A method for synthesizing a polysubstituted indole propionic acid ester derivative

Abstract

The application belongs to the field of organic synthesis and particularly relates to a synthesis method of polysubstituted indole propionate derivatives. Aryl acetate compounds and sulfonyl indole compounds are used as raw materials, and the reaction is carried out through an isothiourea organic small molecule catalyst. The reaction raw materials are simple and easy to obtain, the reaction conditions are mild, the operation is simple, the reaction time is short, the reaction has good diastereoselectivity and high yield, the synthesis method of the polysubstituted indole propionate derivatives overcomes the defects and deficiencies of the existing synthesis method, and has the characteristics of high efficiency, simplicity and wide universality.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing polysubstituted indole propionate derivatives. Background Technology

[0002] The polysubstituted indolepropionate skeleton is an important structural unit in many active drug molecules and natural products, exhibiting excellent pharmacological activities in antidepressant, anxiolytic, and antibacterial applications (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 these skeleton compounds has potential application value in practical life.

[0003] Currently, the most common method for synthesizing indole propionate compounds is the Friedel-Crafts reaction of indole. For example, in 2017, Cheng Jinpei's research group reported a novel two-step reaction catalyzed by squaric acid amide to synthesize indole propionate from acyl phosphate via Friedel-Crafts reaction and hydrolysis (Org. Lett, 2017, 19, 1926-1929); in 2019, Wang Jian's research group reported the synthesis of indole propionic acid via the reaction of indole with α,β-unsaturated aldehydes catalyzed by N-heterocarbene (Adv. Synth. Catal, 2019, 24, 5704-5708). Due to the limitations of these methods, these strategies can only synthesize monosubstituted indole propionate esters and cannot accurately achieve the synthesis of polysubstituted indole propionate esters, especially 2-aryl indole propionate, which still cannot be achieved by existing strategies. This limits the study of structure-activity relationships of compounds and hinders the application of this method in practical production. Therefore, it is of great significance to develop an efficient, simple, and metal-free synthetic method for preparing multi-substituted indole propionate derivatives. Summary of the Invention

[0004] Based on the above objectives, the purpose of this application is to overcome the shortcomings and deficiencies of existing synthetic methods for indole propionate derivatives, and to provide a synthetic method for preparing polysubstituted indole propionate derivatives with high yield and good diastereoselectivity by starting from simple and readily available raw materials and catalyzing with small organic molecule isothiourea.

[0005] Therefore, the technical solution of this application discloses a method for synthesizing multisubstituted indole propionate derivatives, which includes reacting aryl acetate compounds with sulfonyl indole compounds under alkaline reagent and catalyst conditions and then purifying them;

[0006] The aryl acetate compounds have the structural formula shown in Formula I;

[0007] The sulfonyl indole compound has the structural formula shown in Formula II;

[0008] The polysubstituted indole propionate derivative has the structural formula shown in Formula III.

[0009]

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

[0011] R 2 It is an alkyl or aryl group.

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

[0013] Furthermore, the catalyst is any one of isothiourea, azacarbene, and squaric acid amide.

[0014] Preferably, the catalyst is isothiourea.

[0015] Furthermore, the alkaline reagent is K3PO4. 4。

[0016] Furthermore, the reaction conditions are 25–100°C for 10–24 hours.

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

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

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

[0020] The beneficial effects of this application are as follows:

[0021] (1) This invention provides a synthetic method for preparing polysubstituted indole propionate derivatives using readily available raw materials under mild, metal-free reaction conditions, with good diastereoselectivity and high yield, overcoming the shortcomings and deficiencies of existing synthetic methods for preparing polysubstituted indole propionate derivatives. In summary, the synthetic method of this invention is characterized by high efficiency, simplicity, and wide applicability.

[0022] (2) The preparation conditions of this invention are mild, do not require anhydrous and oxygen-free conditions, are easy to operate, have a short reaction time, a high reaction yield, and good diastereoselectivity.

