Intermediate of Rhynchines A compound and synthesis method thereof

Abstract

The invention discloses an intermediate of a natural product Rhynchines A and a synthesis method of the intermediate for the first time, tryptamine is used as a starting raw material, and the intermediate of the Rhynchines A is efficiently constructed through reactions such as amino protection, alkylation, Friedel-Crafts acylation and intramolecular cyclization. The route has the advantages of simple steps, high yield, low cost and the like, and a key technical support is provided for total synthesis and drug development of Rhynchines A.

Description

Technical Field

[0001] The present invention belongs to the field of chemical pharmacy, and particularly relates to a synthesis method and application of Rhynchines A. Background Art

[0002] Uncaria is a plant of the genus Uncaria in the Rubiaceae family, with a wide variety. Uncaria in different regions also varies in species. The hooked stem branches of most Uncaria have medicinal value and have the functions of clearing heat and calming the liver, extinguishing wind and stopping convulsions. In view of the excellent medicinal value of the genus Uncaria, scientists have studied its chemical components. Currently, a variety of chemical components have been isolated and can be divided into five categories, namely alkaloids, triterpenoids, flavonoids, coumarins, lignans, quinones, sterols, and other components. Among these chemical components, alkaloids are the main active pharmacological components. So far, nearly 130 indole alkaloids have been confirmed to have antihypertensive, antiepileptic and antidepressant activities.

[0003] Rhynchines A is a novel indole alkaloid isolated from plants of the genus Uncaria and has significant inhibitory activity against T-type calcium channels (IC 50 value is 6.86 μM) and can be used to treat diseases such as epilepsy, hypertension, and neuropathic pain. Currently, the acquisition of Rhynchines A mainly relies on plant extraction methods, but this method has problems such as complex extraction processes, low yields, and long cycles.

[0004]

[0005] The above structural formula is the basic structure of Rhynchines A, including five rings of 6 / 5 / 7 / 5 / 5. The present invention mainly relates to the synthesis method of the 7 / 5-membered ring of Rhynchines A and also proposes the artificial synthesis method of Rhynchines A for the first time. Summary of the Invention

[0006] The present invention provides a synthesis method of the core 7 / 5-membered ring of Rhynchines A based on classical reactions on the one hand.

[0007] The reaction process of the synthesis method of the present invention is as follows: Using 2-(1H-indol-3-yl)ethan-1-amine (Compound 1) as a raw material, through amino protection on indole, primary amine amino protection, alkylation reaction, Friedel-Crafts acylation reaction, amine deprotection reaction, amide condensation reaction, mesylation and intramolecular cyclization reaction, the 7 / 5-membered ring of Rhynchines A, (2R)-11-benzyl-2-ethyl-1,6,11,12a-tetrahydropyrrolo[1',2':1,2]azepino[4,5-b]indole-3,12(2H,5H)-dione (Compound 9), is obtained.

[0008]

[0009] The present invention specifically may include seven reaction steps:

[0010]

[0011] Step (1): Compound 1 reacts with amino protecting agent 1 under alkaline conditions at room temperature to obtain Compound 2;

[0012] Among them, the amino protecting agent 1 is selected from: benzyloxycarbonyl chloride (CbzCl), allyloxycarbonyl chloride (AllocCl), trifluoroacetic anhydride (TFAA), benzyl bromide, p-toluenesulfonyl chloride (TsCl), Boc anhydride (Boc 2 O), fluorenylmethoxycarbonyl chloride (FmocCl), acetic anhydride, benzoyl chloride, methanesulfonyl chloride, o-nitrobenzenesulfonyl chloride or p-nitrobenzenesulfonyl chloride;

[0013] The PG 1 is selected from benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), trifluoroacetyl, benzyl groups, benzenesulfonyl groups, tert-butoxycarbonyl (Boc) or fluorenylmethoxycarbonyl (Fmoc); preferably, PG 1 is benzyl;

[0014] The alkaline conditions are provided in the presence of sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, or sodium bicarbonate;

[0015] The room temperature is between 0 °C and 25 °C;

[0016] After the first-step reaction, the yield of Compound 2 can reach 67.7%.

