Method for preparing 2, 3-dihydro-1H-indanone derivative by one-pot method

Abstract

The invention is suitable for the technical field of chemical synthesis, and provides a method for preparing a 2, 3-dihydro-1H-indanone derivative by a one-pot method. The method comprises the following steps: mixing a 5 or 7 fluoro-2, 3-dihydro-1H-indanone compound (II), a saturated six-membered heterocyclic compound (III) and an aryl formaldehyde compound (IV) according to the mass ratio of 1: (1.1-1.5): (1.8-2.5), stirring and heating in a solvent to react, and separating after the reaction is completed to obtain the 2, 3-dihydro-1H-indanone derivative. The method can complete the reaction in one step, so that the reaction route is shorter, the cost is lower, and the method is more beneficial to industrial production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, and particularly relates to a one-pot method for preparing 2,3-dihydro-1H-indanone derivatives. Background Technology

[0002] Indanone compounds and their derivatives possess significant biological activities and have important applications in inhibiting tumors, combating neurodegenerative diseases, and protecting crops. For example, CN105622422A discloses a bromohexahydroindanone compound that exhibits excellent inhibitory effects on plant pathogens and also possesses insecticidal activity, making it suitable for the control of various plant diseases and pests. Another example is the anticancer activity of 2-benzylidene indanone compounds, as disclosed in Prakasham AP, Saxena AK, Luqman S, Chanda D, Kaur T, Gupta A, Yadav DK, Chantiya CS, Shanker K, Khan F, Negi AS. Synthesis and anticancer activity of 2-benzylidene indanones through inhibiting tubulin polymerization. Bioorg MedChem. 2012 May 1; 20(9):3049-57. For example, Huang L, Lu C, Sun Y, Mao F, Luo Z, Su T, Jiang H, Shan W, Li X. Multitarget-directed benzyllideneindanone derivatives: anti-β-amyloid (Aβ) aggregation, antioxidant, metal chelation, and monoamine oxidase B (MAO-B) inhibition properties against Alzheimer's disease. J Med Chem. 2012 Oct11; 55(19):8483-92. This paper discloses that benzyllideneindanone derivatives have anti-β-amyloid (Aβ) aggregation, antioxidant, metal chelation, and monoamine oxidase B (MAO-B) inhibition effects, which could be used in the treatment of Alzheimer's disease.

[0003] The preparation of (E)-5-(1-piperidinyl)-2-(arylmethylene)-2,3-dihydro-1H-indanone compounds typically involves two steps (such as...). Figure 1The first step involves preparing intermediate V by heating and refluxing a pyridine solution using formulas II and III as raw materials. The second step involves reacting intermediate V with IV in 95% ethanol at 52°C overnight under argon protection with the presence of sodium hydroxide, to obtain the target compound. This route has many steps, a long reaction time, and complex operation, making it unsuitable for large-scale production. Summary of the Invention

[0004] To address the above problems, this invention provides a 2,3-dihydro-1H-indanone derivative and its preparation method, which can be completed in a single step.

[0005] The following are 2,3-dihydro-1H-indanone derivatives and their preparation methods provided by the present invention, wherein the method includes:

[0006] 2,3-dihydro-1H-indanone compound (II), saturated six-membered heterocyclic compound (III), and aromatic formaldehyde compound (IV) were mixed in a molar ratio of 1:1.1-1.5:1.8-2.5, and the mixture was stirred and heated in a solvent to carry out the reaction. After the reaction was completed, compound (I) was separated.

[0007] The structures of compounds (Ⅰ), (Ⅱ), and (Ⅲ) are as follows:

[0008]

[0009] In the formula, R1 is an aromatic group, and X is C or O. Or F may be located at the 5 or 7 position of 2,3-dihydro-1H-indanone.

[0010] Compared with existing technologies, this application prepares novel 2,3-dihydro-1H-indanone derivatives. The preparation of these 2,3-dihydro-1H-indanone derivatives involves the reaction of 2,3-dihydro-1H-indanone compounds (II), saturated six-membered heterocyclic compounds (III), and aromatic formaldehyde compounds (IV) under specific conditions in a single step, resulting in a shorter reaction route, lower cost, and greater suitability for industrial production. Attached Figure Description

[0011] Figure 1 This is a schematic diagram of the two-step reaction for preparing (E)-5-(1-piperidinyl)-2-(arylmethylene)-2,3-dihydro-1H-indanone compounds;

