JP2012106981A - Method for producing tetrahydroquinoline compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing tetrahydroquinoline compounds, having high efficiency and a low cost.SOLUTION: A tetrahydroquinoline compound represented by general formula (3) is obtained by making a compound represented by general formula (1) and a copper salt represented by general formula (2) react with each other in the presence of a divalent palladium salt in a solvent. In general formulas (1)-(3), R represents hydrogen, an electron attracting group or an electron donating group, Rrepresents hydrogen or an electron attracting group, and X represents any one selected from among fluorine, chlorine, bromine, iodine, and RCOO (Rrepresents a methyl group for which fluorine may substitute).

Description

  The present invention relates to a method for producing a tetrahydroquinoline compound.

  Tetrahydroquinoline compounds are widely present in some natural products and certain molecules with biological activity (Non-Patent Document 1). For example, the antitumor antibiotic Dynemycin is a molecule formed on tetrahydroquinoline and having it as a core structure (Non-patent Documents 2 and 3).

  In recent years, tetrahydroquinoline compounds have been widely reported as antibacterial drugs (Non-Patent Document 4), antifungal drugs (Non-Patent Document 5), or pesticides (Non-Patent Document 6). Tetrahydroquinoline compounds are also widely used in fields such as antidepressant (Non-patent Document 7) and anti-diabetes (Non-patent Document 8) because of their inhibitory action on several enzymes and receptors related to human diseases. Has attracted attention.

  Among them, 2-substituted-1,2,3,4-tetrahydroquinoline compounds, which are one type of tetrahydroquinoline compounds, further include selective estrogen receptor modulators (Non-patent Document 9) and cholesterol ester transfer proteins. It is used to design inhibitors (Non-Patent Document 10). With these biological activities, tetrahydroquinoline compounds can be potential drugs to treat estrogen-affected cancers and osteoporosis caused by cholesterol.

  There have already been many reports on the synthesis of tetrahydroquinoline compounds (Non-Patent Documents 11 to 13). For example, it has been reported that a nitrogen-containing heterocycle is synthesized using a palladium-catalyzed oxidation method, but a 6-membered nitrogen-containing heterocycle is hardly formed under the action of a catalytic amount of palladium (Non-patent Document 14). Dihydroquinolines have been synthesized using Pd (II) catalyzed oxidation methods, but the majority of products are mixtures of 5- and 6-membered heterocycles (Non-Patent Documents 15 and 16). Only quinoline analogs have been synthesized using the Pd (II) catalytic oxidation method (Non-patent Document 17). Further, a tetrahydroquinoline compound was synthesized using a Pd (II) -catalyzed oxidation reaction using Cu (II) as an oxidant, and a mixture of tetrahydroquinoline and dihydroindole was obtained (Non-patent Document 18). ).

Michael, J. P. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 2008, 25, 166-187. Konishi, et al. Crystal and Molecular Structure of Dynemicin A: A Novel 1,5-Diyn-3-ene Antitumor Antibiotic. J. Am. Chem. Soc. 1990, 112, 3715-3716. Wender, P. A., et al. A Photochemically Triggered DNA Cleaving Agent: Synthesis, Mechanistic and DNA Cleavage Studies on a New Analog of the Antitumor Antibiotic Dynemicin. J. Org. Chem. 1993, 58, 5867-5869. Ramesh, E., et al. Synthesis and antibacterial property of quinolines with potent DNA gyrase activity. Bioorg. Med. Chem. 2009, 17, 660-666. Urbina, JM, et al. Inhibitors of the Fungal Cell Wall. Synthesis of 4-Aryl-4-N-arylamine-1-butenes and Related Compounds with Inhibitory Activities on β (1-3) Glucan and Chitin Synthases. Bioorg. Med Chem. 2000, 8, 691-698. Smith, HC, et al. Synthesis and SAR of cis-1-Benzoyl-1,2,3,4-tetrahydroquinoline Ligands for Control of Gene Expression in Ecdysone Responsive Systems.Bioorg. Med. Chem. Lett. 2003, 13, 1943 -1946. Scott, J. D., et al. Tetrahydroquinoline sulfonamides as vasopressin 1b receptor anatgonists. Bioorg. Med. Chem. Lett. 2009, 19, 6018-6022. Parmenon, C., et al. 4,4-Dimethyl-1,2,3,4-tetrahydroquinoline-based PPARα / γ agonists. Part I: Synthesis and pharmacological evaluation. Bioorg. Med. Chem. Lett. 2008, 18, 1617-1622. Wallace, O. B., et al. Tetrahydroquinoline-Based Selective Estrogen Receptor Modulators (SERMs). Bioorg. Med. Chem. Lett. 2003, 13, 1907-1910. Rano, T., et al. Design and synthesis of potent inhibitors of cholesteryl ester transfer protein (CETP) exploiting a 1,2,3,4-tetrahydroquinoline platform. Bioorg. Med. Chem. Lett. 2009, 19, 2456-2460 . Katritzky, A. R., et al. Recent Progress in the Synthesis of 1,2,3,4-tetrahydroquinolines. Tetrahedron 1996, 52, 15031-15070. Larock, R. C., et al. Tetrahedron 1998, 54, 9961-9980. Hara O., et al, Tetrahedron 2007, 63, 6170-6181. Hegedus, L. S., et al, J. M. J. Am. Chem. Soc. 1982, 104, 2444-2451. Larock, R. C., et al. P. J. Org. Chem. 1996, 61, 3584-3585. Roger, M. M., et al. Org. Lett. 2006, 8, 2257-2260. Zhang, Z., et al, Org. Lett. 2008, 10, 173-175. Manzoni, M.R., et al. Organometallics 2004, 23, 5618-5621.