[0017] Second step: Compound 2 reacts with amino protecting agent 2 under alkaline conditions at room temperature to obtain Compound 3.

[0018] Among them, the amino protecting agent 2 is selected from: benzyloxycarbonyl chloride (CbzCl), allyloxycarbonyl chloride (AllocCl), trifluoroacetic anhydride (TFAA), benzyl bromide, p-toluenesulfonyl chloride (TsCl), Boc anhydride (Boc 2 O), fluorenylmethoxycarbonyl chloride (FmocCl), acetic anhydride, benzoyl chloride, methanesulfonyl chloride, o-nitrobenzenesulfonyl chloride or p-nitrobenzenesulfonyl chloride;

[0019] PG 2 is selected from one of benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), trifluoroacetyl, benzyl groups, benzenesulfonyl groups, tert-butoxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc); preferably, PG 2 is benzenesulfonyl;

[0020] Among them, the basic condition is in the presence of triethylamine;

[0021] The room temperature is between 0 °C and 25 °C;

[0022] After the second-step reaction, the yield of compound 3 can reach 82%.

[0023] Step 3: Compound 3 undergoes an alkylation reaction to obtain compound 4;

[0024] Among them, the alkylation reaction includes that compound 3 forms a sodium salt in the presence of sodium hydride and reacts with iodoacetic acid to obtain compound 4; the iodoacetic acid is obtained by reacting chloroacetic acid with potassium iodide;

[0025] The temperature of the alkylation reaction is 50 °C - 100 °C; preferably 85 °C;

[0026] After the third-step reaction, the yield of compound 4 can reach 62%.

[0027] Step 4: Compound 4 reacts with trifluoroacetic anhydride at low temperature in the presence of a Lewis acid to obtain compound 5;

[0028] Among them, the Lewis acid is an ethereal solution of boron trifluoride;

[0029] The low temperature is between -15 °C and 0 °C;

[0030] After the fourth-step reaction, the yield of compound 5 can reach 93%.

[0031] Step 5: Under heating conditions, compound 5 reacts in the presence of sodium benzenethiolate to obtain compound 6;

[0032] Among them, the heating temperature is 35 °C - 45 °C;

[0033] After the fifth-step reaction, the yield of compound 6 can reach 64%.

[0034] Step 6: At room temperature, compound 6 undergoes a condensation reaction with compound 7 in the presence of a condensing agent to obtain compound 8;

[0035] Among them, compound 7 is R-2-(chloromethyl)butanoyl chloride or (R)-2-(hydroxymethyl)butyric acid;

[0036] The condensing agent is selected from one or more of N,N'-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; preferably, the condensing agent is one or two of 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride;

[0037] The room temperature is between 0°C and 25°C;

[0038] After the sixth-step reaction, the yield of compound 8 can reach 87%.

[0039] Step 7: Intramolecular cyclization reaction: Compound 8 reacts with methanesulfonyl chloride under alkaline conditions to form compound 9; Compound 9-1 and compound 9-2 are obtained through column chromatography separation and purification;

[0040] Among them, the alkaline conditions are provided in the presence of one or two of triethylamine, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium bicarbonate, and sodium bicarbonate;

[0041] After the seventh-step reaction, the yield of compound 9 can reach 95%.

[0042] On the other hand, the present invention provides an intermediate for synthesizing Rhynchines A, which has the structure shown below:

[0043]

[0044] Wherein PG 1 and PG 2 each independently selected from one of benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), trifluoroacetyl, benzyl groups, benzenesulfonyl groups, tert-butoxycarbonyl (Boc), or fluorenylmethoxycarbonyl (Fmoc).

[0045] Examples are provided below to assist in understanding the present invention. However, it should be understood that these examples are only used to illustrate the present invention and do not constitute any limitation. The actual protection scope of the present invention is set forth in the claims. It should be understood that any modifications and changes can be made without departing from the spirit of the present invention. Detailed implementation manners

[0046] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with the embodiments. The specific embodiments described herein are only used to explain the present invention and do not constitute any limitation to the present invention. In addition, in the following description, the descriptions of well-known structures and technologies are omitted to avoid unnecessarily confusing the concepts of the present invention. Such structures and technologies are also described in many publications.

