Synthesis method of polysubstituted indole propionate derivative

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of a polysubstituted indole propionate derivative. According to the invention, an aryl acetate compound and a sulfonyl indole compound are used as raw materials, and an organic small molecule catalyst such as isothiourea is used for reaction to obtain the compound. The reaction raw materials are simple and easy to obtain, the reaction condition is mild, the operation is simple and convenient, the reaction time is short, and good diastereoselectivity and high yield are achieved; the defects and deficiencies of the existing synthesis method for preparing the polysubstituted indole propionate derivative in a noninvasive manner are overcome, and the method has the characteristics of high efficiency, simplicity, convenience and wide universality.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing multi-substituted indole propionate derivatives. Background Art

[0002] The multi-substituted indole propionate skeleton structure is an important structural unit of many active pharmaceutical molecules and natural products, and exhibits excellent pharmacological activities in aspects such as antidepressant, anti-anxiety drugs, and antibacterial biological activities (J.Clin.Endocrinol.Metab. 2018, 103, 3083 - 3093; J.Fluoresc. 2017, 27, 1495 - 1503.), and has broad application prospects. Therefore, developing efficient and simple strategies to synthesize such skeleton compounds has potential application value in real life.

[0003] Currently, the most common method for synthesizing indole propionate compounds is the Friedel-Crafts reaction of indole. For example: In 2017, the Cheng Jinpei research group reported a novel method for constructing indole propionate through two-step reactions of Friedel-Crafts reaction and hydrolysis of squaric acid amide-catalyzed indole and acyl phosphate (Org.Lett, 2017, 19, 1926 - 1929); in 2019, the Wang Jian research group reported the reaction of N-heterocyclic carbene-catalyzed indole and α,β-unsaturated aldehyde to synthesize indole propionic acid (Adv.Synth.Catal, 2019, 24, 5704 - 5708). Due to the defects of the methods, these strategies can only synthesize monosubstituted indole propionates, and still cannot accurately achieve the synthesis of multi-substituted indole propionates. In particular, 2-aryl indole propionates still cannot be achieved through the existing strategies, which also limits the study of the structure-activity relationship of compounds and hinders the application of this method in actual production. Therefore, it is of great significance to develop a synthesis method for efficiently, simply, and metal-free preparation of multi-substituted indole propionate derivatives. Summary of the Invention

[0004] Based on the above purposes, the purpose of the present application is to overcome the disadvantages and deficiencies of the existing synthesis methods of indole propionate derivatives, and provide a synthesis method for preparing multi-substituted indole propionate derivatives with high yield and good diastereoselectivity starting from simple and easily available raw materials through the catalysis of organic small molecule isothiourea.

[0005] To this end, the technical solution of the present application discloses a method for synthesizing multi-substituted indole propionate derivatives, which includes reacting an aryl acetate compound with a sulfonyl indole compound under the conditions of a basic reagent and a catalyst and then purifying to obtain;

[0006] Among them, the aryl acetate compound has the structural formula shown in Formula I;

[0007] The sulfonyl indole compounds have the structural formula shown in Formula II;

[0008] The polysubstituted indole propionate derivatives have the structural formula shown in Formula III;

[0009]

[0010] In the formula, R 1 is one of hydrogen, C1-C4 alkyl, trifluoromethyl, alkoxy, halogen, phenyl, ester carbonyl, cyano, nitro connected to any position on the benzene ring;

[0011] R 2 is one of alkyl or aryl.

[0012] Furthermore, the addition equivalent ratio of the aryl acetate compounds, sulfonyl indole compounds, basic reagent, and catalyst is 1:1-2:2-4:0.1-0.2.

[0013] Furthermore, the catalyst is any one of isothiourea, N-heterocyclic carbene, and squaramide.

[0014] Preferably, the catalyst is isothiourea.

[0015] Furthermore, the basic reagent is K 3 PO 4。

[0016] Furthermore, the reaction conditions are to react at 25-100 °C for 10-24 hours.

[0017] Preferably, the reaction conditions are to react at 25 °C for 18 hours.

[0018] Furthermore, the reaction is carried out in at least one organic solvent such as acetonitrile, ethanol, tetrahydrofuran, toluene, chlorobenzene, 1,2-dichloroethane, and dioxane.

[0019] And the polysubstituted indole propionate derivatives obtained according to the above synthesis method.