  An object of the present invention is to provide a method for producing a tetrahydroquinoline compound which is high in efficiency and low in cost with respect to the disadvantages existing in the prior art.

  In order to solve the above problems, according to the method for producing a tetrahydroquinoline compound of the present invention, in the presence of a divalent palladium salt, a compound represented by the following general formula (1) and the following general formula (2 ) Is reacted in a solvent to obtain a tetrahydroquinoline compound represented by the following general formula (3).

In the production method of the present invention, R represents any one selected from hydrogen, fluorine, chlorine, bromine, iodine, a methyl group, and a methoxy group. R ₁ represents any one selected from hydrogen, an acyl group, and a sulfonyl group.
In the production method of the present invention, the copper salt is at least one selected from copper acetate, copper bromide, copper chloride, copper iodide and copper trifluoroacetate.

  In the production method of the present invention, the divalent palladium salt is at least one selected from palladium acetate, palladium chloride, palladium trifluoroacetate, palladium bromide, and dichlorobis (acetonitrile) palladium (II). .

  In the production method of the present invention, the solvent is selected from methanol, ethanol, isopropyl alcohol, tetrahydrofuran, acetone, DMSO, DMF, NMP, acetonitrile, diethyl ether, dichloromethane, toluene, xylene, benzene, and trifluoromethylbenzene. Is at least one kind.

  Moreover, in the manufacturing method of this invention, when making the compound (aniline compound) represented by the said General formula (1) react, an additive is further made to coexist. The additive is at least one selected from potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium carbonate, potassium acetate, sodium acetate, benzoic acid, and acetic acid.

In the production method of the present invention, as the molar ratio of the divalent palladium salt to the compound represented by the general formula (1), the divalent palladium salt: the compound represented by the general formula (1) = 0.1: 1 to 0.4: 1.
Moreover, in the manufacturing method of this invention, as a molar ratio of the said copper salt and the compound represented by the said General formula (1), copper salt: The compound represented by General formula (1) = 1.2: 1- 4: 1.
Moreover, in the manufacturing method of this invention, as a molar ratio of the said additive and the compound represented by the said General formula (1), an additive: The compound represented by General formula (1) = 1.2: 1- 4: 1.

The present invention is described in detail below.
The method for producing the tetrahydroquinoline compound of the present invention has the following reaction formula.

In the above reaction formula, in the presence of a divalent palladium salt (Pd (II)), a compound represented by the general formula (1) (that is, a base substance) and a copper salt represented by the general formula (2) ( CuX ₂ ) is reacted in a solvent to obtain a tetrahydroquinoline compound represented by the general formula (3).

  In the formula, R represents hydrogen, an electron-withdrawing group, or an electron-donating group. Here, specific examples of the electron-withdrawing group include fluorine, chlorine, bromine, iodine and the like, and specific examples of the electron-donating group include , Methyl group, methoxy group and the like. R is preferably hydrogen, chlorine or a methyl group. In the general formulas (1) and (3), R may be located at the ortho, meta, or para position with respect to the carbon atom to which the nitrogen atom is bonded.

R ₁ represents hydrogen or an electron withdrawing group, and specific examples of the electron withdrawing group include an acyl group and a sulfonyl group. R ₁ is preferably a sulfonyl group.