[0047] Unless otherwise defined, all technical terms and scientific and technical terms used in the present invention have the same meanings as those commonly used in the field to which the present invention belongs. For the purpose of explaining this specification, the following definitions will be applied, and when appropriate, terms used in the singular form will also include the plural form, and vice versa.

[0048] Unless the context clearly indicates otherwise, as used herein, the expressions "a" and "an" include plural referents. For example, reference to "a cell" includes a plurality of such cells and equivalents known to those skilled in the art, and the like.

[0049] As used herein, the term "about" means a range of ±20% of the value that follows. In some embodiments, the term "about" means a range of ±10% of the value that follows. In some embodiments, the term "about" means a range of ±5% of the value that follows.

[0050] As used herein, the term "benzyl group" means a group containing a benzylidene group, and the benzene ring can be arbitrarily substituted with 1, 2, 3, or 4 substituents selected from H, F, Cl, Br, I, nitro, cyano, hydroxyl, carboxyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and cycloalkyl.

[0051] As used herein, the term "benzenesulfonyl group" means a group containing a benzenesulfonyl group, and the benzene ring can be arbitrarily substituted with 1, 2, 3, or 4 substituents selected from H, F, Cl, BR, I, nitro, cyano, hydroxyl, carboxyl, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and cycloalkyl.

[0052] The solvents used herein are commercially available. The following abbreviations are used herein:

[0053] TLC: Thin-layer chromatography

[0054] THF: Tetrahydrofuran

[0055] DCM: Dichloromethane

[0056] DMF: Dimethylformamide

[0057] eq: Equivalent

[0058] Concentration N: g / L

[0059] The compounds are named manually or by software. Commercially available compounds are named using the supplier's catalog name. Detailed description of specific embodiments

[0061] The technical solutions of the present invention will be described in detail below in conjunction with examples, but the protection scope of the present invention is not limited thereto.

[0062] Example 1

[0063]

[0064] The first step, protection reaction of the indole nitrogen atom: In a 100 mL round-bottom flask, add 15.6 mL of N,N-dimethylformamide solution. Under an ice bath, add sodium hydride (0.9 g, 22.4 mmol) to the DMF, and stir at room temperature for 10 min. Dissolve tryptamine (3 g, 18.7 mmol) in 15.6 mL of DMF solution. Under an ice bath, slowly add it dropwise to the above DMF solution containing sodium hydride, and stir at room temperature for 30 min. Then, under an ice bath, slowly add benzyl bromide (3.8 g, 22.4 mmol) until the solution turns red, and stir at room temperature for 4 h. Quench with water, extract with ethyl acetate, dry, concentrate, and separate by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain 3.17 g of 2-(1-benzyl-1H-indol-3-yl)ethan-1-amine, with a yield of 67.7%. 1 H NMR(500MHz,CDCl 3 )δ7.66(d,J=7.9Hz,1H),7.36–7.31(m,2H),7.28(d,J=7.6Hz,1H),7.21(t,J=7.3Hz,1H),7.14(t,J=7.0Hz,3H),7.01(s,1H),5.31(s,2H),3.08(d,J=5.8Hz,2H),2.99(t,J=6.7Hz,2H),2.62(s,2H)ppm; 13 C NMR(126MHz,CDCl 3 )δ137.88,136.95,128.89,128.33,127.71,126.98,126.58,122.03,119.29(d,J=3.3Hz),112.58,109.99,49.91,42.11,28.67ppm。

