A preparation method of trifluoromethyl substituted chromone quinoline

Abstract

The invention discloses a preparation method for synthesizing trifluoromethyl-substituted chromonoquinoline, comprising the steps of adding a palladium catalyst, a ligand, norbornene, an additive, trifluoroethylimidoyl chloride, and 3-iodochromone to an organic solvent, reacting at 110 to 130° C. for 16 to 30 hours, and after completion of the reaction, post-processing to obtain the trifluoromethyl-substituted chromonoquinoline compound. The preparation method is simple to operate, has inexpensive and readily available starting materials, high reaction efficiency, and a wide substrate range. Trifluoromethyl-substituted chromonoquinoline compounds substituted with different groups can also be synthesized through substrate design, thereby facilitating operation and broadening the practicality of the method.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing trifluoromethyl-substituted chromone and quinoline by a multi-component one-pot method. Background Art

[0002] Chromones are important oxygen-containing six-membered heterocycles found in a wide range of functional and pharmaceutical molecules, exhibiting a range of biological and pharmaceutical activities (Chem. Rev., 2014, 114, 4960). Many common pharmaceuticals on the market contain chromone molecules, such as Khelline, Rapidil, and Intal (Urol. Res., 2011, 39, 189). Due to the unique properties of the fluorine atom, the trifluoromethyl group can significantly improve the physicochemical properties of the attached parent molecule, such as electronegativity, bioavailability, metabolic stability, and lipophilicity (J. Med. Chem. 2015, 58, 8315-8359).

[0003] Trifluoromethyl-substituted chromone-quinoline compounds contain both chromone and quinoline structures and are an important class of fused heterocycles. Previous research methods on chromones have mainly focused on the functionalization of the 2 and 3 positions of chromones, and there have been few reports on the synthesis of chromone-fused heterocycles. The above-mentioned synthesis methods are generally limited by the disadvantages of harsh reaction conditions, expensive reaction substrates or the need for pre-activation, low yields, and a narrow substrate range. 3-Iodochromone is a cheap and readily available starting material that is often used to construct various chromone-heterocyclic compounds with different structures. It can also be used as a model substrate to efficiently participate in the Catellani reaction to construct various fused heterocyclic compounds.

[0004] Based on this, we developed a method for efficiently synthesizing trifluoromethyl-substituted chromone-quinoline compounds in a one-pot multi-component tandem cyclization reaction catalyzed by transition metal palladium, using cheap and readily available trifluoroethylimidoyl chloride and 3-iodochromone as starting materials, norbornene as the reaction medium, and a transition metal palladium-catalyzed tandem cyclization reaction. Summary of the Invention

[0005] The present invention provides a multi-component one-pot method for synthesizing trifluoromethyl-substituted chromone-quinoline. The preparation method is simple to operate, the reaction raw materials are simple and easily available, it is compatible with various functional groups, has high reaction efficiency and good applicability, and the method can also be expanded to gram-level equivalents, providing the possibility for large-scale application in industrial production and drug development and synthesis.

[0006] A method for preparing a trifluoromethyl-substituted chromonoquinoline comprises the following steps: adding palladium acetate, tri(p-fluorophenyl)phosphine, norbornene, potassium phosphate, trifluoroethylimidoyl chloride, and 3-iodochromone to an organic solvent, reacting at 110-130° C. for 16-30 hours, and after the reaction is complete, post-treating to obtain the trifluoromethyl-substituted chromonoquinoline compound;

[0007] The structure of the trifluoroethylimidoyl chloride is shown in formula (III):

[0008]

[0009] The structure of the 3-iodochromone is shown in formula (II):

[0010]

[0011] The structure of the trifluoromethyl-substituted chromonoquinoline compound is shown in formula (I):

[0012]

[0013] In formulas (I) to (III), R 1 is H, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio or halogen; R 2 C1~C 10 Alkyl, C1-C5 alkoxy or halogen.

[0014] The molar ratio of palladium acetate, tri(p-fluorophenyl)phosphine and potassium phosphate is 0.1:0.2:4;

[0015] The substitution position on the chromone can be the 5, 6 or 7 position.

[0016] The reaction formula is as follows:

[0017]

[0018] The reaction may first undergo the insertion of zero-valent palladium into the carbon-iodine bond of 3-iodochromone and the insertion of norbornene to form a five-membered palladium ring, followed by oxidative addition with the carbon-chlorine bond of trifluoroethylimidoyl chloride to form a tetravalent palladium intermediate, which undergoes reductive elimination to construct a carbon-carbon bond and generate a divalent palladium complex, and then intramolecular carbon-hydrogen activation occurs to form a palladium ring intermediate, while at the same time releasing norbornene; finally, reductive elimination occurs to obtain a trifluoromethyl-substituted chromone and quinoline product.

[0019] In the present invention, the optional post-treatment process includes: filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding trifluoromethyl-substituted chromone-quinoline compound. Column chromatography purification is a commonly used technical means in the field.

[0020] As a preference, R 1 is H, methyl, methylthio, tert-butyl, methoxy, F, Cl or Br; R 2 is H, methyl, methoxy, F, Cl or Br. In this case, the trifluoroethylimidoyl chloride and 3-iodochromone are easily obtained, and the reaction yield is high.

[0021] The various types of trifluoroethylimidoyl chlorides are synthesized using fatty amines, which are relatively cheap and widely found in nature. The amount of the fatty amine used is in excess relative to the 3-iodochromone. Preferably, on a molar basis, the ratio of trifluoroethylimidoyl chloride:3-iodochromone:palladium acetate is 1-3:1:0.05-0.2. More preferably, on a molar basis, the ratio of trifluoroethylimidoyl chloride:3-iodochromone:palladium acetate is 2:1:0.1.

[0022] Preferably, the reaction time is 16 to 30 hours. Too long a reaction time will increase the reaction cost, while on the contrary it will be difficult to ensure the completeness of the reaction.

[0023] In the present invention, any organic solvent that can fully dissolve the raw materials can cause the reaction to occur, but the reaction efficiency varies greatly. An aprotic solvent is preferably used, as the aprotic solvent can effectively promote the reaction. Preferably, the organic solvent is toluene, acetonitrile or dioxane. More preferably, the organic solvent is toluene. In this case, various raw materials can be converted into products at a higher conversion rate.

[0024] The amount of the organic solvent used is sufficient to dissolve the raw materials well. The amount of the organic solvent used for 1 mmol of 3-iodochromone is about 5 to 10 mL.

[0025] Preferably, the catalyst is palladium acetate. Among many palladium catalysts, palladium acetate has a higher reaction efficiency.

[0026] As a further preference, the trifluoromethyl-substituted chromonoquinoline compound is one of the compounds represented by formula (I-1) to formula (I-5):

[0027]

[0028]

[0029] In the above preparation method, the various types of aromatic amines, 3-iodochromone, norbornene, palladium acetate and tri(p-fluorophenyl)phosphine are generally commercially available products and can be easily obtained from the market. The trifluoroethylimidoyl chloride can be quickly synthesized from the corresponding aromatic amine, triphenylphosphine, carbon tetrachloride and trifluoroacetic acid.

[0030] Compared with the prior art, the beneficial effects of the present invention are reflected in: the preparation method is easy to operate and the post-processing is simple; the reaction starting materials are cheap and easily available, the substrate is highly designable, the substrate functional group tolerance range is wide, the reaction efficiency is high, and trifluoromethyl-substituted chromone-quinoline compounds with different position and group substitutions can be designed and synthesized according to actual needs, and the method is highly practical. DETAILED DESCRIPTION

[0031] The present invention will be further described below with reference to specific embodiments.

[0032] According to the raw material ratio in Table 1, palladium acetate, tri(p-fluorophenyl)phosphine, norbornene (0.4 mmol), potassium phosphate, trifluoroethylimidoyl chloride (III), 3-iodochromone (II) and 2 mL of organic solvent were added to a 35 mL Schlenk tube, mixed and stirred evenly, and reacted for 16-30 hours according to the reaction conditions in Table 2. The mixture was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding trifluoromethyl-substituted chromonoquinoline compound (I). The reaction process is shown in the following formula:

[0033]

[0034] Table 1 Amount of raw materials added in Examples 1 to 15

[0035]

[0036] Table 2

[0037]

[0038]

[0039] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Me is a methyl group, OMe is a methoxy group, SMe is a methylthio group, t-Bu is a tert-butyl group, and Toluene is toluene.

[0040] The structural confirmation data of the compounds prepared in Examples 1 to 5 are as follows:

[0041] The NMR of the trifluoromethyl substituted chromone and quinoline compound (I-1) prepared in Example 1 is ( 1 HNMR, 13 C NMR and 19 F NMR) detection data are:

[0042]

[0043] 1 H NMR (400MHz, CDCl3) δ9.70 (s, 1H), 8.40 (d, J = 8.0Hz, 1H), 8.17 (d, J = 8.5Hz, 1H), 7.84(t,J=7.8Hz,1H),7.68(d,J=8.4Hz,2H),7.52(t,J=7.5Hz,1H),2.68(s,3H).

[0044] 13C NMR (101MHz, CDCl3) δ177.6,154.2,147.8,143.3,140.9,138.2(q, 2 J (C-F) =35.1Hz),135.4,131.6,130.4,126.5,125.5,125.4,123.7(q, 1 J (C-F) =275.8Hz),123.4,119.6,118.3,22.5.

[0045] 19 F NMR (377 MHz, CDCl3) δ-66.05.

[0046] Mp190.3-193.1℃

[0047] HRMS(ESI):[M+H] + calcd for C 18 H 11 F3NO2 + 330.0736,found 330.0730.

[0048] The NMR of the trifluoromethyl substituted chromone and quinoline compound (I-2) prepared in Example 2 is ( 1 HNMR, 13 C NMR and 19 F NMR) detection data are:

[0049]

[0050] 1 H NMR (400MHz, CDCl3) δ10.14(d,J=2.1Hz,1H),8.41(dd,J=8.0,1.4Hz,1H),8.15(d,J=8.9Hz,1H ),7.95(dd,J=8.9,2.2Hz,1H),7.91–7.79(m,1H),7.70(d,J=8.3Hz,1H),7.56(t,J=7.5Hz,1H).

[0051] 13 C NMR(101MHz,CDCl3)δ177.1,154.2,150.6(q, 2 J (C-F) =33.7Hz),147.9,140.8,135.8,133.3,132.0,128.8,127.6,126.6,126.4 125.9,123.3,120.7(q,1 J (C-F) =276.2Hz),119.2,118.4.

[0052] 19 F NMR (377 MHz, CDCl3) δ-66.28.

[0053] Mp252.1-254.3℃

[0054] HRMS(ESI):[M+H] + calcd for C 17 H8F3NO2Br + 393.9685, found 393.9667.

[0055] The NMR of the trifluoromethyl substituted chromone and quinoline compound prepared in Example 3 is ( 1 HNMR, 13 C NMR and 19 F NMR) detection data are:

[0056]

[0057] 1 H NMR (400MHz, CDCl3) δ9.70(s,1H),8.25(d,J=8.6Hz,1H),8.07(dd,J=7.9,2.9Hz,1H),7.88–7.77(m,2H),7.75–7.69(m,1H),2.74(s,3H).

[0058] 13 C NMR (101MHz, CDCl3) δ179.0,160.4(d,J=249.9Hz),151.1,148.2,145.9,139.6,137.5(q, 2 J (C-F) =36.0Hz),133.6,128.1,126.0,125.7(d,J=25.8Hz),125.7,123.9(d,J=7.7Hz),121.1(d,J=8.3Hz),120.6(q, 1 J (C-F) =276.1Hz),120.1,111.(d,J=24.5Hz),22.4.

[0059] 19 F NMR(377MHz, CDCl3)δ-66.04,-114.20.

[0060] Mp244.1-246.4℃

[0061] HRMS(ESI):[M+H] + calcd for C 18 H 10 F4NO2 + 348.0642,found 348.0667.

[0062] The NMR of the trifluoromethyl substituted chromone and quinoline compound prepared in Example 4 is ( 1 H NMR, 13 CNMR and 19 F NMR) detection data are:

[0063]

[0064] 1 H NMR (400MHz, CDCl3) δ9.74(s,1H),8.29(d,J=8.9Hz,1H),8.17(d,J=8.5Hz,1H),7.67(dd,J=8 .5,1.7Hz,1H),7.06(dd,J=8.9,2.4Hz,1H),7.01(d,J=2.3Hz,1H),3.99(s,3H),2.68(s,3H).

[0065] 13 C NMR (101MHz, CDCl3) δ176.7,165.6,156.2,147.8,143.0,141.0,138.0(q, 2 J (C-F) =35.1Hz),131.6,130.3,128.0,125.8,125.5,121.0(q, 1 J (C-F) =275.8Hz),119.9,117.41,115.5,99.9,56.1,22.6.

[0066] 19 F NMR (377 MHz, CDCl3) δ-65.91.

[0067] Mp235.7-238.1℃

[0068] HRMS(ESI):[M+H] + calcd for C 19 H 13 F3NO3 + 360.0842,found 360.0850.

[0069] The NMR of the trifluoromethyl substituted chromone and quinoline compound prepared in Example 5 is ( 1 H NMR, 13 CNMR and 19 F NMR) detection data are:

[0070]

[0071] 1 H NMR (400MHz, CDCl3) δ9.65(s,1H),8.16(dd,J=14.8,8.2Hz,2H),7.64(t,J=6.6Hz,2H),7.37(t,J=7.5Hz,1H),2.66(s,3H),2.61(s,3H).

[0072] 13 C NMR (101MHz, CDCl3) δ177.9,152.7,147.5,143.2,140.8,138.3(q, 2 J (C-F) =35.3Hz),136.2,131.5,130.3,128.0,125.5,125.4,125.0,123.9,123.2,120.1(q, 1 J (C-F) =275.3Hz),119.2,22.5,15.4.

[0073] 19 F NMR (377 MHz, CDCl3) δ-66.42.

[0074] Mp260.1-261.7℃.

Claims

1. A method for preparing a trifluoromethyl-substituted chromonoquinoline compound, characterized in that: The method comprises the following steps: adding a palladium catalyst, a ligand, norbornene, an additive, trifluoroethylimidoyl chloride, and 3-iodochromone to an organic solvent; o C. react for 24 hours, and after the reaction is complete, post-process to obtain the trifluoromethyl-substituted chromone-quinoline compound; The structure of the trifluoroethylimidoyl chloride is shown in formula (III): ( III); The structure of the 3-iodochromone is shown in formula (II): (II); The structure of the trifluoromethyl-substituted chromonoquinoline compound is shown in formula (I): （Ⅰ）； In formulas (I) to (III), R 1 is H, C1~C5 alkyl, C1~C5 alkoxy, C1~C5 alkylthio or halogen; R 2 H, C1~C 10 Alkyl, C1~C5 alkoxy or halogen; The organic solvent is toluene; The palladium catalyst is palladium acetate; The ligand is tri(p-fluorophenyl)phosphine; The additive is potassium phosphate.

2. The method for preparing a trifluoromethyl-substituted chromonoquinoline according to claim 1, wherein R 1 is H, methyl, tert-butyl, F, Cl, Br, methoxy or methylthio.

3. The method for preparing trifluoromethyl-substituted chromonoquinoline according to claim 1, wherein R 2 is H, methyl, F, Cl, Br or methoxy.

4. The method for preparing trifluoromethyl-substituted chromonoquinoline according to claim 1, wherein In terms of molar amount, the ratio of 3-iodochromone: trifluoroethylimidoyl chloride: norbornene: palladium catalyst: ligand: additive is 1:1~3:1~3: 0.05~0.2: 0.1~0.3: 3~5.

5. The method for preparing trifluoromethyl-substituted chromonoquinoline according to claim 1, wherein The trifluoromethyl-substituted chromonoquinoline compound is one of the compounds represented by formula (I-1) to formula (I-5): （I-1） （I-2） （I-3） （I-4） （I-5）。

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