[0012] Figure 2 This is a schematic diagram of the one-pot reaction of the present invention;

[0013] Figure 3 It is compound 1 prepared in Example 1 of this invention. 1 ¹H NMR (400MHz, solvent: DMSO-d6);

[0014] Figure 4 It is compound 1 prepared in Example 1 of this invention. 13 C10 NMR (100MHz, solvent: DMSO-d6)

[0015] Figure 5 It is compound 2 prepared in Example 2 of this invention. 1 ¹H NMR (400MHz, solvent: DMSO-d6);

[0016] Figure 6 It is compound 2 prepared in Example 2 of this invention. 13 C10 NMR (100MHz, solvent: DMSO-d6)

[0017] Figure 7 It is compound 3 prepared in Example 3 of this invention. 1 ¹H NMR (400MHz, solvent: DMSO-d6);

[0018] Figure 8 It is compound 3 prepared in Example 3 of this invention. 13 C10 NMR (100MHz, solvent: DMSO-d6)

[0019] Figure 9 It is compound 4 prepared in Example 4 of this invention. 1 ¹H NMR (400MHz, solvent: DMSO-d6);

[0020] Figure 10 It is compound 4 prepared in Example 4 of this invention. 13 C NMR (100MHz, solvent: DMSO-d6);

[0021] Figure 11 It is compound 5 prepared in Example 4 of this invention. 1 ¹H NMR (400MHz, solvent: DMSO-d6);

[0022] Figure 12 It is compound 5 prepared in Example 4 of this invention. 13 C NMR (100MHz, solvent: DMSO-d6);

[0023] Figure 13 It is compound 6 prepared in Example 4 of this invention. 1 ¹H NMR (400MHz, solvent: DMSO-d6);

[0024] Figure 14 It is compound 6 prepared in Example 4 of this invention. 13C NMR (100MHz, solvent: DMSO-d6);

[0025] Figure 15 It is compound 7 prepared in Example 4 of this invention. 1 ¹H NMR (400MHz, solvent: DMSO-d6);

[0026] Figure 16 It is compound 7 prepared in Example 4 of this invention. 13 C NMR (100MHz, solvent: DMSO-d6);

[0027] Figure 17 It is compound 8 prepared in Example 4 of this invention. 1 ¹H NMR (400MHz, solvent: DMSO-d6);

[0028] Figure 18 It is compound 8 prepared in Example 4 of this invention. 13 C NMR (100MHz, solvent: DMSO-d6);

[0029] Figure 19 It is compound 9 prepared in Example 4 of this invention. 1 ¹H NMR (400MHz, solvent: DMSO-d6);

[0030] Figure 20 It is compound 9 prepared in Example 4 of this invention. 13 C NMR (100MHz, solvent: DMSO-d6);

[0031] Figure 21 It is compound 10 prepared in Example 4 of this invention. 1 ¹H NMR (400MHz, solvent: DMSO-d6);

[0032] Figure 22 It is compound 10 prepared in Example 4 of this invention. 13 C NMR (100MHz, solvent: DMSO-d6). Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0034] Indanones and their derivatives possess significant biological activity, especially 2,3-dihydro-1H-indanones, making them a hot research topic. The structures and preparation methods of many indanones and their derivatives have been disclosed. During our research on 2,3-dihydro-1H-indanones, we unexpectedly discovered a 2,3-dihydro-1H-indanone derivative as shown in formula (Ⅰ) and its unique preparation method.

[0035] The carbon atom numbers of 2,3-dihydro-1H-indanone (or its groups) are as follows:

[0036]

[0037] The structure of the 2,3-dihydro-1H-indanone derivative compound (Ⅰ) of the present invention is as follows:

[0038]

[0039] In the formula, R1 is an aromatic group, and X is C or O. It is located at the 5 or 7 position of 2,3-dihydro-1H-indanone.

[0040] The method for preparing 2,3-dihydro-1H-indanone derivative compound (Ⅰ) includes: mixing 2,3-dihydro-1H-indanone compound (Ⅱ), saturated six-membered heterocyclic compound (Ⅲ), and aromatic formaldehyde compound (Ⅳ) in a molar ratio of 1:1.1-1.5:1.8-2.5, stirring and heating in a solvent to carry out the reaction, and separating compound (Ⅰ) after the reaction is completed.

[0041] The structures of compounds (II), (III), and (IV) are as follows:

[0042]

[0043] In the formula, R1 is an aromatic group, X is C or O, and F is located at the 5 or 7 position of 2,3-dihydro-1H-indanone. The reaction process is as follows: Figure 2 As shown.