[0065] The second step, protection reaction of the primary amine nitrogen atom: Dissolve 2-(1-benzyl-1H-indol-3-yl)ethan-1-amine (1 g, 4.12 mmol) in 20 mL of dichloromethane. Under nitrogen protection, slowly add triethylamine (0.86 mL, 6.18 mmol) dropwise to the mixture. Then cool the system in an ice bath, and add o-nitrobenzenesulfonyl chloride (1 g, 4.5 mmol) in this state; transfer to room temperature and stir for 2 h. Quench with water. Extract with dichloromethane, dry, and distill off the solvent under reduced pressure until the solid of N-(2-(1-benzyl-1H-indol-3-yl)ethyl)-4-nitrobenzenesulfonamide is just formed, pour it into 60 mL of petroleum ether for recrystallization, and filter by suction to obtain 1.47 g of N-(2-(1-benzyl-1H-indol-3-yl)ethyl)-4-nitrobenzenesulfonamide, with a yield of 82%. 1 H NMR(500MHz,CDCl 3)δ8.10–7.98(m,1H),7.67–7.54(m,3H),7.34(d,J=7.9Hz,1H),7.32–7.27(m,3H),7.25(s,1H),7.20(d,J=8.3Hz,1H),7.12(t,J=7.3Hz,3H),6.97(t,J=7.4Hz,1H),6.89(s,1H),5.36(t,J=5.3Hz,1H),5.21(s,2H),3.44(q,J=6.5Hz,2H),2.99(t,J=6.6Hz,2H)ppm; 13 C NMR(126MHz,CDCl 3 )δ147.58,137.23,136.93,133.51,133.29,132.64,130.89,128.85,127.75,127.39,126.91(d,J=15.1Hz),125.36,122.02,119.29,118.53,110.37,109.93,50.00,43.82,25.50ppm。

[0066] Step 3, alkylation reaction: N-(2-(1-benzyl-1H-indol-3-yl)ethyl)-4-nitrobenzenesulfonamide (2 g, 4.59 mmol) was dissolved in anhydrous tetrahydrofuran. Under an ice bath, sodium hydride (0.92 g, 22.96 mmol) was slowly added to the tetrahydrofuran, and the mixture was stirred at room temperature for 20 min. Then potassium iodide (0.76 g, 4.59 mmol) was added to the mixed solution. Under nitrogen protection, a chloroacetic acid solution dissolved in tetrahydrofuran was slowly added dropwise, and the mixture was stirred at room temperature for 15 min. Subsequently, the reaction was placed in an oil bath at 85 °C and heated under reflux for 10 h until the reaction solution turned dark brown. The reaction was quenched by adding water, the solvent tetrahydrofuran was removed by distillation under reduced pressure, extracted with ethyl acetate, and the pH of the aqueous phase was adjusted to 1-2 with 6N HCl. Extracted with dichloromethane, dried and concentrated to obtain 1.4 g of N-(2-(1-benzyl-1H-indol-3-yl)ethyl)-N-((4-nitrophenyl)sulfonyl)glycine, with a yield of 62%. 1 H NMR(500MHz,CDCl 3)δ 7.97 (d, J = 7.1 Hz, 1H), 7.58 (t, J = 7.1 Hz, 1H), 7.54–7.47 (m, 3H), 7.32–7.27 (m, 2H), 7.22 (d, J = 8.2 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 5.8 Hz, 3H), 6.92 (s, 1H), 5.20 (s, 2H), 4.23 (s, 2H), 3.70 (t, J = 7.4 Hz, 2H), 3.04 (t, J = 7.4 Hz, 2H) ppm; 13 C NMR (126 MHz, CDCl 3 )δ 173.35, 147.60, 137.37, 136.60, 133.39, 133.20, 131.65, 130.83, 128.82, 127.68 (d, J = 7.7 Hz), 126.88, 126.43, 124.11, 122.00, 119.40, 118.69, 110.85, 109.86, 49.95, 48.96, 47.97, 24.29 ppm.

