KR20110069520A - Novel indolizine derivatives and its preparation method - Google Patents

Abstract

PURPOSE: An indolizine derivative and a method for preparing the same are provided to develop novel drugs and to obtain indolizine derivative with high yield. CONSTITUTION: An indolizine derivative is denoted by chemical formula 1. In chemical formula 1, R is (C1-C7)alkyl; R1 is (C1-C7)alkyl or (C6-C20)aryl(C1-C7)alkyl; R2 is hydrogen or (C1-C7)alkyl; R3 is hydrogen, (C1-C7)alkyl, nitro, or halogen; and R4 and R5 are independently hydrogen or (C1-C7)alkyl. A method for preparing the indolizine derivative comprises a step of reacting pyridine derivatives of chemical formula 4 with organic indium reagent of chemical formula 3 under the presence of palladium catalyst and phospine ligand.

Description

Novel indolizine derivatives and its preparation method

The present invention relates to a novel indoligin derivative and a method for preparing the same. More specifically, the present invention relates to a process for preparing the novel indolizine derivatives through the cross-pairing reaction between the organoindium reagent and the pyridine derivative and the intramolecular cyclization reaction in the presence of a palladium catalyst.

Indolizine derivatives are nitrogen-containing double-ring compounds, which have various biological activities, and are used for the synthesis of various medicines, such as cardiovascular drugs, and are widely used as basic skeletons for the synthesis of natural products. It is also used in the field of precision science and material science because of its optical properties. Synthesis of such indolizine derivatives is known in the molecular chain reaction mainly using a transition metal catalyst, and synthesis of indolizine derivatives through intermolecular reactions is not well known ( J. Am . Chem . Soc . 2001 , 123 , 2074; Org . Lett . 2005 , 7 , 4305; J. Am . Chem . Soc . 2006 , 128 , 12050; J. Am . Chem . Soc . 2007 , 129 , 7742; Org . Lett . 2007 , 9 , 409; J. Org . Chem . 2007 , 72 , 7783; Org . Lett . 2007 , 9 , 3433; Org . Lett. 2007 , 9 , 4323; Org . Lett . 2007 , 9 , 4463; Org . Lett . 2008 , 10 , 2307; Org . Lett . 2009 , 11 , 1187).

However, organoindium reagents obtained in-situ from the reaction of indium with alkyl 4-bromo-2-pentinate derivatives are subjected to cross-linking reactions with pyridine derivatives in the presence of a palladium catalyst and subsequent intramolecular cyclization reactions. Examples of making indolizine derivatives have not been reported in any literature to date.

An object of the present invention is to provide a novel indolizine derivative that is widely used as a basic skeleton in the synthesis of pharmaceuticals and natural products having physiological activity.

Another object of the present invention is to provide a method for preparing the novel indolizine derivative through the cross-pairing reaction between the organoindium reagent and the pyridine derivative and the intramolecular cyclization reaction in the presence of a palladium catalyst.

The present invention provides an indolizine derivative represented by the following Chemical Formula 1 and a preparation method thereof.

[Formula 1]

In addition, the present invention is a method for producing an indolizine derivative represented by the formula (1) is a cross-pair of the organoindium reagent represented by the formula (3) and the pyridine derivative represented by the formula (4) in the presence of a palladium catalyst and a phosphine ligand Characterized in that the indolizin derivative represented by the formula (1) by the erase reaction and intramolecular cyclization reaction.

(3)

[Formula 4]

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, it has a meaning commonly understood by those of ordinary skill in the art. Repeated descriptions of the same technical constitution and operation as those of the conventional art will be omitted.

The present invention provides an indolizine derivative represented by the following formula (1).

[Formula 1]

[In Formula 1, R is (C1-C7) alkyl; R ¹ is (C ¹ -C 7) alkyl or (C 6 -C 20) aryl (C 1 -C 7) alkyl; R ² is hydrogen or (C 1 -C 7) alkyl; R ³ is hydrogen, (C 1 -C 7) alkyl, nitro or halogen; R ⁴ and R ⁵ are independently of each other hydrogen or (C 1 -C 7) alkyl; R ² to R ⁵ may be connected to alkenylene or alkenylene each independently or without a substituent and a fused ring adjacent to each other to form an alicyclic ring or an aromatic ring.]