X represents fluorine, chlorine, bromine, iodine and R ₂ COO (R ₂ represents a methyl group which may be substituted with fluorine. R ₂ COO removed H from the carboxylic acid represented by R ₂ COOH. It is any one selected from the group consisting of a residue, preferably chlorine, bromine or iodine, more preferably bromine.

  In the reaction, the copper salt acts as an oxidant. Specific examples of the copper salt include copper acetate, copper bromide, copper chloride, copper iodide and copper trifluoroacetate. Of these, copper bromide, copper chloride or copper iodide is preferred, and copper bromide is more preferred.

  The molar ratio of the copper salt to the compound represented by the general formula (1), that is, the copper salt: the compound represented by the general formula (1) is 1.2: 1 to 4: 1. , Preferably 1.2: 1 to 3: 1. When the molar ratio is larger than 4: 1, the yield of the catalytic reaction is not changed, but the copper salt is wasted. If the molar ratio is less than 1.2: 1, an incomplete reaction is caused.

  In the reaction, the divalent palladium salt serves as a catalyst. Specific examples of the divalent palladium salt include palladium acetate, palladium chloride, palladium trifluoroacetate, palladium bromide, dichlorobis (acetonitrile) palladium (II), and the like. Of these, palladium bromide is preferred.

  In addition, the molar ratio of the divalent palladium salt to the compound represented by the general formula (1), that is, the divalent palladium salt: the compound represented by the general formula (1) is 0.1: 1 to 0. .4: 1, preferably 0.1: 1 to 0.3: 1. When the molar ratio is larger than 0.4: 1, the yield of the catalytic reaction is not substantially changed, but the divalent palladium salt is wasted. If the molar ratio is less than 0.1: 1, an effective catalytic effect cannot be achieved.

  The above reaction is carried out in a solvent. Specific examples of the solvent include methanol, ethanol, isopropyl alcohol, tetrahydrofuran, acetone, DMSO, DMF, NMP, acetonitrile, diethyl ether, dichloromethane, toluene, xylene, benzene, and trifluoromethylbenzene. Of these, methanol, tetrahydrofuran, DMF, acetonitrile or diethyl ether is preferred, and tetrahydrofuran is more preferred.

Furthermore, the reaction further comprises reacting the compound represented by the general formula (1) with the copper salt in the presence of an additive.
The additive can effectively promote the smooth progress of the reaction. Specific examples of the additive include potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium carbonate, potassium acetate, sodium acetate, benzoic acid, and acetic acid. Of these, potassium acetate, sodium acetate, potassium carbonate and sodium carbonate are preferred, and potassium carbonate is more preferred.

  The molar ratio of the additive to the compound represented by the general formula (1), that is, the additive: the compound represented by the general formula (1) is 1.2: 1 to 4: 1. When the molar ratio is greater than 4: 1, the yield of the catalytic reaction is not substantially changed, but the additive is wasted. When the molar ratio is less than 1.2: 1, the effect of promoting the progress of the reaction cannot be achieved.

The method for producing a tetrahydroquinoline compound of the present invention specifically comprises the following steps.
First step: A compound represented by the general formula (1), a copper salt, and, if necessary, an additive are added to a solvent and stirred.
Second step: Cool.
Third step: Add a divalent palladium salt, raise the temperature, and then stir to obtain a tetrahydroquinoline compound.

In the first step, the stirring is preferably performed at room temperature (20 to 25 ° C.) in an inert gas atmosphere, and the stirring time is preferably 0.5 to 1 hour.
In the second step, it is preferably cooled to -20 to 0 ° C, more preferably to 0 ° C.
In the third step, the temperature is preferably raised to 25 to 45 ° C, more preferably to 25 ° C. And stirring time becomes like this. Preferably it is 1-5 days, More preferably, it is 3 days.

  EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to the following examples.