[0067] Step 4, Friedel-Crafts acylation reaction: N-(2-(1-benzyl-1H-indol-3-yl)ethyl)-N-((4-nitrophenyl)sulfonyl)glycine (0.30 g, 0.6 mmol) was dissolved in dichloromethane. Under nitrogen protection, the mixed solution was placed in a stirring cooler at -15 °C, and trifluoroacetic anhydride (0.18 mL, 1.81 mmol) was slowly added dropwise, and the mixture was stirred at this temperature for 1 h. The temperature was raised to 0 °C, and boron trifluoride diethyl ether solution (0.21 mL, 2.4 mmol) was slowly added dropwise to the system. After the addition was completed, the mixture was stirred at 0 °C for 4 h. The reaction was quenched with saturated sodium bicarbonate solution, and the pH of the system was adjusted to 7-8 with 2N NaOH solution. The mixture was extracted with dichloromethane, dried, concentrated, and separated by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 0.44 g of 6-benzyl-3-((4-nitrophenyl)sulfonyl)-1,3,4,6-tetrahydroazepino[4,5-b]indol-5(2H)-one, with a yield of 93%. 1 HNMR (500 MHz, CDCl 3)δ 7.98 (d, J = 7.4 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.62–7.54 (m, 2H), 7.52 (d, J = 7.4 Hz, 1H), 7.36–7.30 (m, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.24 (s, 1H), 7.21 (d, J = 7.4 Hz, 2H), 7.19–7.14 (m, 2H), 7.05 (d, J = 7.4 Hz, 2H), 5.67 (s, 2H), 4.23 (s, 2H), 3.88 (t, J = 6.4 Hz, 2H), 3.39 (t, J = 6.4 Hz, 2H) ppm; 13 C NMR (126 MHz, CDCl 3 )δ 190.91, 147.71, 139.76, 138.10, 133.73, 132.73, 131.78, 131.54, 131.23, 128.56, 127.15 (d, J = 1.7 Hz), 126.51, 125.90, 124.25, 123.34, 120.92, 111.12, 56.21, 48.23, 46.74, 24.80 ppm.

[0068] Step 5, deprotection reaction of amino group: 6-Benzyl-3-((4-nitrophenyl)sulfonyl)-1,3,4,6-tetrahydroazepino[4,5-b]indol-5(2H)-one (0.28 g, 0.59 mmol) was dissolved in anhydrous acetonitrile, and then sodium benzenethiolate (0.31 g, 2.37 mmol) and potassium carbonate (0.16 g, 1.18 mmol) were added to the mixed solution. It was heated and stirred in an oil bath at 40 °C for 1 h. Filtration was carried out by suction, and the solution was concentrated. It was separated by silica gel column chromatography (ethyl acetate) to obtain 0.124 g of 6-benzyl-1,3,4,6-tetrahydroazepino[4,5-b]indol-5(2H)-one, with a yield of 64%. 1 H NMR (500 MHz, D 2 O)δ 7.87 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 2.7 Hz, 2H), 7.30 (dt, J = 14.3, 4.7 Hz, 4H), 7.06 (d, J = 6.7 Hz, 2H), 5.71 (s, 2H), 4.20 (s, 2H), 3.65 (t, J = 6.3 Hz, 2H), 3.55 (t, J = 6.3 Hz, 2H) ppm; 13 C NMR (126 MHz, D 2O) δ186.35,140.34,138.29,130.60,128.67(d,J=19.3Hz),127.46,126.20,1 25.68, 125.23, 121.48 (d, J = 14.5Hz), 111.32, 52.93, 47.74, 43.95, 20.37ppm.