The 'alkyl' includes both linear or pulverized carbon chains.

으로 연결되어 벤젠고리를 형성할 수 있다.R is methyl, ethyl or propyl; R ¹ is methyl, ethyl, propyl or phenethyl; R ² is hydrogen or methyl; R ³ is hydrogen, methyl, nitro or chloro; R ⁴ and R ⁵ are independently of each other hydrogen or methyl; R ² to R ⁵ are each independently a substituent adjacent to each other and

Can be connected to form a benzene ring.

Indolizine derivatives of the present invention are selected from, but are not limited to, compounds having the structure:

In addition, the present invention includes a method for preparing the 1,3-butadien-2-yl methyl amine derivative represented by Chemical Formula 1 as a right scope, and will be described in detail for the method for preparing the indolizin derivative according to the present invention. do.

A method for preparing an indolizine derivative according to the present invention is a cross-linking reaction and intramolecular cyclization of an indium reagent represented by the following formula (3) and a pyridine derivative represented by the following formula (4) in the presence of a palladium catalyst and a phosphine ligand. The reaction is to prepare an indolizin derivative represented by the following formula (1).

[Formula 1]

(3)

[Formula 4]

[In Formulas 1, 3 and 4, R is (C1-C7) alkyl; R ¹ is (C ¹ -C 7) alkyl or (C 6 -C 20) aryl (C 1 -C 7) alkyl; R ² is hydrogen or (C 1 -C 7) alkyl; R ³ is hydrogen, (C 1 -C 7) alkyl, nitro or halogen; R ⁴ and R ⁵ are independently of each other hydrogen or (C 1 -C 7) alkyl; R ² to R ⁵ may be each independently connected to an alkenylene or alkenylene including or without a substituent and a fused ring adjacent to each other to form an alicyclic ring or an aromatic ring; X is halogen; Z is halogen or -OS (= O) ₂ CF _3. ]

In addition, the organic indium reagent represented by Chemical Formula 3 may include an alkyl 4-bromo-2-pentinate derivative and indium represented by Chemical Formula 2 in the presence of a halide metal salt (MX: M = 1 is an alkali metal, X = halogen). It characterized in that it is prepared by reacting (Indium; In).

[Formula 2]

[In Formula 2, R is (C1-C7) alkyl; R ¹ is (C ¹ -C 7) alkyl or (C 6 -C 20) aryl (C 1 -C 7) alkyl; X is halogen.]

In the method for preparing the indolizine derivative of Chemical Formula 1 according to the present invention, the alkyl 4-bromo-2-pentinate derivative (Chemical Formula 2) is reacted with indium to induce an organic indium reagent (Chemical Formula 3) without additional separation and purification process. Carry out the reaction in situ. In-situ may be halogen or an organic indium reagent (Formula 3) obtained by reacting an alkyl 4-bromo-2-pentinate derivative (Formula 2) with indium in the presence of a halide metal salt. It refers to a production method for carrying out the reaction with a pyridine derivative substituted with trifluoromethanesulfonate (Formula 4).

The reaction vessel used in the production method of the present invention is preferably selected from the group consisting of a round bottom flask, a test tube and a V-vial, more preferably using a V-vial. The reason for using V-vials is to transfer heat energy effectively, and the reaction proceeds in test tubes.

The palladium catalyst used in the preparation method of the present invention is preferably selected from the group consisting of Pd ₂ dba ₃ CHCl ₃ , Pd (OAc) ₂ and Pd (dppf) ₂ , and Pd (OAc) ₂ is used as a catalyst. More preferably.

Ligands used in the preparation method of the present invention are phosphine ligands, triphenylphosphine (PPh ₃ ), (tris (p-trifluoromethyl) phenyl) phosphine (P (4-CF ₃ -C ₆ H) ₄ ) ₃ ), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xantphos), bis (2-diphenylphosphinophenyl) ether (DPEphos) and tri (2-furyl) It is preferable to select at least one member from the group consisting of phosphine (P (2-furyl) ₃ ), and more preferably to use Xantphos.

The palladium catalyst used in the preparation method of the present invention is preferably used 2 to 10 mol%, more preferably 8 mol% based on the pyridine derivative represented by the formula (4).