[0023] (3) The preparation method of the present invention is prepared under metal conditions, and the product has no metal residue.

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

[0025] (5) The preparation method of the present invention has been scaled up in the laboratory and the results are good, which can meet the needs of large-scale application and development in the fields of biomedicine. Attached Figure Description

[0026] Figure 1 This is the hydrogen spectrum of compound 1 from Example 1 of the present invention.

[0027] Figure 2 This is the carbon spectrum of compound 1 from Example 1 of the present invention.

[0028] Figure 3 This is the hydrogen spectrum of compound 2 from Example 2 of the present invention.

[0029] Figure 4 This is the carbon spectrum of compound 2 from Example 2 of the present invention.

[0030] Figure 5 This is the hydrogen spectrum of compound 3 from Example 3 of the present invention.

[0031] Figure 6 This is the carbon spectrum of compound 3 from Example 3 of the present invention.

[0032] Figure 7 This is the hydrogen spectrum of compound 4 from Example 4 of the present invention.

[0033] Figure 8 This is the carbon spectrum of compound 4 from Example 4 of the present invention.

[0034] Figure 9 This is the hydrogen spectrum of compound 5 from Example 5 of the present invention.

[0035] Figure 10 This is the carbon spectrum of compound 5 from Example 5 of the present invention.

[0036] Figure 11 This is a preferred synthesis reaction process diagram of the present invention. Detailed Implementation

[0037] The present invention will be further described in detail below with reference to specific embodiments. This embodiment is implemented based on the technology of the present invention, and detailed implementation methods and specific operating procedures are given to illustrate the inventiveness of the present invention. However, the scope of protection of the present invention is not limited to the following embodiments.

[0038] The embodiments of this application provide a method for synthesizing a polysubstituted indole propionate derivative, which includes reacting an aryl acetate compound with a sulfonyl indole compound under alkaline reagent and catalyst conditions and then purifying the compound.

[0039] The aryl acetate compounds have the structural formula shown in Formula I;

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

[0041] The polysubstituted indole propionate derivative has the structural formula shown in Formula III.

[0042]

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

[0044] R 2 It is an alkyl or aryl group.

[0045] The above reactions use isothiourea, azacarbene, Squamous acid amide Any one of the catalysts can be used, with isothiourea showing the best catalytic effect; the process is carried out under alkaline conditions mediated by K3PO4.

[0046] In the above reaction, the 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 25–100°C for 10–24 hours, preferably 25°C for 18 hours.

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

[0048] Figure 11 The reaction process of a preferred embodiment of this application is as follows: aryl acetate compounds and sulfonyl indole compounds are used as raw materials, isothiourea is used as a catalyst, chlorobenzene is used as a solvent, and potassium phosphate (K3PO4) is used as an alkaline additive. The reaction is carried out at room temperature (rt) for 18 hours to obtain the reaction product (polysubstituted indole propionate derivative).

[0049] Compared with existing technologies, this reaction has simple and readily available raw materials, requires no addition of metal raw materials, has mild reaction conditions, is easy to operate, has a short reaction time, high reaction yield, and good non-corresponding selectivity.

[0050] It should be noted that after the reaction is completed, the reaction product needs to be separated and purified. The separation and purification methods are common in the field, such as slurrying of petroleum ether and ethyl acetate in a 5:1 ratio, column chromatography, etc. This application does not impose any special restrictions.

[0051] The reaction method and technical effects of this application will be described in detail below with reference to specific embodiments.