[0020] The beneficial effects of this application are:

[0021] (1) The present invention provides a synthesis method for preparing polysubstituted indole propionate derivatives with good diastereoselectivity and high yield under mild reaction conditions without metal using simple and readily available raw materials, overcoming the disadvantages and deficiencies of the existing synthesis methods for preparing polysubstituted indole propionate derivatives. In summary, the synthesis method of the present invention has the characteristics of high efficiency, simplicity, and wide generality.

[0022] (2) The preparation conditions of the present invention are mild, without the need for anhydrous and anaerobic conditions, the operation is simple, the reaction time is short, the reaction yield is high, and it has good diastereoselectivity.

[0023] (3) The preparation method of the present invention is carried out under metal conditions, and there is no metal residue in the product.

[0024] (4) The raw materials used in the preparation method of the present invention are simple and easily available, and have good substrate applicability.

[0025] (5) The preparation method of the present invention has completed scale-up experiments in the laboratory, and the effect is good, which can meet the large-scale application and development in the fields of biomedicine and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the hydrogen spectrum of Compound 1 in Example 1 of the present invention.

[0027] Figure 2 is the carbon spectrum of Compound 1 in Example 1 of the present invention.

[0028] Figure 3 is the hydrogen spectrum of Compound 2 in Example 2 of the present invention.

[0029] Figure 4 is the carbon spectrum of Compound 2 in Example 2 of the present invention.

[0030] Figure 5 is the hydrogen spectrum of Compound 3 in Example 3 of the present invention.

[0031] Figure 6 is the carbon spectrum of Compound 3 in Example 3 of the present invention.

[0032] Figure 7 is the hydrogen spectrum of Compound 4 in Example 4 of the present invention.

[0033] Figure 8 is the carbon spectrum of Compound 4 in Example 4 of the present invention.

[0034] Figure 9 is the hydrogen spectrum of Compound 5 in Example 5 of the present invention.

[0035] Figure 10 is the carbon spectrum of Compound 5 in Example 5 of the present invention.

[0036] Figure 11 is a preferred synthetic reaction process diagram of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0037] The present invention will be further described in detail below in conjunction with specific embodiments. These embodiments are implemented on the premise of the technology of the present invention, and the detailed implementation manners and specific operation processes are given to illustrate the creativity of the present invention. However, the protection scope of the present invention is not limited to the following embodiments.

[0038] An embodiment of the present application provides a method for synthesizing a multi-substituted indole propionate derivative, which includes reacting an aryl acetate compound with a sulfonyl indole compound under the conditions of a basic reagent and a catalyst and then purifying to obtain;

[0039] Among them, the aryl acetate compound has the structural formula shown in Formula I;

[0040] The sulfonyl indole compound has the structural formula shown in Formula II;

[0041] The multi-substituted indole propionate derivative has the structural formula shown in Formula III;

[0042]

[0043] In the formula, R 1 is one of hydrogen, C1-C4 alkyl, trifluoromethyl, alkoxy, halogen, phenyl, ester carbonyl, cyano, nitro connected to any position on the benzene ring;

[0044] R 2 is one of alkyl or aryl.

[0045] The above reaction uses isothiourea, N-heterocyclic carbene, Squaramide any one of them as the catalyst, and among them, isothiourea has the best catalytic effect; it is carried out under the basic condition mediated by K 3 PO 4 mediated basic conditions.

[0046] In the above reaction, the addition equivalent ratio of the aryl acetate compound, the sulfonyl indole compound, the basic reagent, and the catalyst is 1:2:2:0.2. The reaction conditions are to react at 25-100 °C for 10-24 hours, preferably to react at 25 °C for 18 hours.

[0047] In the above reaction, the reaction is carried out in at least one organic solvent among acetonitrile, ethanol, tetrahydrofuran, toluene, chlorobenzene, 1,2-dichloroethane, dioxane, and preferably chlorobenzene.

[0048] Figure 11 is the reaction process of a preferred embodiment of the present application. Among them, an aryl acetate compound and a sulfonyl indole compound are used as raw materials, isothiourea is used as the catalyst, chlorobenzene is used as the solvent, and potassium phosphate (K 3 PO 4is a basic additive, and the reaction product (multi-substituted indole propionate derivative) is obtained by reacting at room temperature (rt) for 18 h.

[0049] Compared with the prior art, the reaction raw materials are simple to obtain, no metal raw materials need to be added, the reaction conditions are mild, the operation is simple, the reaction time is short, the reaction yield is high, and it has good diastereoselectivity.

[0050] It should be noted that after the reaction is completed, the reaction product needs to be separated and purified. The separation and purification method is a common method in the art. For example, it can be slurried with petroleum ether and ethyl acetate at 5:1, column chromatography, etc. This application does not make special restrictions.

[0051] Next, the reaction method and technical effects of this application will be specifically described with specific examples.

[0052] Example 1

[0053] Prepare the multi-substituted indole propionate compound 1 with the following structural formula:

[0054]

[0055] Take a 10 mL dry reaction tube, and successively add 2,4,6-trichlorophenyl-2-phenylacetate (aryl acetate compound) (0.1 mmol), 3-(p-toluenesulfonylmethyl)-1H-indole (sulfonyl indole compound) (0.2 mmol), isothiourea catalyst (20 mol%), K 3 PO 4 (0.2 mmol) and solvent chlorobenzene solution (2.0 mL). The whole reaction system is exposed to air without argon protection. Subsequently, the whole mixture system in the reaction tube is reacted at 25 °C for 18 hours. Cool to room temperature, and obtain the crude product by vacuum distillation. Then, separate and purify it by column chromatography to obtain a yellow solid product with a yield of 76%. The structural characterization data are as follows:

[0056] 1 1H NMR (600 MHz, DMSO-d6) δ 10.71 (1H, d, J 2.5), 7.66–7.58 (5H, m), 7.56–7.50 (2H, m), 7.45 (1H, d, J 2.5), 7.17 (2H, s), 7.17–7.10 (2H, m), 7.05 (2H, d, J 7.8), 6.93 (1H, ddd, J 8.1, 7.0, 1.2), 6.86 (1H, ddd, J 8.0, 7.0, 1.0), 5.29 (1H, d, J 12.5), 5.06 (1H, d, J12.5), 2.18 (3H, s); The hydrogen spectrum is shown in the appendix Figure 1 .

[0057] 13 C NMR(151MHz, DMSO-d6) δ 169.91, 142.73, 141.14, 137.46, 136.09, 135.53, 131.81, 129.29, 129.09, 129.07, 128.85, 128.67, 127.91, 127.05, 123.05, 121.25, 118.79, 118.76, 115.99, 111.58, 55.34, 44.51, 21.02. Its carbon spectrum is shown in the appendix Figure 2 。

[0058] HR-MS(ESI-TOF) calcd for C 30 H 23 Cl 3 NO 2 + [M + H] + , the theoretical value is 534.0789, and the measured value is 534.0784.

[0059] Example 2

[0060] Prepare the polysubstituted indole propionate compound 2 with the following structural formula:

[0061]

[0062] Take a 10 mL dry reaction tube, and successively add 2,4,6-trichlorophenyl 2-(4-methoxyphenyl)acetate (aryl acetate compound) (0.1 mmol), 3-(p-toluenesulfonylmethyl)-1H-indole (0.2 mmol) (sulfonyl indole compound), isothiourea catalyst (20 mol%), K 3 PO 4 (0.2 mmol) and chlorobenzene solution (2.0 mL) as the solvent. The whole reaction system is exposed to air without argon protection. Subsequently, the whole mixture system in the reaction tube is reacted at 25 °C for 18 hours. Cool to room temperature, and obtain the crude product by vacuum distillation. Then, separate and purify it by column chromatography to obtain a yellow solid product with a yield of 74%. The structural characterization data are as follows:

[0063] 1 H NMR(400MHz, CDCl 3) δ 7.80 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.43 (dd, J = 14.7, 8.3 Hz, 4H), 7.17 (d, J = 5.2 Hz, 3H), 7.10–6.96 (m, 4H), 6.90 (d, J = 2.0 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 5.10 (d, J = 12.3 Hz, 1H), 4.82 (d, J = 12.3 Hz, 1H), 3.70 (s, 3H), 2.26 (s, 3H); The hydrogen NMR spectrum is shown in the appendix Figure 3 .

[0064] 13 C NMR (101 MHz, CDCl 3 ) δ 169.54, 158.98, 142.72, 139.65, 136.09, 135.97, 131.75, 129.85, 129.74, 129.21, 128.58, 128.53, 128.32, 126.94, 121.91, 121.68, 119.33, 119.26, 116.86, 113.87, 110.92, 55.83, 55.16, 44.82, 21.01. The carbon NMR spectrum is shown in the appendix Figure 4 。

[0065] HR-MS (ESI-TOF) calcd for C 31 H 25 Cl 3 NO 3 + [M + H] + , theoretical value 564.0895, measured value 564.0895.

[0066] Example 3

[0067] Prepare the polysubstituted indole propionate compound 3 with the following structural formula:

[0068]

[0069] Take a 10 mL dry reaction tube and successively add 2,4,6-trichlorophenyl 2-(3-methoxyphenyl)acetate (0.1 mmol) (aryl acetate compound), 3-(p-toluenesulfonylmethyl)-1H-indole (0.2 mmol) (sulfonyl indole compound), isothiourea catalyst (20 mol%), K 3 PO 4(0.2 mmol) and chlorobenzene solution of the solvent (2.0 mL). The entire reaction system was exposed to air without argon protection. Subsequently, the entire mixture in the reaction tube was reacted at 25 °C for 18 hours. After cooling to room temperature, the crude product was obtained by distillation under reduced pressure, and then purified by column chromatography to obtain a yellow solid product with a yield of 74%. The structural characterization data are as follows:

[0070] 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (s, 1H), 7.51 (t, J = 8.8 Hz, 1H), 7.45 (d, J = 7.9 Hz, 2H), 7.19–6.85 (m, 12H), 6.74–6.46 (m, 1H), 5.11 (d, J = 12.2 Hz, 1H), 4.85 (d, J = 12.2 Hz, 1H), 3.68 (s, 3H), 2.26 (s, 3H): The hydrogen NMR spectrum is shown in the appendix Figure 5 .

[0071] 13 C NMR (101 MHz, CDCl 3 ) δ 169.18, 159.47, 142.72, 139.53, 137.91, 136.14, 135.95, 131.80, 129.75, 129.39, 129.22, 128.50, 128.34, 126.91, 121.92, 121.61, 121.36, 119.34, 119.24, 116.81, 114.40, 113.32, 110.92, 56.65, 55.21, 44.78, 21.02. The carbon NMR spectrum is shown in the appendix Figure 6 .

[0072] HR-MS (ESI-TOF) calcd for C 31 H 25 Cl 3 NO 3 + [M + H] + , theoretical value 564.0895, measured value 564.0895.

[0073] Example 4

[0074] Prepare the polysubstituted indole propionate compound 4 with the following structural formula:

[0075]

[0076] Take a 10 mL dry reaction tube and sequentially add 2,4,6-trichlorophenyl 2-(2-bromophenyl)acetate (0.1 mmol) (aryl acetate compound), 3-(p-toluenesulfonylmethyl)-1H-indole (0.2 mmol) (sulfonyl indole compound), isothiourea catalyst (20 mol%), K 3 PO 4 (0.2 mmol) and solvent chlorobenzene solution (2.0 mL). The entire reaction system is exposed to air without argon protection. Subsequently, the entire mixture in the reaction tube is reacted at 25 °C for 18 hours. Cool to room temperature, and obtain the crude product by distillation under reduced pressure. Then, separate and purify it by column chromatography to obtain a yellow solid product with a yield of 65%. The structure characterization data are as follows:

[0077] dr: 9:1 1 1H NMR (600 MHz, DMSO) δ 11.05 (s, 0.1H), 10.82 (s, 0.9H), 7.93 (d, J = 7.0 Hz, 0.1H), 7.82 (d, J = 7.0 Hz, 0.9H), 7.61 (ddd, J = 55.1, 41.3, 8.3 Hz, 6H), 7.32–7.09 (m, 6H), 7.00–6.85 (m, 2H), 5.64 (d, J = 12.5 Hz, 0.1H), 5.56 (d, J = 12.4 Hz, 0.9H), 5.24 (t, J = 11.4 Hz, 1H), 2.22 (s, 2.7H), 2.09 (s, 0.3H); The hydrogen spectrum is shown in the appendix Figure 7 .