The phosphine ligand used in the preparation method of the present invention preferably uses 8 to 40 mol%, more preferably 16 mol% based on the palladium catalyst to be used.

Indium used in the production method of the present invention is preferably used 1 to 2 equivalents, more preferably 1 equivalent to the alkyl 4-bromo-2-pentinate derivative represented by the formula (2). .

The alkyl 4-bromo-2-pentinate derivative represented by Formula 2 used in the preparation method of the present invention preferably uses 1 to 4 equivalents, more preferably 3 equivalents to indium. .

The solvent used in the production method of the present invention is a conventional organic solvent, it is preferable to use dimethylformamide (DMF), tetrahydrofuran (THF) or a mixed solvent thereof, tetrahydrofuran (THF) as a solvent It is more preferable to use.

In addition, the halide metal salt used in the manufacturing method of this invention can select and use 1 or more types from the group which consists of LiX, NaX, and KX. In this case, X is F, Cl, Br, I, more preferably NaI, more preferably 2 to 5 equivalents, more preferably 3 equivalents to indium.

The reaction temperature is carried out at 70 to 110 ° C, more preferably at 90 ° C.

The reaction time may vary depending on the reactants, the type of solvent, and the amount of the solvent. After confirming that the pyridine derivative represented by Chemical Formula 4 as a starting material is completely consumed through TLC, the reaction is completed. After the reaction is completed, the solvent may be distilled off under reduced pressure after the extraction process, and the target product may be separated and purified through a conventional method such as column chromatography.

Indolizine derivatives according to the present invention can be used as a very important intermediate for the synthesis of drugs or natural products can help in the creation and development of compounds with excellent biological activity, including the development of new drugs. In addition, a method for preparing an indolizine derivative according to the present invention crosses an organoindium reagent obtained in-situ from the reaction of an indium and an alkyl 4-bromo-2-pentinate derivative in the presence of a pyridine derivative and a palladium catalyst. The clearing reaction and subsequent intramolecular cyclization have the advantage of producing an indolizine derivative in high yield.

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

Example 1 Preparation of 1-ethoxycarbonyl-3-methylindolidine (1-ethoxycarbonyl-3-methylindolizine)

Into the V-vial was added indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-2-pentinate (185 mg, 0.9 mmol), and THF (0.8) mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organic indium reagent. In another reaction vessel, Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos THF (0.4 mL) was added to (28 mg, 0.048 mmol) and 2-pyridyltrifluoromethanesulfonate (46 μl, 0.3 mmol), and the solution was added to the prepared organic indium reagent. The reaction was terminated after stirring at 90 ° C. for 1.5 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. After the solvent was removed, the residue was separated by column chromatography to obtain the title compound 1-ethoxycarbonyl-3-methyl-indoligin (1-ethoxycarbonyl-3-methyl-indolizine) (45 mg, 75%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 7.0 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 7.04 (s , 1H), 6.77 (t, J = 6.8 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H)

Example 2 Preparation of 1-ethoxycarbonyl-3-ethylindolizine (1-ethoxycarbonyl-3-ethylindolizine)

Into the V-vial was added indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-2-hexynate (197 mg, 0.9 mmol), and THF (0.8) mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organic indium reagent. In another reaction vessel, Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos (28 mg, 0.048 mmol) and 2-pyridyltrifluoromethanesulfonate (46 μl, 0.3 mmol) were added to THF (0.4 mL), and the solution was added to the prepared organic indium reagent. The reaction was terminated after stirring at 90 ° C. for 2 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. After the solvent was removed, the residue was separated by column chromatography to obtain the title compound 1-ethoxycarbonyl-3-ethyl-indolizine (49 mg, 75%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.20 (dt, J = 9.0, 1.2, 1.0 Hz, 1H), 7.82 (d, J = 7.0 Hz, 1H), 7.10-7.01 (m, 2H), 6.75 ( td, J = 7.0, 1.1, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.78 (q, J = 7.5 Hz, 2H), 1.41 (t, J = 7.1 Hz, 6H)

Example 3 Preparation of 1-ethoxycarbonyl-3-propylindolizine (1-ethoxycarbonyl-3-propylindolizine)