[0044] Under these conditions, compounds (II), (III), and (IV) can generate compound (I) in one step, making the preparation process simpler and easier for industrial production.

[0045] It should be noted that F needs to be located at the 5th or 6th position of the 2,3-dihydro-1H-indanone group in compound (II). If it is located at the 4th or 6th position, it is not reactive. F at the 5th or 6th position is easily substituted by piperidine or morpholine, undergoing a nucleophilic substitution reaction. At the same time, piperidine or morpholine also mediates the Aldol condensation reaction between compound (II) and compound (IV), yielding compound (I) in one step. In addition, compounds (II), (III), and (IV) need to be mixed in a molar ratio of 1:1.1–1.5:1.8–2.5 to ensure better reaction. When the proportion of compound (II) is too high, other side reactions are likely to occur, reducing the yield.

[0046] In some specific embodiments, the temperature at which the reaction is carried out by heating is 25°C-80°C. Preferably, the temperature at which the reaction is carried out by heating is 50°C. Temperature affects not only the reaction time and yield, but also the products formed. For example, when the reaction temperature is too low, compounds (II) and (III) cannot react in one step to obtain the target product, and intermediates will be formed, requiring a second step of reaction to obtain the target product. When the temperature is too high, different compounds are formed, and the target product cannot be obtained. Through extensive research, it was unexpectedly discovered that, based on the above, compounds (II), (III), and (IV) can react in one step to generate compound (I) at 25°C-80°C, and in particular, the yield is highest at 50°C.

[0047] In this application, compound (Ⅳ) has an aromatic group (R1), which refers to a group containing a closed cyclic conjugated system, i.e., containing an aromatic ring. Preferably, the aromatic ring has electron-withdrawing atoms such as N and S, or the aromatic ring is substituted by electron-withdrawing groups such as nitro, hydroxyl, ether, carboxyl, etc. Preferably, the electron-withdrawing group is located at the para position of the aldehyde group, so that the carbonyl carbon of the aldehyde carries more positive charge and produces almost no steric hindrance, making the carbonyl carbon of the aldehyde more easily attacked by the enol anion and reacting. In some specific embodiments, compound (Ⅳ) is selected from at least one of the following:

[0048]

[0049] In some specific embodiments, compound (III) is piperidine, and the yield is higher when piperidine is used.

[0050] In some specific embodiments, the solvent is one or more selected from ethanol, acetonitrile, tetrahydrofuran, and dichloromethane. Preferably, the solvent is ethanol.

[0051] In some specific embodiments, the reaction time for stirring and heating in the solvent is 2-16 hours. Preferably, the reaction time for stirring and heating in the solvent is 2-6 hours. After 2 hours of reaction, most of the substrate has reacted, and the reaction is complete after 6 hours. 16 hours ensures that the reaction is completely completed under all conditions.

[0052] In some specific embodiments, the weight-to-volume ratio of piperidine to solvent is 1 g: 1 mL to 100 mL.

[0053] In some specific embodiments, the compound (Ⅰ) is one of the following:

[0054]

[0055] In some specific embodiments, the separation of compound (Ⅰ) after the reaction is completed includes: monitoring the reaction until it is complete by TLC, removing the solvent by rotary evaporation, extracting with ethyl acetate, drying with anhydrous sodium sulfate, and then separating compound (Ⅰ) by column chromatography.

[0056] To better illustrate the present invention, specific examples are listed below.

[0057] Example 1

[0058] Preparation of (E)-5-(1-piperidinyl)-2-(pyridin-4-methylene)-2,3-dihydro-1H-indanone (1).

[0059] In a magnetically charged reactor, 1.50 g (0.01 mol) of 5-fluoro-2,3-dihydro-1H-indanone, 1.61 g (0.015 mol) of pyridine-4-carboxaldehyde, 1.70 g (0.02 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 50 °C with stirring and monitored by TLC for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 2.19 g of a yellow solid, with a yield of 72%.

[0060] The compound 1 H RMR, 13 The detection data of C NMR and MS are as follows. 1 H RMR, 13 CNMR respectively as follows Figure 3 and Figure 4 .

[0061] 1H NMR (400MHz, DMSO-d6) δ: 8.69-8.64 (m, 2H), 7.72-7.63 (m, 2H), 7.59 (d, J = 8.8Hz, 1H), 7.30-7.27 (m, 1H),7.06-6.99(m,1H),6.99(d,J=2.2Hz,1H),4.02(s,2H),3.48(t,J=5.2Hz,4H),1.68-1.55(m,6H).

[0062] 13 C NMR (100MHz, DMSO-d6) δ: 189.9, 155.6, 152.8, 150.1, 142.7, 141.6, 126.8, 126.2, 125.7, 124.1, 114.1, 108.4, 47.9, 31.9, 24.9, 24.1.

[0063] MS(ESI) m / z: 305.1 [M+H] + ].

[0064] Example 2

[0065] Preparation of (E)-2-(4-nitrophenylmethylene)-5-(1-piperidinyl)-2,3-dihydro-1H-indanone (2).

[0066] In a magnetically charged reactor, 1.50 g (0.010 mol) of 5-fluoro-2,3-dihydro-1H-indanone, 2.26 g (0.015 mol) of 4-nitrobenzaldehyde, 1.70 g (0.02 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 50 °C with stirring and monitored by TLC for 16 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 2.40 g of a yellow solid, with a yield of 69%.

[0067] The compound 1 H RMR, 13 The C NMR and MS data are as follows. 1 H RMR, 13 C NMR respectively as follows Figure 5 and Figure 6 .

[0068] 1H NMR (400MHz, DMSO-d6) δ: 8.33–8.27 (m, 2H), 8.01–7.93 (m, 2H), 7.59 (d, J = 8.7Hz, 1H), 7.46–7. 40(m,1H),7.05–6.97(m,2H),4.03(d,J=2.2Hz,2H),3.49(t,J=5.2Hz,4H),1.69–1.51(m,6H).

[0069] 13 C NMR (100MHz, DMSO-d6) δ: 189.9, 155.6, 152.8, 146.9, 142.2, 140.9, 131.1, 127.2, 126.2, 125.7, 123.9, 114.1, 108.4, 47.9, 32.1, 24.9, 24.1.

[0070] MS(ESI) m / z: 349.2 [M+H] + ].

[0071] Example 3

[0072] Preparation of (E)-2-(4-methoxyphenylmethylene)-5-(1-piperidinyl)-2,3-dihydro-1H-indanone (3).

[0073] In a magnetically charged reactor, 1.50 g (0.010 mol) of 5-fluoro-2,3-dihydro-1H-indanone, 2.04 g (0.015 mol) of 4-methoxybenzaldehyde, 1.70 g (0.02 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 50 °C with stirring and monitored by TLC for 8 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 2.93 g of a yellow solid, with a yield of 88%.

[0074] The compound 1 H RMR, 13 The C NMR and MS data are as follows. 1 H RMR, 13 C NMR respectively as follows Figure 7 and Figure 8 .

[0075] 1H NMR (400MHz, DMSO-d6) δ: 7.70–7.63 (m, 2H), 7.55 (d, J = 9.4Hz, 1H), 7.34–7.30 (m, 1H), 7.08–7.0 1(m,2H),7.01–6.95(m,2H),3.90(s,2H),3.81(s,3H),3.43(t,J=5.0Hz,4H),1.65–1.54(m,6H).

[0076] 13 C NMR (100MHz, DMSO-d6) δ: 190.7,160.1,155.3,152.4,134.2,132.1,129.8 ,128.1,126.9,125.1,114.5,114.1,108.9,55.3,48.1,32.1,24.9,24.1.

[0077] MS(ESI) m / z: 334.2 [M+H] + ].

[0078] Example 4

[0079] Preparation of (E)-5-(1-piperidinyl)-2-(thiophene-3-methylene)-2,3-dihydro-1H-indanone (4).

[0080] In a magnetically charged reactor, 1.50 g (0.010 mol) of 5-fluoro-2,3-dihydro-1H-indanone, 1.68 g (0.015 mol) of thiophene-3-carboxaldehyde, 1.70 g (0.02 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 50 °C with stirring and monitored by TLC for 8 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 2.47 g of a yellow solid, with a yield of 80%.

[0081] The compound 1 H RMR, 13 The C NMR and MS data are as follows. 1 H RMR, 13 C NMR respectively as follows Figure 9 and Figure 10 .

[0082] 1H NMR (400MHz, DMSO-d6) δ: 7.98 (d, J=2.9Hz, 1H), 7.69 (dd, J=5.0, 2.9Hz, 1H), 7.55 (d, J=8.6Hz, 1H), 7.51–7 .47(m,1H),7.41-7.39(m,1H),7.03–6.96(m,2H),3.88-3.85(m,2H),3.45-3.41(m,4H),1.69–1.54(m,6H).

[0083] 13 C NMR (100MHz, DMSO-d6) δ: 190.7, 155.4, 152.3, 137.7, 135.1, 129.3, 128.4, 127.3, 127.1, 125.2, 123.8, 114.1, 108.8, 48.1, 31.9, 24.9, 24.1.

[0084] MS(ESI) m / z: 310.1 [M+H + ].

[0085] Example 5

[0086] Preparation of (E)-2-(4-hydroxyphenylmethylene-5-(1-piperidinyl)-2,3-dihydro-1H-indanone (5).

[0087] In a magnetically charged reactor, 1.50 g (0.010 mol) of 5-fluoro-2,3-dihydro-1H-indanone, 1.83 g (0.015 mol) of 4-hydroxybenzaldehyde, 1.70 g (0.02 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 50 °C with stirring and monitored by TLC for 8 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 2.94 g of a yellow solid, with a yield of 92%.

[0088] The compound 1 H RMR, 13 The C NMR and MS data are as follows. 1 H RMR, 13 C NMR respectively as follows Figure 11 and Figure 12 .

[0089] 1H NMR (400MHz, DMSO-d6) δ: 10.03 (s, 1H), 7.63–7.46 (m, 3H), 7.28 (d, J = 2.1Hz, 1H), 7.09– 6.95(m,2H),6.90–6.74(m,2H),3.89(s,2H),3.42(t,J=4.8Hz,4H),1.75–1.50(m,6H).

[0090] 13 C NMR (100MHz, DMSO-d6) δ: 190.8, 158.8, 155.3, 152.3, 133.1, 132.4, 130.4, 127.1, 126.5, 125.1, 115.9, 114.1, 108.9, 48.1, 32.1, 24.9, 24.1.

[0091] MS(ESI) m / z: 320.2 [M+H + ].

[0092] Example 6

[0093] Preparation of (E)-4-((1-oxo-5-(piperidin-1-yl)-1,3-dihydro-2H-indene-2-yl)methyl)benzoic acid (6).

[0094] In a magnetically charged reactor, 1.50 g (0.010 mol) of 5-fluoro-2,3-dihydro-1H-indanone, 2.25 g (0.015 mol) of 4-formylbenzoic acid, 1.70 g (0.02 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 50 °C with stirring and monitored by TLC for 8 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 3.30 g of a yellow solid, with a yield of 95%.

[0095] The compound 1 H RMR, 13 The C NMR and MS data are as follows. 1 H RMR, 13 C NMR respectively as follows Figure 13 and Figure 14 .

[0096] 1H NMR (400MHz, DMSO-d6) δ: 8.03–7.98(m,2H),7.84–7.77(m,2H),7.60–7.52(m,1H),7.4 0–7.35(m,1H),7.01-0.98(m,2H),3.99(s,2H),3.47-3.43(m,4H),1.69–1.54(m,6H).

[0097] 13 C NMR (100MHz, DMSO-d6) δ: 190.2,167.1,155.5,152.7,139.6,139.1,131.3 ,130.3,129.7,128.5,126.4,125.5,114.1,108.6,47.9,32.1,24.9,24.1.

[0098] MS(ESI) m / z: 348.2 [M+H] + ].

[0099] Example 7

[0100] Preparation of (E)-5-morpholino-2-(pyridin-4-ylmethylene)-2,3-dihydro-1H-indanone (7).

[0101] In a magnetically charged reactor, 1.50 g (0.010 mol) of 5-fluoro-2,3-dihydro-1H-indanone, 1.6 g (0.015 mol) of pyridine-4-carboxaldehyde, 1.74 g (0.02 mol) of morpholine, and 10 mL of ethanol were added. The mixture was heated to 50 °C with stirring and monitored by TLC for 16 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 1.56 g of a yellow solid, with a yield of 51%.

[0102] The compound 1 H RMR, 13 The C NMR and MS data are as follows. 1 H RMR, 13 C NMR respectively as follows Figure 15 and Figure 16 .

[0103] 1 H NMR (400MHz, DMSO-d6)δ: 8.71–8.61(m,2H),7.72–7.61(m,3H),7.33(s,1H) ,7.11–7.02(m,2H),4.04(s,2H),3.78–3.72(m,4H),3.39(t,J=4.9Hz,4H).

[0104] 13 C NMR (100MHz, DMSO-d6) δ: 190.4, 156.1, 152.6, 150.3, 142.4, 141.2, 127.4, 127.4, 125.5, 124.1, 114.2, 108.8, 65.8, 46.8, 31.9.

[0105] MS(ESI) m / z: 307.1 [M+H] + ].

[0106] Example 8

[0107] Preparation of (E)-7-(piperidin-1-yl)-2-(thiophen-3-ylmethylene)-2,3-dihydro-1H-indanone (8).

[0108] In a magnetically charged reactor, 1.50 g (0.010 mol) of 7-fluoro-2,3-dihydro-1H-indanone, 1.68 g (0.015 mol) of thiophene-3-carboxaldehyde, 1.70 g (0.02 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 50 °C with stirring and monitored by TLC for 8 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 2.97 g of a yellow solid, with a yield of 96%.

[0109] The compound 1 H RMR, 13 The C NMR and MS data are as follows. 1 H RMR, 13 C NMR respectively as follows Figure 17 and Figure 18 .

[0110] 1 H NMR(400MHz, DMSO-d6)δ: 8.00(d,J=2.8Hz,1H),7.70-7.68(m,1H),7.53–7.42(m,3H),7.02(d,J=7.3Hz ,1H),6.83(d,J=8.2Hz,1H),3.93(s,2H),3.11(t,J=5.2Hz,4H),1.74-1.71(m,4H),1.59-1.54(m,2H).

[0111] 13 C NMR (100MHz, DMSO-d6) δ: 190.6, 152.4, 151.9, 137.6, 135.7, 134.4, 129.5, 128.5, 127.3, 124.5, 117.1, 114.8, 52.2, 31.7, 25.6, 23.7.

[0112] MS(ESI) m / z: 310.0 [M+H + ].

[0113] Example 9

[0114] Preparation of (E)-2-(4-methoxyphenylmethylene)-7-(piperidin-1-yl)-2,3-dihydro-1H-indanone (9).

[0115] In a magnetically charged reactor, 1.50 g (0.010 mol) of 7-fluoro-2,3-dihydro-1H-indanone, 2.04 g (0.015 mol) of 4-methoxybenzaldehyde, 1.70 g (0.02 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 50 °C with stirring and monitored by TLC for 16 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 2.47 g of a yellow solid, with a yield of 74%.

[0116] The compound 1 H RMR, 13 The C NMR and MS data are as follows. 1 H RMR, 13 C NMR respectively as follows Figure 19 and Figure 20 .

[0117] 1 H NMR (400MHz, DMSO-d6) δ: 7.76–7.61 (m, 2H), 7.49 (t, J = 7.7Hz, 1H), 7.37 (s, 1H), 7.09–7.01 (m, 3H), 6.84 (d,J=8.2Hz,1H),3.97(s,2H),3.82(s,3H),3.12(t,J=5.3Hz,4H),1.75–1.69(m,5H),1.65–1.47(m,3H).

[0118] 13 C NMR (100MHz, DMSO-d6) δ: 190.7,160.2,152.6,152.1,135.6,133.5,132.2 ,130.6,127.9,127.1,117.1,114.8,114.5,55.4,52.2,31.8,25.6,23.7.

[0119] MS(ESI) m / z: 334.2 [M+H] + ].

[0120] Example 10

[0121] Preparation of (E)-4-((1-O-7-(piperidin-1-yl)-1,3-dihydro-2H-indene-2-ylmethylene)methyl)benzoic acid (10).

[0122] In a magnetically charged reactor, 1.50 g (0.010 mol) of 7-fluoro-2,3-dihydro-1H-indanone, 2.25 g (0.015 mol) of 4-formylbenzoic acid, 1.70 g (0.02 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 50 °C with stirring and monitored by TLC for 16 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 2.64 g of a yellow solid, with a yield of 76%.

[0123] The compound 1 H RMR, 13 The C NMR and MS data are as follows. 1 H RMR, 13 C NMR respectively as follows Figure 21 and Figure 22 .

[0124] 1 H NMR (400MHz, DMSO-d6) δ: 8.01 (d, J=8.1Hz, 2H), 7.83 (d, J=8.1Hz, 2H), 7.54–7.47 (m, 1H), 7.43 (s, 1H), 7.02 (d, J= 7.4Hz, 1H), 6.84 (dd, J=8.5, 2.8Hz, 1H), 4.05 (s, 2H), 3.12 (t, J=5.2Hz, 4H), 1.74–1.69 (m, 4H), 1.61–1.50 (m, 2H).