Production Example 1
The following compounds S1 to S6 were synthesized according to known methods (see Rogers MM, Wendlandt JE, Guzei IA, Stahl SS, Org. Lett. 2006, 8, 2257-2260.) And used in the following examples. Used for the production of tetrahydroquinoline compounds.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 31.5 mg (0.1 mmol) of the base material S1, 27.6 mg (0.2 mmol) of potassium carbonate, 67.0 mg (0.3 mmol) of copper bromide in 3 ml of tetrahydrofuran After stirring at room temperature (20 ° C) for 60 minutes, cooling to 0 ° C and stirring for 15 minutes, 5.3 mg (0.02 mmol) of palladium bromide was added, and the temperature was naturally increased to room temperature (20 ° C). Warm and stir, follow by TLC until the reaction is complete, filter to remove insolubles and elute with silica gel column chromatography with petroleum ether: ethyl acetate = 10: 1 to give 30.0 mg of white solid. The yield was 76%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (d, J = 8Hz, 2H), 7.26-7.15 (m, 3H), 7.10 (t, J = 8Hz, 1H), 6.80 (d, J = 8Hz, 1H), 4.40-4.31 (m, 1H), 3.69-3.63 (m, 1H), 3.36-3.29 (m, 1H), 2.53 (s, 3H), 2.42 (s, 3H), 2.30-2.22 (m, 1H), 2.10-2.03 (m, 1H), 1.34-1.10 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 144.2, 139.6, 139.2, 136.0, 134.4, 130.2, 129.8, 127.9, 127.3, 124.9, 57.5, 37.3, 31.0, 26.4, 21.8, 19.8.
HRMS (micromass LCT) C ₁₈ H ₂₀ BrNO ₂ S calculated 393.0398, measured 393.0379.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 33.6 mg (0.1 mmol) of the base material S2, 27.6 mg (0.2 mmol) of potassium carbonate, 67.0 mg (0.3 mmol) of copper bromide in 3 ml of tetrahydrofuran After stirring at room temperature (20 ° C) for 60 minutes, cooling to 0 ° C and stirring for 15 minutes, 5.3 mg (0.02 mmol) of palladium bromide was added, and the temperature was naturally increased to room temperature (20 ° C). Warm and stir, follow by TLC until the reaction is complete, filter to remove insolubles and elute with silica gel column chromatography with petroleum ether: ethyl acetate = 10: 1 to give 27.8 mg of white solid. The yield was 67%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (d, J = 8Hz, 2H), 7.37 (d, J = 8Hz, 1H), 7.27 (d, J = 8Hz, 2H), 7.14 (t, J = 8Hz, 1H), 6.96 (d, J = 8Hz, 1H), 4.42-4.32 (m, 1H), 3.59-3.53 (m, 1H), 3.20-3.13 (m, 1H), 2.45-2.36 (m, 4H ), 2.26-2.20 (m, 1H), 1.70-1.60 (m, 1H), 1.41-1.30 (m, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 144.5, 141.6, 136.1, 135.1, 133.4, 130.0, 129.4, 128.4, 128.2, 126.0, 57.1, 36.5, 31.1, 26.7, 21.8.
HRMS (Micromass LCT) Calculated for C ₁₇ H ₁₇ BrClNO ₂ S, 412.9852, found 412.9823.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 33.6 mg (0.1 mmol) of the base material S3, 27.6 mg (0.2 mmol) of potassium carbonate, 67.0 mg (0.3 mmol) of copper bromide in 3 ml of tetrahydrofuran After stirring at room temperature (20 ° C) for 60 minutes, cooling to 0 ° C and stirring for 15 minutes, 5.3 mg (0.02 mmol) of palladium bromide was added, and the temperature was naturally increased to room temperature (20 ° C). Stir warm and follow by TLC until the reaction is complete, filter to remove insolubles and elute with petroleum ether: ethyl acetate = 10: 1 by silica gel column chromatography to give 37.7 mg of white solid. The yield was 91%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 8Hz, 1H), 7.35 (d, J = 8Hz, 2H), 7.24-7.17 (m, 3H), 6.97-6.95 (m, 1H) , 4.39-4.31 (m, 1H), 3.72-3.67 (m, 1H), 3.41-3.35 (m, 1H), 2.39 (s, 3H), 2.30-2.22 (m, 1H), 2.17-2.08 (m, 1H), 1.64-1.44 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 144.3, 136.4, 135.3, 134.1, 131.9, 129.9, 129.3, 127.7, 127.5, 127.3, 56.8, 36.3, 28.5, 25.0, 21.8.
HRMS (micromass LCT) C ₁₇ H ₁₇ BrClNO ₂ S calculated, 412.9852, found 412.9850.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 31.5 mg (0.1 mmol) of the base material S5, 27.6 mg (0.2 mmol) of potassium carbonate, 67.0 mg (0.3 mmol) of copper bromide in 3 ml of tetrahydrofuran After stirring at room temperature (20 ° C) for 60 minutes, cooling to 0 ° C and stirring for 15 minutes, 5.3 mg (0.02 mmol) of palladium bromide was added, and the temperature was naturally increased to room temperature (20 ° C). Stir warm and follow by TLC until the reaction is complete, filter to remove insolubles and elute with silica gel column chromatography with petroleum ether: ethyl acetate = 10: 1 to give 33.9 mg of white solid. The yield was 86%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J = 8Hz, 1H), 7.33 (d, J = 8Hz, 2H), 7.17 (d, J = 8Hz, 2H), 7.07-7.03 (m, 1H), 6.77 (s, 1H), 4.36-4.28 (m, 1H), 3.75-3.71 (m, 1H), 3.38-3.32 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H) , 2.26-2.19 (m, 1H), 2.18-2.10 (m, 1H), 1.59-1.41 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 143.9, 136.3, 135.6, 134.7, 132.7, 129.7, 128.4, 128.0, 127.9, 127.3, 56.9, 36.6, 29.0, 25.1, 21.8, 21.2.
