,N'-diphenylisothiouronium iodide 10 3.0 CH ₂ Cl ₂ 40 30 minutes 97 Example 14 S-benzyl-N,N'-diphenylisothiouronium iodide 10 3.0 CH ₃ CN 60 40 minutes 92 Example 15 S-benzyl-N,N'-diphenylisothiouronium iodide 10 3.0 THF 60 40 minutes 90 Example 16 S-benzyl-N,N'-diphenylisothiouronium iodide 10 3.0 MeOH 60 2 hours 75 Example 17 S-benzyl-N,N'-diphenylisothiouronium iodide 10 3.0 CHCl ₃ 25 1 hours 98 Example 18 S-benzyl-N,N'-diphenylisothiouronium iodide 10 2.5 CHCl ₃ 25 1 hours 98 Example 19 S-benzyl-N,N'-diphenylisothiouronium iodide 10 2.2 CHCl ₃ 25 1 hours 75 Example 20 S-benzyl-N,N'-diphenylisothiouronium iodide 5 2.5 CHCl ₃ 25 1 hours 98 Example 21 S-benzyl-N,N'-diphenylisothiouronium iodide 5 2.5 CH ₂ Cl ₂ 25 1 hours 71 Example 22 S-methyl-N,N'-diphenylisothiouronium iodide 5 2.5 CHCl ₃ 25 2 hours 98 Comparative Example 1 - 0 2.5 CHCl ₃ 25 1 hours 0 Comparative Example 2 - 0 2.5 CHCl ₃ 60 24 hours 6 Comparative Example 3 S-benzyl isothiouronium iodide 5 2.5 CHCl ₃ 25 1 hours 0

The 2-substituted 1 that can be widely used as an important raw material or intermediate in the field of pharmaceutical chemistry by effectively reducing the 2-substituted quinoline under mild reaction conditions in the presence of a catalyst having a specific structure according to the present invention and a cold ester ,2,3,4-tetrahydroquinoline compounds can be efficiently prepared.

The description of the present invention described above is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (9)

A 2-substituted quinoline compound represented by the following formula (2) is subjected to a hydrogenation conversion reaction in the presence of an isothiouronium salt represented by the following formula (3) and a thioester represented by the following formula (4), and the 2-substituted Method for preparing 1,2,3,4-tetrahydroquinoline compound:
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

(In Formulas 1 to 3,
R is C1-C7 alkyl or

ego;
R ¹¹ to R ¹⁵ are each independently hydrogen, halogen, nitro, C1-C7 alkyl, C1-C7 alkoxy, C3-C7 cycloalkyl, hydroxy or C6-C12 aryl;
R ¹ is C1-C10 alkyl or C6-C20 arylC1-C10 alkyl;
R ² and R ³ are each independently halogen, nitro or haloC1-C10 alkyl;
a and b are each independently an integer from 0 to 5;
X ^- is a halogen anion, BPh ₄ ^- , BF ₄ ^- , PF ₆ ^- , R ⁴ CO ₂ ^- , R ⁵ SO ₃ ^- or (R ⁵ ) ₂ PO ₂ ^- ;
R ⁴ is hydrogen, C1-C10 alkyl, haloC1-C10 alkyl, C6-C20 aryl or C3-C20 heteroaryl;
R ⁵ is hydrogen, C1-C10 alkyl, C6-C20 aryl or C3-C20 heteroaryl;
The heteroaryl includes one or more heteroatoms selected from N, O and S.) The method of claim 1,
The isothiouronium salt is selected from the following formulas 3-1 to 3-4, the preparation method:
[Formula 3-1]

[Formula 3-2]

[Formula 3-3]

[Formula 3-4]

(In Formulas 3-1 to 3-4,
R ¹ is C 1 -C 7 alkyl;
X ^- is Cl ^- , Br ^- , I ^- , BPh ₄ ^- , BF ₄ ^- , PF ₆ ^- , R ⁴ CO ₂ ^- , R ⁵ SO ₃ ^- or (R ⁵ ) ₂ PO ₂ ^- ;
R ⁴ is hydrogen, C1-C7 alkyl, haloC1-C7 alkyl, C6-C12 aryl or C3-C12 heteroaryl;
R ⁵ is hydrogen, C1-C7 alkyl, C6-C12 aryl or C3-C12 heteroaryl;
R' and R'' are each independently hydrogen, halogen, nitro or haloC1-C7 alkyl;
Y is halogen.) 3. The method of claim 2,
The X ^- is Cl ^- , Br ^- or I ^- , the manufacturing method. The method of claim 1,
The isothiouronium salt of Formula 3 is to be used in the range of 0.01 to 0.1 moles based on 1 mole of the 2-substituted quinoline compound of Formula 2, the manufacturing method. The method of claim 1,
The method for producing a method, wherein the thioester of Formula 4 is used in the range of 2 to 3 moles based on 1 mole of the 2-substituted quinoline compound of Formula 2 above. The method of claim 1,
The reaction will be carried out at 20 to 70 ℃, the manufacturing method. The method of claim 1,
The reaction is carried out in one or two or more organic solvents selected from the group consisting of chloroform, dichloromethane, dichloroethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile and dimethylformamide, manufacturing method. delete The method of claim 1,
The 2-substituted 1,2,3,4-tetrahydroquinoline compound is selected from the following structure, the preparation method: