Synthesis method of (tetrahydro) quinoline compound or (tetrahydro) isoquinoline compound

Abstract

The invention relates to a synthesis method of a (tetrahydro) quinoline compound and a (tetrahydro) isoquinoline compound. Specifically, halogenated pyridine and alkyne (alkene) hydrocarbon are prepared under the action of illumination. According to the invention, a series of (tetrahydro) quinoline compounds and (tetrahydro) isoquinoline compounds are obtained from simple and easily available raw materials.

Description

Technical Field

[0001] The invention relates to a method for synthesizing (tetrahydro)quinoline compounds and (tetrahydro)isoquinoline compounds. Background Art

[0002] Quinoline is one of the most common aromatic heterocyclic compounds, and natural products with quinoline as the skeleton are widely present. Among the top 200 small molecule drugs in global sales, there are several drugs with quinoline skeleton structure, contributing nearly 10 billion US dollars in sales. The traditional method for quinoline synthesis requires starting from aromatic hydrocarbons with more substituents and preparing quinoline through methods such as dehydration condensation. The traditional method requires detailed synthesis route design and relatively cumbersome steps and paths, and does not have the economy of reaction steps.

[0003] Compared with the traditional quinoline synthesis method, the raw materials used in the present invention are simple and easy to obtain, the reaction conditions are mild, and quinoline compounds that are more complex than traditional synthetic quinoline can be constructed. At the same time, this method can also be used to construct compounds such as isoquinoline, (tetrahydro)quinoline, and (tetrahydro)isoquinoline.

[0004] In summary, this paper describes a method for the synthesis of (tetrahydro)quinolines and (tetrahydro)isoquinolines under simple and mild conditions. Summary of the invention

[0005] The object of the present invention is to provide a method for synthesizing (tetrahydro)quinoline compounds and (tetrahydro)isoquinoline compounds.

[0006]

[0007] Reaction 1: Synthesis of (iso)quinoline; Reaction 2: Synthesis of tetrahydro(iso)quinoline

[0008] The specific operation steps are as follows (reaction formula 1, 2):

[0009] The reaction is carried out in a reactor, and halogenated pyridine 1, alkyne or olefin 2, a photocatalyst, an acid and a solvent are added in sequence, and the reaction is carried out under light of a certain wavelength at room temperature for 10-48 hours. After the reaction is completed, a (tetrahydro)quinoline compound and a (tetrahydro)isoquinoline compound 3 are separated and obtained.

[0010] The molar ratio of the halogenated pyridine 1 and the alkyne or olefin 2 is 1:1-10, preferably 1:2-4.

[0011] The acid is one or two of acetic acid, propionic acid, hydrochloric acid, p-methylphenylsulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid, preferably trifluoroacetic acid. The amount of the acid used is 1-5 molar equivalents of the amount of the halogenated pyridine 1, preferably 1-2 molar equivalents.

[0012] The photocatalyst used is tris(2-phenyl)pyridine iridium Ir(ppy) 3 , (4,4'-di-tert-butyl-2,2'-bipyridyl)bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridyl)phenyl)iridium hexafluorophosphate (Ir[dF(CF 3 )ppy] 2 (dtbpy))PF 6 , bis((2-phenyl)pyridine)(4,4'-di-tert-butyl-2,2'-bipyridyl)iridium hexafluorophosphate [Ir(ppy) 2 (dtbbpy)]PF 6 , bis((2-phenyl)pyridine)(1,1'-dimethyl-2,2'-biimidazole)iridium hexafluorophosphate [Ir(ppy) 2 (bim)]PF 6 , bis((2-phenyl)pyridine)(1,10-phenanthroline)iridium hexafluorophosphate [Ir(ppy) 2 (phen)]PF 6 , terpyridyl ruthenium chloride hexahydrateRu(bpy) 3 Cl 2 6H 2 O, Tris(1,10-phenanthroline)ruthenium hexafluorophosphateRu(phen) 3 (PF 6 ) 2 One or more of the following, preferably tris(2-phenyl)pyridine iridium Ir(ppy) 3 ; The amount of photocatalyst used is 1-5% molar equivalent, preferably 5% molar equivalent.

[0013] The solvent is one or more of trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, ethyl acetate, acetonitrile, toluene, tetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether, preferably hexafluoroisopropanol; the amount of the solvent is 1-5 ml, preferably 5 ml, per mmol of the halogenated pyridine compound 1.

[0014] The wavelength of the light is a blue-violet LED light source between 360nm-460nm, preferably a light source with a wavelength of about 420-430nm.

[0015] The present invention has the following advantages:

[0016] Firstly, the raw material of the reaction, halogenated pyridine, is simple, readily available, and inexpensive, and the reaction system is mild. Secondly, the method can be used to synthesize (tetrahydro)quinoline and (tetrahydro)isoquinoline, and the reaction route is universal. Finally, the obtained product has high added value and can be used to synthesize various natural products and drugs. DETAILED DESCRIPTION

[0017] In order to better understand the present invention, the following examples are provided for illustration. The reaction materials and results of Examples 1-10 are shown in Table 1.

[0018] Table 1 Reaction results of different substituents

[0019]

[0020]

[0021]

[0022]

[0023]

[0024] Among them, the halogenated pyridine raw materials in the table are all commercially available compounds, the alkyne and olefin substrates 2a, 2b, 2d, 2e, 2h, 2i, and 2j are all commercially available compounds, and the remaining 2c, 2f, and 2g are known compounds.

[0025] Example 1

[0026] The reaction was carried out in a photoreactor, and halogenated pyridine 1a (0.2 mmol), alkyne or olefin 2a (0.4 mmol) and photocatalyst di((2-phenyl)pyridine)(4,4'-di-tert-butyl-2,2'-bipyridine)iridium hexafluorophosphate [Ir(ppy) 2 (dtbbpy)]PF 6 (2 mol% of the amount of halopyridine 1a), acetic acid (0.2 mmol) and hexafluoroisopropanol 4 mL were reacted at room temperature under light of 420-430 nm for 18 hours. After the reaction, (tetrahydro)quinoline compound and (tetrahydro)isoquinoline compound 3a were separated by column chromatography in a yield of 73%. The compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0027] The test data are as follows:

[0028] (3a):white solid,mp65-67℃.46.0mg,73%,R f =0.15(petroleum ether / ethyl acetate 5 / 1). 1H NMR(400MHz,Chloroform-d)δ8.81(dd,J=4.2,1.7Hz,1H),8.05(dd,J=8.3,1.9Hz,1H),7.89(s,1H),7.60( s,1H),7.30(dd,J=8.3,4.2Hz,1H),4.20(q,J=7.1Hz,4H),3.77(s,2H),3.72(s,2H),1.25(t,J=7.1Hz,6H); 13 HRMS calculated for C 18 H 20 NO 4 [M+H] + 314.1387, found 314.1388.

[0029] Embodiment 2:

[0030] The operation process and conditions are the same as those of Example 1, except that, in addition to the difference in the raw materials described in Table 1, the acid is trifluoroacetic acid, and the added amount is 3.0 molar equivalents (3.0 molar equivalents of the amount of halopyridine 1), and the yield of the product 3b is 63%. The structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0031] Embodiment 3:

[0032] The operation process and conditions were the same as those in Example 1, except that the raw materials described in Table 1 were different. The yield of product 3c was 75%, and the structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0033] Embodiment 4:

[0034] The operation process and conditions are the same as those in Example 1, except that the raw materials described in Table 1 are different. The yield of product 3d is 65%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0035] Embodiment 5:

[0036] The operation process and conditions are the same as those of Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the photocatalyst is tris(2-phenyl)pyridine iridium Ir(ppy) 3, the amount is 5 mol% (0.05 molar equivalent of 1 amount of halogenated pyridine), the yield of product 3e is 57%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0037] Embodiment 6:

[0038] The operation process and conditions are the same as those of Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the photocatalyst is tris(2-phenyl)pyridine iridium Ir(ppy) 3 , the amount is 2 mol% (0.05 molar equivalent of 1 halogenated pyridine), the yield of product 3f is 54%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0039] Embodiment 7:

[0040] The operation process and conditions are the same as those of Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the photocatalyst is tris(2-phenyl)pyridine iridium Ir(ppy) 3 , the amount is 2 mol% (0.02 molar equivalent of 1 halogenated pyridine), the product 3g yield is 72%, the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry. The product and its analogs are used to synthesize natural product irudidine derivatives with anticancer activity. References: [1] Robert Gaston, Jr., Werner J. Geldenhuys, and Gregory B. Dudley J. Org. Chem. 2020, 85, 13429-13437.

[0041] Embodiment 8:

[0042] The operation process and conditions are the same as those of Example 1, except that, in addition to the differences described in Table 1, the photocatalyst is (4,4'-di-tert-butyl-2,2'-bipyridyl)bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridyl)phenyl)iridium hexafluorophosphate (Ir[dF(CF 3 )ppy] 2 (dtbpy))PF 6 , the amount is 2 mol% (0.02 molar equivalent of 1 amount of halogenated pyridine), the yield of product 3h is 56%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0043] Embodiment 9:

[0044] The operation process and conditions are the same as those of Example 1, except that, in addition to the differences described in Table 1, the photocatalyst is (4,4'-di-tert-butyl-2,2'-bipyridyl)bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridyl)phenyl)iridium hexafluorophosphate (Ir[dF(CF 3 )ppy] 2 (dtbpy))PF 6 , the amount is 2 mol% (0.02 molar equivalent of 1 halogenated pyridine), and the reaction is carried out under light of 450-460 nm wavelength. The yield of product 3i is 51%. The structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0045] Embodiment 10:

[0046] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, in addition to the differences described in Table 1, the solvent was trifluoroethanol, the amount was 4 mL, the yield of the product 3j was 73%, and the structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0047] Embodiment 11:

[0048] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, in addition to the differences described in Table 1, the solvent was trifluoroethanol, the amount was 4 mL, the yield of the product 3j was 73%, and the structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0049] Embodiment 12:

[0050] The operation process and conditions are the same as those of Example 1, except that, in addition to the differences described in Table 1, the photocatalyst is (4,4'-di-tert-butyl-2,2'-bipyridyl)bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridyl)phenyl)iridium hexafluorophosphate (Ir[dF(CF 3 )ppy] 2 (dtbpy))PF 6 , the amount is 5 mol% (0.05 molar equivalent of halogenated pyridine 1), the yield of product 31 is 73%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0051] Embodiment 13:

[0052] The operation process and conditions are the same as those of Example 1, except that, in addition to the differences described in Table 1, the photocatalyst is (4,4'-di-tert-butyl-2,2'-bipyridyl)bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridyl)phenyl)iridium hexafluorophosphate (Ir[dF(CF 3 )ppy]2 (dtbpy))PF 6 , the amount is 5 mol% (0.05 molar equivalent of halogenated pyridine 1), the yield of product 3m is 43%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0053] Embodiment 14:

[0054] The operation process and conditions are the same as those of Example 1, except that, in addition to the differences described in Table 1, the acid is trifluoroacetic acid, the amount added is 1.0 molar equivalent (1.0 molar equivalent of 1 amount of halopyridine), the yield of the product 3n is 55%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0055] Embodiment 15:

[0056] The operation process and conditions are the same as those of Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the acid is p-toluenesulfonic acid, the amount added is 2.0 molar equivalents (2.0 molar equivalents of halogenated pyridine 1), the yield of the product 3o is 54%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0057] Embodiment 16:

[0058] The operation process and conditions are the same as those of Example 1, except that, in addition to the differences described in Table 1, the acid is p-toluenesulfonic acid, the amount added is 3.0 molar equivalents (3.0 molar equivalents of 1 amount of halogenated pyridine), the yield of the product 3p is 52%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0059] Embodiment 17:

[0060] The operation process and conditions are the same as those of Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the photocatalyst is tris(2-phenyl)pyridine iridium Ir(ppy) 3 , the amount is 5 mol% (0.05 molar equivalent of 1 amount of halogenated pyridine), the yield of product 3q is 56%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0061] Embodiment 18:

[0062] The operation process and conditions are the same as those of Example 1, except that, in addition to the differences described in Table 1, the photocatalyst is (4,4'-di-tert-butyl-2,2'-bipyridyl)bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridyl)phenyl)iridium hexafluorophosphate (Ir[dF(CF 3 )ppy] 2 (dtbpy))PF6 , the amount is 2 mol% (0.02 molar equivalent of halogenated pyridine 1), the yield of product 3r is 83%, and the compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry, which is a known compound. References: [2] Sarbendu Maiti, Basudeb Achari, Ranjan Mukhopadhyay and Asish Kr. Banerjee J. Chem. Soc., Perkin Trans. 2002, 1, 1769–1773.

[0063] Embodiment 19:

[0064] The operation process and conditions are the same as those of Example 1, except that, in addition to the differences described in Table 1, the photocatalyst is (4,4'-di-tert-butyl-2,2'-bipyridyl)bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridyl)phenyl)iridium hexafluorophosphate (Ir[dF(CF 3 )ppy] 2 (dtbpy))PF 6 , the amount is 5 mol% (0.05 molar equivalent of 1 amount of halogenated pyridine), and the reaction is carried out under light of 390-400nm wavelength. The yield of product 3s is 62%. The structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0065] Embodiment 20:

[0066] The operation process and conditions are the same as those of Example 1, except that, in addition to the differences described in Table 1, the acid is trifluoroacetic acid, the amount added is 3.0 molar equivalents (3.0 molar equivalents of 1 amount of halogenated pyridine), and the reaction is carried out under light of a wavelength of 450-460 nm. The yield of the product 3t is 73%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0067] Embodiment 21:

[0068] The operation process and conditions are the same as those of Example 1, except that, in addition to the differences described in Table 1, the acid is trifluoroacetic acid, the amount added is 3.0 molar equivalents (3.0 molar equivalents of 1 amount of halopyridine), the yield of the product 3u is 95%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0069] Comparative Example 1:

[0070] The raw materials, operating procedures and conditions were the same as those in Example 1, except that, in addition to the differences described in Table 1, no photocatalyst was added and no product 3a was obtained.

[0071] Comparative Example 2:

[0072] The raw materials, operation process and conditions were the same as those in Example 1, except that, in addition to the differences described in Table 1, no acid was added and no product 3a was obtained.

Claims

1. A method for producing a (tetrahydro)quinoline compound or a (tetrahydro)isoquinoline compound, characterized in that: The substituted halopyridine 1, alkyne and / or olefin 2 shown in the following formula are used as raw materials to generate (tetrahydro)quinoline compounds or (tetrahydro)isoquinoline compounds 3, and the reaction formula is as follows: Wherein, in the reaction formula (1) and / or the reaction formula (2), in the halogenated pyridine compound 1, X may be one or more of chlorine, bromine, and iodine atoms, and the substitution position may be one or more of the ortho and para positions of the pyridine nitrogen atom. When X is an iodine atom, the substitution position may also be extended to the meta position of the pyridine nitrogen atom (i.e., if there is a halogen substituent at the ortho and / or para position of the pyridine nitrogen atom, the substituent X may be one or more of chlorine, bromine, and iodine, i.e., if there is a halogen substituent at the meta position of the pyridine nitrogen atom, the substituent X may be iodine); the halogenated pyridine compound may not contain or may contain other substituents R 1 , other substituents may be one or more of methyl, ethyl, hydroxymethyl, methoxy, ethoxy, and acetylamino; For reaction formula (1), in alkyne 2, R 2 , R 3 Each of them is independently a hydrogen atom, a methyl group, or a p-cyanophenyl group, etc., one or more thereof; Z is an oxygen atom, a methylene group, and one or more thereof of a substituent group represented by the following formula; In reaction formula (2), in olefin 2, Z is an oxygen atom and one or more of the substituents shown in the above formula.

2. The method for preparing a (tetrahydro)quinoline compound and a (tetrahydro)isoquinoline compound 3 according to claim 1, characterized in that: The specific steps are as follows: The reaction is carried out in a reactor, and halogenated pyridine 1, alkyne and / or olefin 2, a photocatalyst, an acid and a solvent are added in sequence, and the reaction is carried out under light at room temperature for 10-48 hours. After the reaction is completed, a (tetrahydro)quinoline compound and / or a (tetrahydro)isoquinoline compound 3 is separated and obtained.

3. The method according to claim 2, characterized in that: The molar ratio of the halogenated pyridine 1 to the alkyne and / or olefin 2 is 1:1-10, preferably 1:2-4.

4. The method according to claim 2, characterized in that: The acid is one or more of acetic acid, propionic acid, hydrochloric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid, preferably trifluoroacetic acid; the amount of the acid is 1-5 times the molar equivalent of the amount of the halogenated pyridine 1, preferably 1-2 times the molar equivalent.

5. The method according to claim 2, characterized in that: The photocatalysts used were tris(2-phenyl)pyridine iridium complex Ir(ppy)3, (4,4'-di-tert-butyl-2,2'-bipyridine)bis(3,5-difluoro-2-(5-(trifluoromethyl)-2-pyridyl)phenyl)iridium hexafluorophosphate (Ir[dF(CF3)ppy]2(dtbpy))PF6, bis((2-phenyl)pyridine)(4,4'-di-tert-butyl-2,2'-bipyridine)iridium hexafluorophosphate [Ir(ppy)2(dtbbpy)]PF6, bis((2-phenyl)pyridine)(1,1'- One or more of dimethyl-2,2'-biimidazole) iridium hexafluorophosphate [Ir(ppy)2(bim)]PF6, bis((2-phenyl)pyridine)(1,10-phenanthroline) iridium hexafluorophosphate [Ir(ppy)2(phen)]PF6, terpyridine ruthenium chloride hexahydrate Ru(bpy)3Cl2·6H2O, tris(1,10-phenanthroline) ruthenium hexafluorophosphate Ru(phen)3(PF6)2, 9-mesityl-10-methylacridine perchlorate Acr-MesClO4, Rose Bengal, and Acid Red 94, preferably tris(2-phenyl)pyridine iridium Ir(ppy)3; the amount of the photocatalyst used is 1-5% molar equivalent of the halogenated pyridine 1, preferably 3-5% molar equivalent.

6. The method according to claim 2, characterized in that: The solvent is one or more of trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, ethyl acetate, acetonitrile, toluene, tetrahydrofuran, 1,4-dioxane, and ethylene glycol dimethyl ether, preferably hexafluoroisopropanol; the amount of the solvent is 1-5 ml, preferably 3-5 ml, per 0.2 mmol of halogenated pyridine.

7. The method according to claim 2, characterized in that: The wavelength of the light is a blue-violet LED light source between 360nm-460nm, preferably a light source with a wavelength of 420-440nm.

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