HRMS (micromass LCT) C ₁₈ H ₂₀ BrNO ₂ S calculated 393.0398, measured 393.0392.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 31.5 mg (0.1 mmol) of the base material S5, 27.6 mg (0.2 mmol) of potassium carbonate, 67.0 mg (0.3 mmol) of copper bromide in 3 ml of tetrahydrofuran The mixture was stirred at room temperature (20 ° C.) for 60 minutes, cooled to 0 ° C. and stirred for 15 minutes, and then 2.7 mg (0.01 mmol) of palladium bromide was added, and the mixture naturally rose to room temperature (20 ° C.). Warm and stir, follow by TLC until the reaction is complete, filter to remove insolubles and elute with silica gel column chromatography with petroleum ether: ethyl acetate = 10: 1 to give 20.9 mg of white solid. The yield was 53%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J = 8Hz, 1H), 7.33 (d, J = 8Hz, 2H), 7.17 (d, J = 8Hz, 2H), 7.07-7.03 (m, 1H), 6.77 (s, 1H), 4.36-4.28 (m, 1H), 3.75-3.71 (m, 1H), 3.38-3.32 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H) , 2.26-2.19 (m, 1H), 2.18-2.10 (m, 1H), 1.59-1.41 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 143.9, 136.3, 135.6, 134.7, 132.7, 129.7, 128.4, 128.0, 127.9, 127.3, 56.9, 36.6, 29.0, 25.1, 21.8, 21.2.
HRMS (micromass LCT) C ₁₈ H ₂₀ BrNO ₂ S calculated 393.0398, measured 393.0392.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 31.5 mg (0.1 mmol) of the base material S5, 27.6 mg (0.2 mmol) of potassium carbonate, 67.0 mg (0.3 mmol) of copper bromide in 3 ml of tetrahydrofuran The mixture was stirred at room temperature (20 ° C.) for 60 minutes, cooled to 0 ° C. and stirred for 15 minutes, and then 4.0 mg (0.015 mmol) of palladium bromide was added, and the temperature naturally increased to room temperature (20 ° C.). Warm and stir, follow by TLC until the reaction is complete, filter to remove insolubles and elute with silica gel column chromatography with petroleum ether: ethyl acetate = 10: 1 to give 27.2 mg of white solid. The yield was 69%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J = 8Hz, 1H), 7.33 (d, J = 8Hz, 2H), 7.17 (d, J = 8Hz, 2H), 7.07-7.03 (m, 1H), 6.77 (s, 1H), 4.36-4.28 (m, 1H), 3.75-3.71 (m, 1H), 3.38-3.32 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H) , 2.26-2.19 (m, 1H), 2.18-2.10 (m, 1H), 1.59-1.41 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 143.9, 136.3, 135.6, 134.7, 132.7, 129.7, 128.4, 128.0, 127.9, 127.3, 56.9, 36.6, 29.0, 25.1, 21.8, 21.2.
HRMS (micromass LCT) C ₁₈ H ₂₀ BrNO ₂ S calculated 393.0398, measured 393.0392.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 31.5 mg (0.1 mmol) of the base material S5, 27.6 mg (0.2 mmol) of potassium carbonate, 67.0 mg (0.3 mmol) of copper bromide in 3 ml of tetrahydrofuran The mixture was stirred at room temperature (20 ° C) for 60 minutes, then cooled to 0 ° C and stirred for 15 minutes, and then 8.1 mg (0.03 mmol) of palladium bromide was added, and the mixture naturally rose to room temperature (20 ° C). Warm and stir, follow by TLC until the reaction is complete, filter to remove insolubles and elute with silica gel column chromatography with petroleum ether: ethyl acetate = 10: 1 to give 35.1 mg of white solid. The yield was 89%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J = 8Hz, 1H), 7.33 (d, J = 8Hz, 2H), 7.17 (d, J = 8Hz, 2H), 7.07-7.03 (m, 1H), 6.77 (s, 1H), 4.36-4.28 (m, 1H), 3.75-3.71 (m, 1H), 3.38-3.32 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H) , 2.26-2.19 (m, 1H), 2.18-2.10 (m, 1H), 1.59-1.41 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 143.9, 136.3, 135.6, 134.7, 132.7, 129.7, 128.4, 128.0, 127.9, 127.3, 56.9, 36.6, 29.0, 25.1, 21.8, 21.2.
HRMS (micromass LCT) C ₁₈ H ₂₀ BrNO ₂ S calculated 393.0398, measured 393.0392.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 31.5 mg (0.1 mmol) of the base material S5, 27.6 mg (0.2 mmol) of potassium carbonate, 67.0 mg (0.3 mmol) of copper bromide in 3 ml of tetrahydrofuran The mixture was stirred at room temperature (20 ° C.) for 60 minutes, cooled to 0 ° C. and stirred for 15 minutes. Then, 10.6 mg (0.04 mmol) of palladium bromide was added, and the mixture naturally rose to room temperature (20 ° C.). Warm and stir, follow by TLC until the reaction is complete, filter to remove insolubles and elute with silica gel column chromatography with petroleum ether: ethyl acetate = 10: 1 to give 35.1 mg of white solid. The yield was 89%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J = 8Hz, 1H), 7.33 (d, J = 8Hz, 2H), 7.17 (d, J = 8Hz, 2H), 7.07-7.03 (m, 1H), 6.77 (s, 1H), 4.36-4.28 (m, 1H), 3.75-3.71 (m, 1H), 3.38-3.32 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H) , 2.26-2.19 (m, 1H), 2.18-2.10 (m, 1H), 1.59-1.41 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 143.9, 136.3, 135.6, 134.7, 132.7, 129.7, 128.4, 128.0, 127.9, 127.3, 56.9, 36.6, 29.0, 25.1, 21.8, 21.2.
HRMS (micromass LCT) C ₁₈ H ₂₀ BrNO ₂ S calculated 393.0398, measured 393.0392.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 31.5 mg (0.1 mmol) of the base material S5, 27.6 mg (0.2 mmol) of potassium carbonate, 26.8 mg (0.12 mmol) of copper bromide and 3 ml of tetrahydrofuran After stirring at room temperature (20 ° C) for 60 minutes, cooling to 0 ° C and stirring for 15 minutes, 5.3 mg (0.02 mmol) of palladium bromide was added, and the temperature was naturally increased to room temperature (20 ° C). Warm and stir, follow by TLC until the reaction is complete, filter to remove insolubles and elute by silica gel column chromatography with petroleum ether: ethyl acetate = 10: 1 to give 29.9 mg of white solid. The yield was 76%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J = 8Hz, 1H), 7.33 (d, J = 8Hz, 2H), 7.17 (d, J = 8Hz, 2H), 7.07-7.03 (m, 1H), 6.77 (s, 1H), 4.36-4.28 (m, 1H), 3.75-3.71 (m, 1H), 3.38-3.32 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H) , 2.26-2.19 (m, 1H), 2.18-2.10 (m, 1H), 1.59-1.41 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 143.9, 136.3, 135.6, 134.7, 132.7, 129.7, 128.4, 128.0, 127.9, 127.3, 56.9, 36.6, 29.0, 25.1, 21.8, 21.2.
HRMS (micromass LCT) C ₁₈ H ₂₀ BrNO ₂ S calculated 393.0398, measured 393.0392.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 31.5 mg (0.1 mmol) of the base material S5, 27.6 mg (0.2 mmol) of potassium carbonate, 89.4 mg (0.4 mmol) of copper bromide in 3 ml of tetrahydrofuran After stirring at room temperature (20 ° C) for 60 minutes, cooling to 0 ° C and stirring for 15 minutes, 5.3 mg (0.02 mmol) of palladium bromide was added, and the temperature was naturally increased to room temperature (20 ° C). Stir warm and follow by TLC until the reaction is complete, filter to remove insolubles and elute with silica gel column chromatography with petroleum ether: ethyl acetate = 10: 1 to give 33.9 mg of white solid. The yield was 86%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J = 8Hz, 1H), 7.33 (d, J = 8Hz, 2H), 7.17 (d, J = 8Hz, 2H), 7.07-7.03 (m, 1H), 6.77 (s, 1H), 4.36-4.28 (m, 1H), 3.75-3.71 (m, 1H), 3.38-3.32 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H) , 2.26-2.19 (m, 1H), 2.18-2.10 (m, 1H), 1.59-1.41 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 143.9, 136.3, 135.6, 134.7, 132.7, 129.7, 128.4, 128.0, 127.9, 127.3, 56.9, 36.6, 29.0, 25.1, 21.8, 21.2.
HRMS (micromass LCT) C ₁₈ H ₂₀ BrNO ₂ S calculated 393.0398, measured 393.0392.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 31.5 mg (0.1 mmol) of the base material S5, 16.6 mg (0.12 mmol) of potassium carbonate, 67.0 mg (0.3 mmol) of copper bromide in 3 ml of tetrahydrofuran After stirring at room temperature (20 ° C) for 60 minutes, cooling to 0 ° C and stirring for 15 minutes, 5.3 mg (0.02 mmol) of palladium bromide was added, and the temperature was naturally increased to room temperature (20 ° C). Warm and stir, follow by TLC until reaction is complete, filter to remove insolubles and elute with silica gel column chromatography with petroleum ether: ethyl acetate = 10: 1 to give 31.9 mg of white solid. The yield was 81%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J = 8Hz, 1H), 7.33 (d, J = 8Hz, 2H), 7.17 (d, J = 8Hz, 2H), 7.07-7.03 (m, 1H), 6.77 (s, 1H), 4.36-4.28 (m, 1H), 3.75-3.71 (m, 1H), 3.38-3.32 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H) , 2.26-2.19 (m, 1H), 2.18-2.10 (m, 1H), 1.59-1.41 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 143.9, 136.3, 135.6, 134.7, 132.7, 129.7, 128.4, 128.0, 127.9, 127.3, 56.9, 36.6, 29.0, 25.1, 21.8, 21.2.
HRMS (micromass LCT) C ₁₈ H ₂₀ BrNO ₂ S calculated 393.0398, measured 393.0392.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 31.5 mg (0.1 mmol) of the base material S5, 55.2 mg (0.4 mmol) of potassium carbonate, and 67.0 mg (0.3 mmol) of copper bromide were added to 3 ml of tetrahydrofuran. After stirring at room temperature (20 ° C) for 60 minutes, cooling to 0 ° C and stirring for 15 minutes, 5.3 mg (0.02 mmol) of palladium bromide was added, and the temperature was naturally increased to room temperature (20 ° C). Warm and stir, follow by TLC until the reaction is complete, filter to remove insolubles and elute with silica gel column chromatography with petroleum ether: ethyl acetate = 10: 1 to give 31.1 mg of white solid. The yield was 79%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (d, J = 8Hz, 1H), 7.33 (d, J = 8Hz, 2H), 7.17 (d, J = 8Hz, 2H), 7.07-7.03 (m, 1H), 6.77 (s, 1H), 4.36-4.28 (m, 1H), 3.75-3.71 (m, 1H), 3.38-3.32 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H) , 2.26-2.19 (m, 1H), 2.18-2.10 (m, 1H), 1.59-1.41 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 143.9, 136.3, 135.6, 134.7, 132.7, 129.7, 128.4, 128.0, 127.9, 127.3, 56.9, 36.6, 29.0, 25.1, 21.8, 21.2.
HRMS (micromass LCT) C ₁₈ H ₂₀ BrNO ₂ S calculated 393.0398, measured 393.0392.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 30.1 mg (0.1 mmol) of the base material S4, 27.6 mg (0.2 mmol) of potassium carbonate, 67.0 mg (0.3 mmol) of copper bromide in 3 ml of tetrahydrofuran After stirring at room temperature (20 ° C) for 60 minutes, cooling to 0 ° C and stirring for 15 minutes, 5.3 mg (0.02 mmol) of palladium bromide was added, and the temperature was naturally increased to room temperature (20 ° C). Warm and stir, follow by TLC until the reaction is complete, filter to remove insolubles and elute with silica gel column chromatography with petroleum ether: ethyl acetate = 10: 1 to give 32.3 mg of white solid. The yield was 85%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 (d, J = 8Hz, 1H), 7.32 (d, J = 8Hz, 2H), 7.27-7.22 (m, 1H), 7.17-7.10 (m, 3H) , 6.96 (d, J = 8Hz, 1H), 4.40-4.31 (m, 1H), 3.75-3.71 (m, 1H), 3.40-3.34 (m, 1H), 2.37 (s, 3H), 2.32-2.24 ( m, 1H), 2.22-2.12 (m, 1H), 1.62-1.47 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 144.0, 135.6, 135.3, 134.9, 129.7, 128.1, 127.7, 127.3, 127.2, 126.5, 57.0, 36.5, 28.9, 25.2, 21.8.
HRMS (micromass LCT) C ₁₇ H ₁₈ BrNO ₂ S calculated, 379.0242, measured 379.0237.