[0069] Step 6, amide condensation reaction: Under nitrogen atmosphere, 6-benzyl-1,3,4-6-tetrahydroazacycloheptane [4,5-b] indole-5 (2H) -one (0.323 g, 0.825 mmol) and N, N-diisopropylethylamine (0.224 g, 1.73 mmol) were added to 2 mL of dichloromethane and stirred at room temperature for 10 min. The reaction system was a light yellow clear solution. (R) -2- (Hydroxymethyl) butyric acid (0.097 g, 0.825 mmol) dissolved in 2 mL of dichloromethane solvent was added to the cooled reaction mixture at 0°C, followed by 1-hydroxybenzotriazole (0.112 g, 0.825 mmol) and EDCI (0.174 g, 0.908 mmol) at 0°C, and stirred at room temperature overnight. The dichloromethane was removed by spinning, and ethyl acetate and saturated brine were added for extraction. The mixture was dried and concentrated to obtain 0.28 g of (R)-6-phenyl-3-(2-(hydrogenmethyl)butyl)-1,3,4,6-tetrahydro-4 4 4,5-[4,5-b]5 5 5 5(2H)-one with a yield of 87%. 1 H NMR (500 MHz, CDCl 3 )δ7.69(dd,J=21.5,8.1Hz,1H),7.46–7.31(m,2H),7.24–7.13(m,4H),7. 06(d,J=7.1Hz,1H),6.99(d,J=7.0Hz,1H),5.88–5.69(m,2H),4.51–4.27( m,2H),3.90(t,J=6.4Hz,2H),3.70–3.49(m,2H),3.42(t,J=6.0Hz,2H),2 .65(d,J=3.1Hz,2H),1.55–1.36(m,2H),0.75(dd,J=11.7,7.1Hz,3H)ppm; 13 C NMR (126 MHz, CDCl 3)δ 190.31, 176.27, 139.96, 138.13, 128.52 (d, J = 7.6 Hz), 127.51, 127.22, 126.77 (d, J = 8.1 Hz), 126.33, 121.14, 120.94, 110.87, 62.86, 56.96, 47.98, 44.89, 43.96, 23.69, 21.86, 11.60 ppm.

[0070] Step 7, intramolecular cyclization reaction: (R)-6-phenyl-3-(2-(hydroxymethyl)butyl)-1,3,4,6-tetrahydro-4,5-[4,5-b]pyrrolo[2H]-one (0.096 g, 0.246 mmol) was dissolved in dichloromethane. Methanesulfonyl chloride (0.021 mL, 0.27 mmol) was added under an ice bath, followed by triethylamine (0.041 mL, 0.3 mmol). Stirring was continued for 2 h under an ice bath. Extraction was carried out with dichloromethane, followed by drying and concentration to obtain a sulfonate compound (0.106 g, yield 92%). The sulfonate compound (0.106 g, 0.226 mmol) was dissolved in anhydrous dichloromethane, and then ground anhydrous potassium carbonate (0.125 g, 0.904 mmol) and a small amount of 18-crown-6 (0.013 g, 0.049 mmol) were added. The mixture was heated under reflux in an oil bath at 60 °C for 10 h, filtered by suction and concentrated, and separated by column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain (2R,12aR)-11-benzyl-2-ethyl-1,6,11,12a-tetrahydropyrrolo[1',2':1,2]azepino[4,5-b]indole-3,12(2H,5H)-dione, 1 H NMR (500 MHz, CDCl 3 )δ 7.75 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 3.4 Hz, 2H), 7.28–7.20 (m, 4H), 6.97 (d, J = 7.1 Hz, 2H), 5.80 (q, J = 16.1 Hz, 2H), 4.39 (dd, J = 8.5, 1.9 Hz, 1H), 4.07–3.93 (m, 1H), 3.72–3.49 (m, 2H), 3.26–3.16 (m, 1H), 2.60 (ddd, J = 12.3, 8.3, 2.0 Hz, 1H), 2.13–2.02 (m, 1H), 1.87 (ddd, J = 12.4, 9.1, 5.0 Hz, 2H), 1.71 (s, 1H), 0.95 (t, J = 7.4 Hz, 3H) ppm; 13 C NMR (126 MHz, CDCl 3)δ192.42,176.70,140.04,138.41,131.42,128.59,127.30(d,J = 8.8Hz),126.32,125.87,125.42,121.11,120.93,110.75,64.10,48.17,42.09,41.19,28.49,24.01,23.70,11.41ppm;