[0052] Example 1

[0053] Prepare the following polysubstituted indole propionate compound 1:

[0054]

[0055] A 10 mL dry reaction tube was used, and 0.1 mmol of 2,4,6-trichlorophenyl-2-phenylacetic acid ester (aryl acetate compound), 0.2 mmol of 3-(p-toluenesulfonylmethyl)-1H-indole (sulfonylindole compound), 20 mol% isothiourea catalyst, 0.2 mmol of K3PO4, and 2.0 mL of chlorobenzene solution were added sequentially. The entire reaction system was exposed to air without argon protection. The mixture in the reaction tube was then reacted at 25 °C for 18 hours. After cooling to room temperature, the crude product was obtained by vacuum distillation, followed by purification 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 (600MHz, DMSO-d⁶) δ 10.71 (¹H, d, J 2.5), 7.66–7.58 (⁵H, m), 7.56–7.50 (⁂H, m), 7.45 (¹H, d, J 2.5), 7.17 (⁂H, s), 7.17–7.10 (⁂H, m), 7.05 (⁂H, 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, J 12.5), 2.18 (⁃H, s); its ¹H NMR spectrum is attached. Figure 1 .

[0057] 13C 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. The carbon spectrum is attached. Figure 2 .

[0058] HR-MS (ESI-TOF) calcd for C 30 H 23 Cl3NO2 + [M+H] + The theoretical value is 534.0789, and the measured value is 534.0784.

[0059] Example 2

[0060] Prepare the following multi-substituted indole propionate compound 2:

[0061]

[0062] A 10 mL dry reaction tube was used, and 0.1 mmol of 2,4,6-trichlorophenyl-2-(4-methoxyphenyl)acetate (an aryl acetate compound), 0.2 mmol of 3-(p-toluenesulfonylmethyl)-1H-indole (a sulfonyl indole compound), 20 mol% isothiourea catalyst, 0.2 mmol of K3PO4, and 2.0 mL of chlorobenzene solution were added sequentially. The entire reaction system was exposed to air without argon protection. The mixture in the reaction tube was then reacted at 25 °C for 18 hours. After cooling to room temperature, the crude product was obtained by vacuum distillation, followed by purification by column chromatography to obtain a yellow solid product with a yield of 74%. The structural characterization data are as follows:

[0063] 1 ¹H NMR (400MHz, CDCl₃) 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); its ¹H NMR spectrum is attached. Figure 3 .

[0064] 13 C10 NMR (101 MHz, CDCl3) 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 spectrum is attached. Figure 4 .

[0065] HR-MS (ESI-TOF) calcd for C 31 H 25 Cl3NO3 + [M+H] + The theoretical value is 564.0895, and the measured value is 564.0895.

[0066] Example 3

[0067] Prepare the following multi-substituted indole propionate compound 3:

[0068]

[0069] A 10 mL dry reaction tube was used, and 0.1 mmol of 2,4,6-trichlorophenyl-2-(3-methoxyphenyl)acetate (aryl acetate), 0.2 mmol of 3-(p-toluenesulfonylmethyl)-1H-indole (sulfonyl indole), 20 mol% isothiourea catalyst, 0.2 mmol of K3PO4, and 2.0 mL of chlorobenzene solution were added sequentially. The entire reaction system was exposed to air without argon protection. The mixture in the reaction tube was then reacted at 25 °C for 18 hours. After cooling to room temperature, the crude product was obtained by vacuum distillation, followed by purification by column chromatography to obtain a yellow solid product with a yield of 74%. The structural characterization data are as follows:

[0070] 1 ¹H NMR (400MHz, CDCl₃) δ 7.80 (s, 1H), 7.51 (t, J = 8.8Hz, 1H), 7.45 (d, J = 7.9Hz, 2H), 7.19–6.85 (m, 12H), 6.74–6.46 (m, 1H), 5.11 (d, J = 12.2Hz, 1H), 4.85 (d, J = 12.2Hz, 1H), 3.68 (s, 3H), 2.26 (s, 3H): The ¹H NMR spectrum is attached. Figure 5 .

[0071] 13 C NMR (101MHz, CDCl3) 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 spectrum is shown in the appendix. Figure 6 .

[0072] HR-MS (ESI-TOF) calcd for C 31 H 25 Cl3NO3 + [M+H] + Theoretical value: 564.0895; Measured value: 564.0895.