[0125] 13 C NMR (100MHz, DMSO-d6) δ: 190.3,166.9,152.7,152.2,139.5,138.2,136.1 ,130.8,130.4,129.8,129.3,126.7,116.9,114.9,52.1,31.8,25.6,23.7.

[0126] MS(ESI) m / z: 348.1 [M+H] + ].

[0127] Example 11

[0128] (E)-5-(1-piperidinyl)-2-(pyridin-4-methylene)-2,3-dihydro-1H-indanone (1) was prepared by heating at 25°C.

[0129] In a magnetically charged reactor, 1.50 g (0.010 mol) of 5-fluoro-2,3-dihydro-1H-indanone, 1.61 g (0.015 mol) of pyridine-4-carboxaldehyde, 1.70 g (0.02 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 25 °C with stirring and monitored by TLC for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 0.76 g of a yellow solid, with a yield of 25%. The compound... 1 H RMR, 13 The C NMR and MS data are consistent with those of Example 1.

[0130] Example 12

[0131] (E)-5-(1-piperidinyl)-2-(pyridin-4-methylene)-2,3-dihydro-1H-indanone (1) was prepared by heating at 80 °C.

[0132] In a magnetically charged reactor, 1.50 g (0.010 mol) of 5-fluoro-2,3-dihydro-1H-indanone, 1.61 g (0.015 mol) of pyridine-4-carboxaldehyde, 1.70 g (0.02 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 80 °C with stirring and monitored by TLC for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 0.42 g of a yellow solid, with a yield of 14%. 1 H RMR, 13 The C NMR and MS data are consistent with those of Example 1.

[0133] Example 13

[0134] The molar ratio of 5-fluoro-2,3-dihydro-1H-indanone, pyridine-4-carboxaldehyde, and piperidine to indanone (1) was 1:1.5:1.

[0135] In a magnetically charged reactor, 1.50 g (0.010 mol) of 5-fluoro-2,3-dihydro-1H-indanone, 1.61 g (0.015 mol) of pyridine-4-carboxaldehyde, 0.85 g (0.01 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 50 °C with stirring and monitored by TLC for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 1.28 g of a yellow solid, with a yield of 42%. The compound... 1 H RMR, 13 The C NMR and MS data are consistent with those of Example 1.

[0136] Example 14

[0137] The molar ratio of 5-fluoro-2,3-dihydro-1H-indanone, pyridine-4-carboxaldehyde, and piperidine to (E)-5-(1-piperidinyl)-2-(pyridin-4-methylene)-2,3-dihydro-1H-indanone (1) was 1:1.5:1.8.

[0138] In a magnetically charged reactor, 1.50 g (0.010 mol) of 5-fluoro-2,3-dihydro-1H-indanone, 1.61 g (0.015 mol) of pyridine-4-carboxaldehyde, 1.53 g (0.018 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 50 °C with stirring and monitored by TLC for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 2.63 g of a yellow solid, with a yield of 51%. The compound... 1 H RMR, 13 The C NMR and MS data are consistent with those of Example 1.

[0139] Example 15

[0140] The molar ratio of 5-fluoro-2,3-dihydro-1H-indanone (1), pyridine-4-carboxaldehyde and piperidine was 1:1.1:2.5.

[0141] In a magnetically charged reactor, 1.50 g (0.010 mol) of 5-fluoro-2,3-dihydro-1H-indanone, 1.18 g (0.011 mol) of pyridine-4-carboxaldehyde, 2.13 g (0.025 mol) of piperidine, and 10 mL of ethanol were added. The mixture was heated to 50 °C with stirring and monitored by TLC for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The reactants were extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to column chromatography to give 2.95 g of a yellow solid, with a yield of 58%. The compound... 1 H RMR, 13 The C NMR and MS data are consistent with those of Example 1.

[0142] Comparative Example 1

[0143] The reaction was carried out using 2,3-dihydro-1H-indanone as a substrate.

[0144] In a reactor with magnetic flux, 2,3-dihydro-1H-indanone (1.32 g, 0.010 mol), pyridine-4-carboxaldehyde (1.61 g, 0.015 mol), piperidine (1.70 g, 0.02 mol), and 10 mL of ethanol were added. The mixture was heated to 50 °C and stirred. The reaction was monitored by TLC. The target compound with the following formula could not be obtained.