Into the V-vial was added indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-2-heptinoate (210 mg, 0.9 mmol), and THF (0.8) mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organic indium reagent. In another reaction vessel, Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos were added. THF (0.4 mL) was added to (28 mg, 0.048 mmol) and 2-iodopyridine (32 μl, 0.3 mmol), and the solution was added to the prepared organic indium reagent. After stirring at 90 ° C. for 1.5 hours, the reaction was terminated. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound 1-ethoxycarbonyl-3-propylindolizine (56 mg, 81%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (dt, J = 9.0, 1.2 Hz, 1H), 7.84 (d, J = 7.0 Hz, 1H), 7.05-7.00 (m, 2H), 6.73 (td, J = 6.7, 1.3 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 1.80 (t, J = 7.5 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.05 (t , J = 7.5 Hz, 3H)

Example 4 Preparation of 1-ethoxycarbonyl-3-phenethylindoligin (1-ethoxycarbonyl-3-phenethylindolizine)

Indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-6-phenyl-2-hexynate (266 mg, 0.9 mmol) were added to the V-vial and the solvent was added thereto. Phosphorus THF (0.8 mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organoindium reagent. Pd (OAc) ₂ (5.4 mg, 0.024 mmol) THF (0.4 mL) was added to (28 mg, 0.048 mmol) and 2-pyridyltrifluoromethanesulfonate (46 μl, 0.3 mmol), and the solution was added to the prepared organic indium reagent. The reaction was terminated after stirring at 90 ° C. for 4 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound 1-ethoxycarbonyl-3-phenethylindolizine (1-ethoxycarbonyl-3-phenethylindolizine) (71 mg, 81%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.20 (d, J = 9.0 Hz, 1H), 7.77 (d, J = 7.1 Hz, 1H), 7.31 (t, J = 7.1 Hz, 2H), 7.25-7.22 (m, 3H), 7.03 (dd, J = 9.0, 6.6 Hz, 2H), 6.71 (t, J = 6.6 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.09 (s, 4H), 1.41 ( t, J = 7.1 Hz, 3H)

Example 5 Preparation of 1-ethoxycarbonyl-3,5-dimethylindolizine (1-ethoxy-carbonyl-3,5-dimethylindolizine)

Into the V-vial was added indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-2-pentinate (185 mg, 0.9 mmol), and THF (0.8) mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organic indium reagent. In another reaction vessel, Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos TH28 (0.4 mL) was added to (28 mg, 0.048 mmol) and 6-methyl-2-pyridyltrifluoromethanesulfonate (72 mg, 0.3 mmol), and the solution was added to the prepared organic indium reagent. It was. The reaction was terminated after stirring at 90 ° C. for 4 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography to obtain 1-ethoxycarbonyl-3,5-dimethylindolizine (54 mg, 76%) as a title compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, J = 9.0 Hz, 1H), 6.92 (s, 1H), 6.82 (dd, J = 9.0, 6.7 Hz, 1H), 6.34 (d, J = 6.6 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.83 (s, 3H), 2.79 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H)

Example 6 Preparation of 1-ethoxycarbonyl-3,6-dimethylindolizine (1-ethoxy-carbonyl-3,6-dimethylindolizine)

Into the V-vial was added indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-2-pentinate (185 mg, 0.9 mmol), and THF (0.8) mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organic indium reagent. In another reaction vessel, Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos TH28 (0.4 mL) was added to (28 mg, 0.048 mmol) and 5-methyl-2-pyridyltrifluoromethanesulfonate (72 mg, 0.3 mmol), and the solution was added to the prepared organic indium reagent. It was. The reaction was terminated after stirring at 90 ° C. for 3 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. After the solvent was removed, the residue was separated by column chromatography to obtain 1-ethoxycarbonyl-3,6-dimethylindolizine (48 mg, 74%) as a title compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (d, J = 9.1 Hz, 1H), 7.57 (s, 1H), 6.97 (s, 1H), 6.90 (dd, J = 9.1, 1.2 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 2.33 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H)

Example 7 Preparation of 1-ethoxycarbonyl-3,7-dimethylindolizine (1-ethoxy-carbonyl-3,7-dimethylindolizine)

Into the V-vial was added indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-2-pentinate (185 mg, 0.9 mmol), and THF (0.8) mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organic indium reagent. In another reaction vessel, Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos THF (0.4 mL) was added to (28 mg, 0.048 mmol) and 4-methyl-2-iodopyridine (66 mg, 0.3 mmol), and the solution was added to the prepared organic indium reagent. The reaction was terminated after stirring at 90 ° C. for 2 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound 1-ethoxycarbonyl-3,7-dimethylindolizine (53 mg, 81%). Got it.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.69 (d, J = 7.0 Hz, 1H), 6.95 (s, 1H), 6.61 (dd, J = 7.0, 1.7 Hz, 1H) , 4.35 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H)

Example 8 Preparation of 1-ethoxycarbonyl-3-ethyl-5-methylindolisin (1-ethoxy-carbonyl-3-ethyl-5-methylindolizine)

Into the V-vial was added indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-2-hexynate (197 mg, 0.9 mmol), and THF (0.8) mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organic indium reagent. In another reaction vessel, Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos TH28 (0.4 mL) was added to (28 mg, 0.048 mmol) and 6-methyl-2-pyridyltrifluoromethanesulfonate (72 mg, 0.3 mmol), and the solution was added to the prepared organic indium reagent. It was. The reaction was terminated after stirring at 90 ° C. for 4 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography, and the title compound 1-ethoxycarbonyl-3-ethyl-5-methylindolizine (54 mg, 76% )

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, J = 9.0 Hz, 1H), 7.03 (s, 1H), 6.86 (dd, J = 9.0, 6.7 Hz, 1H), 6.39 (d, J = 6.7 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.26 (q, J = 7.3 Hz, 2H) , 2.86 (s, 3H), 1.42-1.25 (m, 6H)

Example 9 Preparation of 1-ethoxycarbonyl-5-methyl-3-propylindolizine (1-ethoxy-carbonyl-5-methyl-3-propylindolizine)

Into the V-vial was added indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-2-heptinoate (210 mg, 0.9 mmol), and THF (0.8) mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organic indium reagent. In another reaction vessel, Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos were added. TH28 (0.4 mL) was added to (28 mg, 0.048 mmol) and 5-methyl-2-pyridyltrifluoromethanesulfonate (72 mg, 0.3 mmol), and the solution was added to the prepared organic indium reagent. It was. The reaction was terminated after stirring at 90 ° C. for 1.5 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ solution (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound 1-ethoxycarbonyl-5-methyl-3-propylindolizine (56 mg, 76%). Got.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (d, J = 9.4 Hz, 1H), 7.61 (s, 1H), 6.98 (s, 1H), 6.88 (dd, J = 9.0, 1.3 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.31 ( s, 3H), 1.87-1.75 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.5 Hz, 3H)

Example 10 Preparation of 1-ethoxycarbonyl-7-methyl-3-propylindolizine (1-ethoxy-carbonyl-7-methyl-3-propyl-indolizine)

Into the V-vial was added indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-2-heptinoate (210 mg, 0.9 mmol), and THF (0.8) mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organic indium reagent. In another reaction vessel, Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos were added. TH28 (0.4 mL) was added to (28 mg, 0.048 mmol) and 4-methyl-2-pyridyl trifluoromethanesulfonate (72 mg, 0.3 mmol), and the solution was added to the prepared organic indium reagent. It was. The reaction was terminated after stirring at 90 ° C. for 2 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound 1-ethoxycarbonyl-7-methyl-3-propyl-indolizine (61 mg, 83 %) Was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.74 (d, J = 7.1 Hz, 1H), 6.94 (s, 1H), 6.58 (dd, J = 7.1, 1.6 Hz, 1H) , 4.35 (q, J = 7.1 Hz, 2H), 2.73 (t, J = 7.5 Hz, 2H), 2.38 (s, 3H), 1.83-1.74 (m, 2H), 1.43 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H)

Example 11 Preparation of 1-ethoxycarbonyl-3-phenethyl-7-methylindolisin (1-ethoxycarbonyl-3-phenethyl-7-methylindolizine)

Into the V-vial add indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-6-phenyl-2-hexynate (266 mg, 0.9 mmol) THF (0.8 mL), a solvent, was stirred at room temperature to prepare an organic indium reagent, and Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos were added to another reaction vessel. THF (0.4 mL) was added to (28 mg, 0.048 mmol) and 4-methyl-2-iodopyridine (66 mg, 0.3 mmol), and the reaction solution was added to the prepared organic indium reagent. The reaction was terminated after stirring at 90 ° C. for 2 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound 1-ethoxycarbonyl-3-phenethyl-7-methylindolisin (65 mg, 70 %) Was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.68 (d, J = 7.1 Hz, 1H), 7.31 (t, J = 7.1 Hz, 2H), 7.25-7.21 (m, 3H), 7.03 (s, 1H), 6.56 (dd, J = 7.1, 1.7 Hz, 1H), 4.36 (s, J = 7.1 Hz, 2H), 3.09-3.05 (m, 4H), 2.38 (s, 3H ), 1.41 (t, J = 7.1 Hz, 3H)

Example 12 Preparation of 1-ethoxycarbonyl-6-chloro-3-methylindoligin (1-ethoxy-carbonyl-6-chloro-3-methyl-indolizine)

Into the V-vial was added indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-2-pentinate (185 mg, 0.9 mmol), and THF (0.8) mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organic indium reagent. In another reaction vessel, Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos THF (0.4 mL) was added to (28 mg, 0.048 mmol) and 5-chloro-2-iodopyridine (72 mg, 0.3 mmol), and the solution was added to the prepared organic indium reagent. After stirring for 7 hours at 90 ℃, the reaction was terminated. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound 1-ethoxycarbonyl-6-chloro-3-methyl-indolizine (56 mg, 79 %) Was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, J = 9.6 Hz, 1H), 7.82 (s, 1H), 7.04 (s, 1H), 6.98 (dd, J = 9.6, 1.7 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.44 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H)

Example 13 Preparation of 1-ethoxycarbonyl-6-chloro-3-ethylindolizine (1-ethoxy-carbonyl-6-chloro-3-ethylindolizine)

Into the V-vial was added indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-2-hexynate (197 mg, 0.9 mmol), and THF (0.8) mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organic indium reagent. In another reaction vessel, Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos (28 mg, 0.048 mmol) and 5-chloro-2-pyridyltrifluoromethanesulfonate (79 mg, 0.3 mmol) were added with THF (0.4 mL), followed by stirring. The solution was added to the prepared organic indium reagent. It was. The reaction was terminated after stirring at 90 ° C. for 2 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound 1-ethoxycarbonyl-6-chloro-3-ethylindolizine (61eth, 81%). Got.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (d, J = 9.5 Hz, 1H), 7.84 (s, 1H), 7.05 (s, 1H), 6.97 (dd, J = 9.5, 1.7 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.76 (t, J = 7.5 Hz, 2H), 1.41 ( t, J = 7.3 Hz, 6H)

Example 14 Preparation of 1-ethoxycarbonyl-3-methyl-6-nitroindolisin (1-ethoxycarbonyl-3-methyl-6-nitroindolizine)

Into the V-vial was added indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-2-pentinate (185 mg, 0.9 mmol), and THF (0.8) mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organic indium reagent. In another reaction vessel, Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos (28 mg, 0.048 mmol) and 5-nitro-2-pyridyltrifluoromethanesulfonate (82 mg, 0.3 mmol) were added to THF (0.4 mL), and the solution was stirred in the prepared organic indium reagent. Added. The reaction was terminated after stirring at 90 ° C. for 14 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound 1-ethoxycarbonyl-3-methyl-6-nitroindolizine (45 mg, 60 %) Was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.96 (d, J = 1.7 Hz, 1H), 8.25 (d, J = 10.0 Hz, 1H), 7.74 (dd, J = 10.0, 2.0 Hz, 1H), 7.21 (d, J = 0.7 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.58 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H)

Example 15 Preparation of 1-ethoxycarbonyl-3-phenethyl-6-nitroindolizine (1-ethoxycarbonyl-3-phenethyl-6-nitroindolizine)

Indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-6-phenyl-2-hexynate (266 mg, 0.9 mmol) were added to the V-vial and the solvent was added thereto. Phosphorus THF (0.8 mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organoindium reagent. Pd (OAc) ₂ (5.4 mg, 0.024 mmol) (28 mg, 0.048 mmol) and 5-nitro-2-pyridyltrifluoromethanesulfonate (82 mg, 0.3 mmol) were added to THF (0.4 mL), followed by stirring. The solution was added to the prepared organic indium reagent. Added. The reaction was terminated after stirring at 90 ° C. for 16 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound 1-ethoxycarbonyl-3-phenethyl-6-nitroindolizine (58 mg, 57 %) Was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (d, J = 1.8 Hz, 1H), 8.22 (d, J = 10.0 Hz, 1H), 7.69 (dd, J = 10.0, 1.8 Hz, 1H), 7.30 -7.17 (m, 6H), 4.39 (q, J = 7.1 Hz, 2H), 3.22-3.10 (m, 4H), 1.42 (t, J = 7.1 Hz, 3H)

Example 16 1,5-dimethylpyrrolo [1,2-a] quinoline-3-carboxylic acid ethyl ester (1,5-Dimethylpyrrolo [1,2-a] quinoline-3-carboxylic acid ethyl ester Manufacturing

Into the V-vial was added indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-2-pentinate (185 mg, 0.9 mmol), and THF (0.8) mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organic indium reagent. In another reaction vessel, Pd (OAc) ₂ (5.4 mg, 0.024 mmol) and Xantphos (28 mg, 0.048 mmol) and 4-methyl-2-quinolinyltrifluoromethanesulfonate (87 mg, 0.3 mmol) were added to THF (0.4 mL), followed by stirring. Was added. The reaction was terminated after stirring at 90 ° C. for 2 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography, and the title compound 1,5-dimethylpyrrolo [1,2-a] quinoline-3-carboxylic acid ethyl ester (1,5-Dimethylpyrrolo [1, 2-a] quinol-ine-3-carboxylic acid ethyl ester) (56 mg, 70%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40 (d, J = 8.5 Hz, 1H), 8.09 (s, 1H), 7.84 (dd, J = 8.1, 1.5 Hz, 1H), 7.55-7.51 (m, 1H), 7.45-7.41 (m, 1H), 6.89 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.92 (s, 3H), 2.55 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H)

Example 17 5-Methyl-1-phenethylpyrrolo [1,2-a] quinoline-3-carboxylic ethyl ethyl ester (5-Methyl-1-phenethylpyrrolo [1,2-a] quinoline-3- carboxylic acid ethyl ester)

Indium (69 mg, 0.6 mmol), sodium iodide (135 mg, 0.9 mmol) and ethyl 4-bromo-6-phenyl-2-hexynate (266 mg, 0.9 mmol) were added to the V-vial and the solvent was added thereto. Phosphorus THF (0.8 mL) was added to the mixture, and the mixture was stirred at room temperature to prepare an organoindium reagent. Pd (OAc) ₂ (5.4 mg, 0.024 mmol) (28 mg, 0.048 mmol) and 4-methyl-2-quinolinyltrifluoromethanesulfonate (87 mg, 0.3 mmol) were added to THF (0.4 mL), and the solution was stirred in the prepared organic indium reagent. Added. The reaction was terminated after stirring at 90 ° C. for 4 hours. After cooling to room temperature, the mixture was extracted with CH ₂ Cl ₂ (20 mL × 3) and washed with saturated aqueous NaHCO ₃ (20 mL) and saturated aqueous NaCl solution (20 mL). The extracted organic layer was dried over anhydrous MgSO ₄ and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound, 5-methyl-1-phenethylpyrrolo [1,2-a] quinoline-3-carboxylic ethyl ester (5-Methyl-1-phenethyl-yrrolo [1,2-a] quinoline-3-carboxylic acid ethyl ester) (54 mg, 76%) was obtained.

¹ H NMR (400 MHz, CDCl _{3 ,} 25 ° C., TMS): δ = 8.35 (d, J = 8.6 Hz, 1H), 8.14 (s, 1H), 7.87 (dd, J = 8.0, 1.4 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.39-7.27 (m, 5H), 7.04 (s, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.57 (t, J = 8.5, 8.0 Hz, 2H), 3.18 (t, J = 8.5, 8.0 Hz, 2H), 2.58 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H)

Claims (14)

Indolizine derivatives represented by Formula 1 below: [Formula 1]

[In Formula 1, R is (C1-C7) alkyl; R ¹ is (C ¹ -C 7) alkyl or (C 6 -C 20) aryl (C 1 -C 7) alkyl; R ² is hydrogen or (C 1 -C 7) alkyl; R ³ is hydrogen, (C 1 -C 7) alkyl, nitro or halogen; R ⁴ and R ⁵ are independently of each other hydrogen or (C 1 -C 7) alkyl; R ² to R ⁵ may be connected to alkenylene or alkenylene each independently or without a substituent and a fused ring adjacent to each other to form an alicyclic ring or an aromatic ring.] The method of claim 1, R is methyl, ethyl or propyl; R ¹ is methyl, ethyl, propyl or phenethyl; R ² is hydrogen or methyl; R ³ is hydrogen, methyl, nitro or chloro; R ⁴ and R ⁵ are independently of each other hydrogen or methyl; R ² to R ⁵ are each independently a substituent adjacent to each other and

Indolizine derivatives, characterized in that can be connected to form a benzene ring. 3. The method of claim 2, The indolizine derivative is an indolizine derivative, characterized in that selected from compounds of the following structure:

An indolizine characterized in that the indolizin derivative represented by the following formula (1) is prepared by reacting a pyrodine derivative represented by the following formula (4) with a pyridine derivative represented by the following formula (4) in the presence of a palladium catalyst and a phosphine ligand ) Preparation of Derivatives. [Formula 1]

(3)

[Formula 4]

[In Formulas 1, 3 and 4, R is (C1-C7) alkyl; R ¹ is (C ¹ -C 7) alkyl or (C 6 -C 20) aryl (C 1 -C 7) alkyl; R ² is hydrogen or (C 1 -C 7) alkyl; R ³ is hydrogen, (C 1 -C 7) alkyl, nitro or halogen; R ⁴ and R ⁵ are independently of each other hydrogen or (C 1 -C 7) alkyl; R ² to R ⁵ may be each independently connected to an alkenylene or alkenylene including or without a substituent and a fused ring adjacent to each other to form an alicyclic ring or an aromatic ring; X is halogen; Z is halogen or -OS (= O) ₂ CF _3. ] The method of claim 4, wherein The organoindium reagent represented by the following Chemical Formula 3 may include an alkyl 4-bromo-2-pentinate derivative and an indium (Indium) represented by the following Chemical Formula 2 in the presence of a halide metal salt (MX: M = 1 valent alkali metal, X = halogen). It is prepared by reacting In). (3)

[Formula 2]

[In Formulas 2 and 3, R is (C1-C7) alkyl; R ¹ is (C ¹ -C 7) alkyl or (C 6 -C 20) aryl (C 1 -C 7) alkyl; X is halogen.] The method of claim 4, wherein Wherein said palladium catalyst is selected from the group consisting of Pd ₂ dba ₃ CHCl ₃ , Pd (OAc) ₂ and Pd (dppf) ₂ . The method of claim 4, wherein Wherein said phosphine ligand is at least one member selected from the group consisting of PPh ₃ , P (4-CF ₃ -C ₆ H ₄ ) ₃ , Xantphos, DPEphos and P (2-furyl) ₃ . The method of claim 5, Alkyl 4-bromo-2-pentynoate derivative is used in the range of 1 to 4 equivalents relative to indium. The method of claim 5, M is Li, Na or K manufacturing method characterized in that. The method of claim 6, The amount of the palladium catalyst is used, characterized in that 2 to 10 mol% based on the pyridine derivative represented by the formula (4). The method of claim 7, wherein The amount of the phosphine ligand is prepared using 8 to 40 mol% based on the palladium catalyst. The method of claim 5, The halide metal salt is a method for producing 2 to 5 equivalents to indium. The method of claim 4, wherein The reaction is carried out under dimethylformamide (DMF), tetrahydrofuran (THF) or a mixed solvent thereof. The method of claim 13, The reaction is characterized in that the tetrahydrofuran (THF) is carried out at 70 to 110 ℃ as a solvent.