  In a nitrogen gas atmosphere at room temperature (20 ° C.), 31.7 mg (0.1 mmol) of the base material S6, 27.6 mg (0.2 mmol) of potassium carbonate, 67.0 mg (0.3 mmol) of copper bromide in 3 ml of tetrahydrofuran After stirring at room temperature (20 ° C) for 60 minutes, cooling to 0 ° C and stirring for 15 minutes, 5.3 mg (0.02 mmol) of palladium bromide was added, and the temperature was naturally increased to room temperature (20 ° C). Stir warm and follow by TLC until the reaction is complete, filter to remove insolubles and elute with silica gel column chromatography with petroleum ether: ethyl acetate = 10: 1 to give 33.2 mg of white solid. The yield was 81%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (d, J = 8Hz, 1H), 7.31 (d, J = 8Hz, 2H), 7.16 (d, J = 8Hz, 2H), 6.81-6.76 (m, 1H), 6.51-6.48 (m, 1H), 4.33-4.25 (m, 1H), 3.78 (s, 3H), 3.74-3.69 (m, 1H), 3.38-3.32 (m, 1H), 2.38 (s, 3H), 2.24-2.12 (m, 2H), 1.54-1.34 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.0, 143.9, 136.8, 135.4, 129.7, 129.5, 128.1, 127.3, 113.0, 112.2, 56.9, 55.6, 36.7, 29.2, 25.6, 21.8.
HRMS (micromass LCT) C ₁₈ H ₂₀ BrNO ₃ S calculated, 409.0347, measured 409.0352.