[0145] Comparative Example 2

[0146] The reaction was carried out using 4-fluoro-2,3-dihydro-1H-indanone as a substrate.

[0147] In a reactor with magnetic flux, 1.50 g of 4-fluoro-2,3-dihydro-1H-indanone (0.010 mol), 1.61 g of pyridine-4-carboxaldehyde (0.015 mol), 1.70 g of piperidine (0.02 mol), and 10 mL of ethanol were added. The mixture was heated to 50 °C and stirred. The reaction was monitored by TLC. The target compound with the following formula could not be obtained.

[0148] As can be seen from the above examples and comparative examples, using 5 or 7-fluoro-2,3-dihydro-1H-indanone (compound (II)), piperidine or morpholine (compound (III)), and aromatic formaldehyde (compound (IV)) in a solvent under stirring and heating, an Aldol condensation reaction can occur, and simultaneously a nucleophilic substitution reaction can occur, yielding 5 or 7-(piperidinyl or morpholinyl)-2-(aromatic-methylene)-2,3-dihydro-1H-indanone (compound (I)) in a one-pot reaction. Using 4 or 6... Replacing 5- or 7-fluoro-2,3-dihydro-1H-indanone with 2,3-dihydro-1H-indanone prevents the nucleophilic substitution reaction, thus failing to yield the target compound (Comparative Example 2). Using 2,3-dihydro-1H-indanone instead of 5- or 7-fluoro-2,3-dihydro-1H-indanone also fails to induce the Aldol condensation reaction under the same conditions, failing to yield the target compound (Comparative Example 1). This demonstrates that the method described in this application has very stringent requirements regarding the substrate, and the substrate cannot be arbitrarily changed.

[0149] The yields of the target compounds in Examples 1 to 10, 14, and 15 were all above 50%, while the yields in Examples 11, 12, and 13 were all below 50%. The comparison shows that: ① the reaction temperature affects the yield of the target compounds, with a higher yield at a heating temperature of 50°C; ② the ratio of the three substrates affects the yield of the target compounds. Preferably, the molar ratio of compounds (II), (III), and (IV) is 1:1.1–1.5:1.8–2.5, with the optimal ratio being 1:1.5:2.

[0150] In summary, this application provides a novel 2,3-dihydro-1H-indanone derivative compound (Ⅰ). Furthermore, by reacting compounds (Ⅱ), (Ⅲ), and (Ⅳ) under specific conditions, compound (Ⅰ) can be obtained in one step with a high yield. The reaction is simpler and less costly, providing strong support for further research and application of 2,3-dihydro-1H-indanone compounds.

[0151] It is understood that those skilled in the art can combine various implementation methods in the above embodiments under the guidance of the above examples to obtain technical solutions with multiple implementation methods.

[0152] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the one-pot preparation of 2,3-dihydro-lH-indenone derivatives (I) characterized in that, The method comprises: The 2,3-dihydro-1H-indenone compound (II), the saturated six-membered heterocyclic compound (III), and the aromatic aldehyde compound (IV) are mixed in a mass ratio of 1:1.1-1.5:1.8-2.5, and the reaction is carried out by stirring and heating in a solvent; and the compound (I) is separated after the reaction is completed. The structures of the compound (I), the compound (II), the compound (III), and the compound (IV) are respectively as follows: wherein R1is an aromatic group, and X is C or O, or F is located at the 5- or 7-position of the 2,3-dihydro-lH-indenone.

2. The method of claim 1, wherein, The temperature for the reaction by heating is 25-80 DEG C.

3. The method of claim 1, wherein, The temperature for the reaction by heating is 50 DEG C.

4. The method of claim 1, wherein, The compound (IV) is at least one selected from the following:

5. The method of claim 1, wherein, The compound (III) is piperidine.

6. The method of claim 1, wherein, The solvent is one or more of ethanol, acetonitrile, tetrahydrofuran, and dichloromethane.

7. The method of claim 1, wherein, The reaction time for the reaction by stirring and heating in the solvent is 2-16 hours.

8. The method of claim 1, wherein, The weight-volume ratio of the piperidine to the solvent is 1g:1ml-100ml.

9. The method of claim 1, wherein, The compound (I) is one of the following:

10. The method of claim 1, wherein, The separation of the compound (I) after the reaction is completed comprises: monitoring by TLC until the reaction is completed, removing the solvent by rotary evaporation, extracting with ethyl acetate, drying with anhydrous sodium sulfate, and separating the compound (I) by column chromatography.

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