[0071] and (2R,12aS)-11-benzyl-2-ethyl-1,6,11,12a-tetrahydropyrrolo[1',2':1,2]azepino[4,5-b]indole-3,12(2H,5H)-dione: 1 H NMR(500MHz,CDCl 3 )δ7.72(d,J = 8.1Hz,1H),7.46(d,J = 3.6Hz,2H),7.28–7.18(m,4H),6.95(d,J = 6.5Hz,2H),5.85(d,J = 16.0Hz,1H),5.67(d,J = 16.1Hz,1H),4.39(t,J = 7.5Hz,1H),4.21(dt,J = 13.3,5.0Hz,1H),3.66–3.53(m,1H),3.41(ddd,J = 13.3,9.8,3.6Hz,1H),3.29–3.18(m,1H),2.34(dd,J = 14.7,7.6Hz,2H),1.70(ddd,J = 15.0,7.4,3.9Hz,1H),1.14–1.00(m,1H),0.92(t,J = 6.8Hz,1H),0.79(t,J = 7.4Hz,3H)ppm; 13 C NMR(126MHz,CDCl 3 )δ193.56,176.51,140.25,138.46,130.47,128.56,127.34(d,J = 6.7Hz),126.52,126.24,125.77,121.31,120.89,110.68,66.23,48.17,42.72,40.84,28.70,25.64,24.33,11.49ppm. The ratio of the two compounds is 2:1, with a total of 0.080 g and a yield of 95%.

[0072] As described above, it is only the specific implementation manner of the present invention and cannot be used to limit the protection scope of the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing an intermediate compound 9 of Rhynchines A, comprising the following steps: Step (1), compound 1 reacts with amino protecting agent 1 under alkaline conditions at room temperature to obtain compound 2; Step (2), compound 2 reacts with amino protecting agent 2 under alkaline conditions at room temperature to obtain compound 3; Step (3), compound 3 is subjected to an alkylation reaction to obtain compound 4; Step (4), compound 4 reacts with trifluoroacetic anhydride at low temperature in the presence of a Lewis acid to obtain compound 5; Step (5), under heating conditions, compound 5 reacts in the presence of sodium thiophenol to obtain compound 6; Step (6), compound 6 undergoes a condensation reaction with compound 7 in the presence of a condensing agent at room temperature to obtain compound 8; Step (7), compound 8 reacts with methanesulfonyl chloride under alkaline conditions to obtain compound 9.

2. The synthesis method according to claim 1, wherein The amino protecting agent 1 and the amino protecting agent 2 are each independently selected from: benzyloxycarbonyl chloride (CbzCl), allyloxycarbonyl chloride (AllocCl), trifluoroacetic anhydride (TFAA), benzyl bromide, p-toluenesulfonyl chloride (TsCl), Boc anhydride (Boc2O), fluorenylmethyloxycarbonyl chloride (FmocCl), acetic anhydride, benzoyl chloride, methanesulfonyl chloride, o-nitrobenzenesulfonyl chloride or p-nitrobenzenesulfonyl chloride; PG 1 One selected from benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), trifluoroacetyl, benzyl, benzylsulfonyl, tert-butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc); preferably, PG 1 It is benzyl type; PG 2 One selected from benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), trifluoroacetyl, benzyl, benzylsulfonyl, tert-butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc); preferably, PG 2 It is a benzenesulfonyl group.

3. The synthesis method according to claim 1, wherein the alkaline condition in step (1) is provided in the presence of one or two of sodium hydride, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate.

4. The synthesis method according to claim 1, wherein the alkylation reaction in step (3) comprises reacting compound 3 with sodium hydride to form a sodium salt, which is then reacted with iodoacetic acid to obtain compound 4.

5. The synthesis method according to claim 1, wherein the Lewis acid in step (4) is a diethyl ether solution of boron trifluoride.

6. The synthesis method according to claim 1, wherein the heating temperature in step (5) is 35°C to 45°C.

7. The synthesis method according to claim 1, wherein the compound 7 in step (6) is R-2-(chloromethyl)butyryl chloride or (R)-2-(hydroxymethyl)butyric acid; The condensing agent is one or more of N,N'-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

8. The synthesis method according to claim 1, wherein the alkaline condition in step (7) is provided in the presence of one or two of triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, and sodium hydroxide; The low temperature is -10°C to 10°C, preferably 0°C.

9. A compound having the structure shown below: Among them PG 1 and PG 2 Each is independently selected from one of benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), trifluoroacetyl, benzyl, benzyl, phenylsulfonyl, tert-butyloxycarbonyl (Boc) or fluorenylmethyloxycarbonyl (Fmoc).

10. Use of the compound according to claim 9 in the preparation of Rhynchines A.

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