[0078] 13 13C NMR (151 MHz, DMSO) δ 168.96, 142.57, 140.23, 136.23, 136.12, 135.94, 133.20, 131.99, 130.08, 129.60, 129.34, 129.14, 128.91, 128.77, 128.60, 126.84, 126.06, 121.83, 121.53, 119.02, 118.87, 115.68, 111.70, 54.20, 44.47, 21.03. The carbon spectrum is shown in the appendix Figure 8 。

[0079] HR-MS (ESI-TOF) calcd for C 30 H 22 BrCl 3 NO 2 + [M + H] + , theoretical value 611.9894, measured value 611.9895.

[0080] Example 5

[0081] Prepare the polysubstituted indole propionate compound 5 with the following structural formula:

[0082]

[0083] Take a 10 mL dry reaction tube and successively add 2,4,6-trichlorophenyl 2-(thiophen-2-yl)acetate (0.1 mmol) (aryl acetate compound), 3-(p-toluenesulfonylmethyl)-1H-indole (0.2 mmol) (sulfonyl indole compound), isothiourea catalyst (20 mol%), K 3 PO 4 (0.2 mmol) and a solution of chlorobenzene as the solvent (2.0 mL). The entire reaction system is exposed to air without argon protection. Subsequently, the entire mixture in the reaction tube is reacted at 25 °C for 18 hours. Cool to room temperature, and obtain the crude product by distillation under reduced pressure. Then, separate and purify it by column chromatography to obtain a yellow solid product with a yield of 65%. The structural characterization data are as follows:

[0084] 1 1H NMR (400 MHz, Chloroform-d) δ 7.82 (1H, s), 7.49 (3H, dd, J 47.4, 7.8), 7.21–6.96 (10H, m), 6.81 (1H, dd, J 5.2, 3.5), 5.17 (1H, d, J 12.2), 5.08 (1H, d, J 12.2), 2.25 (3H, s): The 1H NMR spectrum is shown in the appendix Figure 9 .

[0085] 13 13C NMR (101 MHz, Chloroform-d) δ 168.50, 142.65, 139.19, 138.82, 136.34, 135.97, 131.94, 129.70, 129.31, 128.45, 128.40, 127.19, 126.89, 126.58, 125.24, 122.02, 121.34, 119.44, 119.17, 116.76, 111.00, 51.74, 46.29, 21.02. The 13C NMR spectrum is shown in the appendix Figure 10 。

[0086] HR-MS (ESI-TOF) calcd for C 28 H 21 Cl 3 NO 2 S + [M+H] +, theoretical value 540.0353, measured value 540.0354

[0087] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the purpose and scope of the technical solutions of the present invention, and they should all be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing a polysubstituted indole propionic acid ester derivative, characterized in that: The method comprises reacting an arylacetate compound with a sulfonyl indole compound under alkaline reagent and catalyst conditions and then purifying the compound; Wherein, the aromatic acetate compound has the structural formula shown in Formula I; The sulfonylindole compound has a structural formula shown in Formula II; The polysubstituted indole propionic acid ester derivative has the structural formula shown in Formula III; In the formula, R 1 is one of hydrogen, C1-C4 alkyl, trifluoromethyl, alkoxy, halogen, phenyl, ester carbonyl, cyano and nitro connected to any position of the benzene ring; R 2 It is an alkyl group or an aryl group.

2. The synthesis method according to claim 1, characterized in that: The equivalent ratio of the aromatic acetate compound, the sulfonylindole compound, the alkaline reagent and the catalyst is 1:1-2:2-4:0.1-0.

2.

3. The synthesis method according to claim 1, characterized in that: The catalyst is any one of isothiourea, azacarbene and squaramide.

4. The synthesis method according to claim 1, characterized in that: The catalyst is isothiourea.

5. The synthesis method according to claim 1, characterized in that: The alkaline reagent is K3PO4.

6. The synthesis method according to claim 1, characterized in that: The reaction conditions are 25-100° C. and 10-24 hours.

7. The synthesis method according to claim 4, characterized in that: The reaction conditions are 25° C. for 18 hours.

8. The synthesis method according to claim 1, characterized in that: The reaction is carried out in any one organic solvent selected from the group consisting of acetonitrile, ethanol, tetrahydrofuran, toluene, chlorobenzene, 1,2-dichloroethane and dioxane.

9. A polysubstituted indole propionic acid ester derivative obtained according to any one of the synthesis methods of claims 1-8.

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