[0073] Example 4

[0074] Prepare the following multi-substituted indole propionate compound 4:

[0075]

[0076] A 10 mL dry reaction tube was used, and 0.1 mmol of 2,4,6-trichlorophenyl-2-(2-bromophenyl)acetate (aryl acetate), 0.2 mmol of 3-(p-toluenesulfonylmethyl)-1H-indole (sulfonyl indole), 20 mol% isothiourea catalyst, 0.2 mmol of K3PO4, and 2.0 mL of chlorobenzene solution were added sequentially. The entire reaction system was exposed to air without argon protection. The mixture in the reaction tube was then reacted at 25 °C for 18 hours. After cooling to room temperature, the crude product was obtained by vacuum distillation, followed by purification by column chromatography to obtain a yellow solid product with a yield of 65%. The structural characterization data are as follows:

[0077] dr:9:1 1¹H NMR (600MHz, DMSO) δ 11.05 (s, 0.1H), 10.82 (s, 0.9H), 7.93 (d, J = 7.0Hz, 0.1H), 7.82 (d, J = 7.0Hz, 0.9H), 7.61 (ddd, J = 55.1, 41.3, 8.3Hz, 6H), 7.32–7.09 (m, 6H), 7.00–6.85 (m, 2H), 5.64 (d, J = 12.5Hz, 0.1H), 5.56 (d, J = 12.4Hz, 0.9H), 5.24 (t, J = 11.4Hz, 1H), 2.22 (s, 2.7H), 2.09 (s, 0.3H); its ¹H NMR spectrum is attached. Figure 7 .

[0078] 13 C NMR (151MHz, 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 BrCl3NO2 + [M+H] + Theoretical value: 611.9894, measured value: 611.9895.

[0080] Example 5

[0081] Prepare the following multi-substituted indole propionate compound 5:

[0082]

[0083] A 10 mL dry reaction tube was used, and 0.1 mmol of 2,4,6-trichlorophenyl-2-(thiophen-2-yl)acetate (an aryl acetate compound), 0.2 mmol of 3-(p-toluenesulfonylmethyl)-1H-indole (a sulfonyl indole compound), 20 mol% isothiourea catalyst, 0.2 mmol of K3PO4, and 2.0 mL of chlorobenzene solution were added sequentially. The entire reaction system was exposed to air without argon protection. The mixture in the reaction tube was then reacted at 25 °C for 18 hours. After cooling to room temperature, the crude product was obtained by vacuum distillation, followed by purification 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 (400MHz, 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 attached. Figure 9 .

[0085] 13 C 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 carbon spectrum is shown in the appendix. Figure 10 .

[0086] HR-MS (ESI-TOF) calcd for C 28 H 21 Cl3NO2S + [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 and not to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing a multi-substituted indole propionate derivative, characterized in that, This includes the purification process following the reaction of aryl acetate compounds with sulfonyl indole compounds under alkaline reagent and catalyst conditions; The aryl acetate compounds have the structural formula shown in Formula I; The sulfonyl indole compound has the structural formula shown in Formula II; The polysubstituted indole propionate derivative has the structural formula shown in Formula III. ； In the formula, R 1 It is one of the following: hydrogen, C1-C4 alkyl, trifluoromethyl, alkoxy, halogen, phenyl, ester carbonyl, cyano, and nitro, which are attached to any position on the benzene ring; R 2 It is one of alkyl or aryl groups; The catalyst is any one of isothiourea, azacarbene, and squaric acid amide; the alkaline reagent is K3PO4.

2. The synthesis method according to claim 1, characterized in that, The equivalent ratio of the aryl acetate compound, sulfonyl indole compound, basic reagent, and catalyst is 1:1 to 2:2 to 4:0.1 to 0.

2.

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

4. The synthesis method according to claim 1, characterized in that, The reaction conditions are 25~100℃ for 10~24 hours.

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

6. The synthesis method according to claim 1, characterized in that, The reaction is carried out in any one of the following organic solvents: acetonitrile, ethanol, tetrahydrofuran, toluene, chlorobenzene, 1,2-dichloroethane, and dioxane.

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