Claims (11)

In the presence of a divalent palladium salt, a compound represented by the following general formula (1) and a copper salt represented by the following general formula (2) are reacted in a solvent to obtain the following general formula (3): A method for producing a tetrahydroquinoline compound, comprising obtaining the tetrahydroquinoline compound represented.

  The production method according to claim 1, wherein R represents any one selected from hydrogen, fluorine, chlorine, bromine, iodine, a methyl group, and a methoxy group. The production method according to claim ₁ , wherein R ₁ represents any one selected from hydrogen, an acyl group, and a sulfonyl group.   The method according to claim 1, wherein the copper salt is at least one selected from copper acetate, copper bromide, copper chloride, copper iodide, and copper trifluoroacetate.   The divalent palladium salt is at least one selected from palladium acetate, palladium chloride, palladium trifluoroacetate, palladium bromide, and dichlorobis (acetonitrile) palladium (II). The manufacturing method as described in.   The solvent is at least one selected from methanol, ethanol, isopropyl alcohol, tetrahydrofuran, acetone, DMSO, DMF, NMP, acetonitrile, diethyl ether, dichloromethane, toluene, xylene, benzene, and trifluoromethylbenzene. The manufacturing method according to claim 1, wherein the manufacturing method is characterized.   Furthermore, the compound represented by the said General formula (1) and the said copper salt are made to react in presence of an additive, The manufacturing method of Claim 1 characterized by the above-mentioned.   8. The additive according to claim 7, wherein the additive is at least one selected from potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate, potassium acetate, sodium acetate, benzoic acid, and acetic acid. Manufacturing method.   As a molar ratio between the divalent palladium salt and the compound represented by the general formula (1), the divalent palladium salt: the compound represented by the general formula (1) = 0.1: 1 to 0.4. The manufacturing method according to claim 1, wherein the manufacturing method is one.   The molar ratio of the copper salt to the compound represented by the general formula (1) is copper salt: the compound represented by the general formula (1) = 1.2: 1 to 4: 1, The manufacturing method according to any one of claims 1 to 8.   As a molar ratio of the additive and the compound represented by the general formula (1), the additive: the compound represented by the general formula (1) = 1.2: 1 to 4: 1 The manufacturing method according to claim 7 or 8.