Synthetic method and application of alkaloid (-)-psychotriadine and analogue thereof

Abstract

The invention relates to a synthesis method of alkaloid, and discloses a synthesis method of alkaloid (-)-psychotriadine and analogues thereof, and the synthesis method comprises the following steps: taking a tryptamine derivative as an initial raw material, taking an asymmetric Meerwein-Eschenmoser-Claisen rearrangement reaction and a Fischer indolation and Plancher rearrangement reaction as key reactions, and realizing the preparation of (-)-psychotriadine through a nine-step linear synthesis route. The method disclosed by the invention has gram-level amplification capability, and the problem of medicine source bottleneck of a natural sample and homologues thereof in future medicine research can be solved; meanwhile, it is verified through a Luciferase reporter gene experiment that (-)-psychotriadine and tetrahydropsychotriadine have the transcriptional activation activity of LXR [alpha] and LXR [beta], and the (-)-psychotriadine and the tetrahydropsychotriadine show the potential treatment effect on the Alzheimer's disease.

Description

TECHNICAL FIELD

[0001] The application relates to a synthesis method of an alkaloid, in particular to a synthesis method and application of an alkaloid (-)-psychotriadine and analogues thereof. BACKGROUND

[0002] Dimeric cyclol alkaloids are an important member of the indole alkaloid family, since calycanthine was first isolated in 1888, dimeric cyclol alkaloids have attracted the attention of scientists all over the world. The structure is diverse, the biological synthesis pathway is unique, and the products have wide biological activity. The biological activity and complex structure of these products stimulate people's interest in their synthesis.

[0003] Psychotriadine has been speculated as a natural homolog containing a piperidine and indoline skeleton, but so far it has not been successfully isolated, and it has not been obtained by chemical conversion of known family members. Garg team innovatively adopts solid-state photodecarbonylation as a key reaction, and realizes the 15-step racemate total synthesis of the compound based on the symmetry strategy, but the total yield is only 0.35%, the yield is low, and the process route is long, which cannot meet the further research demand of its performance. SUMMARY

[0004] In order to solve the above technical problems, the application provides a synthesis method and application of an alkaloid (-)-psychotriadine and analogues thereof, so as to shorten the reaction path, improve the yield, and solve the "drug source bottleneck" problem.

[0005] In order to achieve the above purpose, the technical scheme of the application is as follows:

[0006] The synthesis method of the alkaloid (-)-psychotriadine and analogues thereof comprises the following steps:

[0007] In the first step, compound 1 and compound 2 are used as starting materials, and a chiral intermediate 3 is synthesized through Meerwein-Eschenmoser-Claisen rearrangement; then after removing the Boc protecting group, an oxidized indole compound 4 is obtained;

[0008] In the second step, the oxidized indole compound 4 is subjected to Ti(O-iPr)4 to construct a piperidine ring to obtain compound 5;

[0009] In the third step, the double bond of compound 5 is subjected to oxidation cutting to obtain an aldehyde compound 6;

[0010] In the fourth step, compound 6 and phenylhydrazine are subjected to Fischer indole synthesis and Plancher rearrangement to obtain a seven-membered ring compound 7;

[0011] In the fifth step, the Phth protecting group of compound 7 is converted to a methyl ester protecting group to obtain compound 8, and the ester group is further reduced to a methyl group to obtain compound 9;

[0012] In the sixth step, compound 9 is reacted with NCS to obtain compound 10, i.e. alkaloid (-)-psychotriadine, through a skeletal rearrangement reaction;

[0013] In the seventh step, compound 10 is reduced by diisobutylaluminum hydride to obtain compound 11, i.e. tetrahydropyschotradine;

[0014] The specific reaction process is as follows:

[0015]

[0016] In the above scheme, the specific method of the first step is as follows: a known compound 1 and After the molecular sieve is added to dichloromethane and cooled to 0°C, DABCO is added, then NCS is added, and stirred at 0°C for 2h, compound 2 and methanesulfonic acid are added, the reaction is gradually increased to room temperature, and the reaction is carried out at room temperature for 24h, the reaction solution is filtered with a sand core funnel containing diatomite, washed with DCM, and the filtrate is concentrated in vacuum to obtain the crude product of the oxidized indole compound 3;

[0017] The crude product of the oxidized indole compound 3 is dissolved in DCM and cooled to 0°C, then trifluoroacetic acid is added, the reaction is warmed to room temperature and stirred for 6 hours; the reaction is quenched by adding sodium hydroxide aqueous solution at 0°C; the mixture is transferred to a separatory funnel, extracted with DCM, and the combined organic phase is dried over anhydrous magnesium sulfate, and purified by column chromatography to obtain compound 4.

[0018] In the above scheme, the specific method of the second step is as follows:

[0019] Compound 4 is dissolved in tetrahydrofuran, Ti(O-iPr)4 is added at room temperature, the reaction is warmed to 130°C and stirred for 20 hours; after the reaction is completed, it is cooled to room temperature, quenched with saturated potassium sodium tartrate solution, extracted with ethyl acetate, the combined organic layer is washed with water and saturated brine respectively, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure; finally, compound 5 is obtained by silica gel column chromatography.

[0020] In the above scheme, the specific method of the third step is as follows:

[0021] Compound 5 was dissolved in dichloromethane and cooled to -78°C, and ozone was bubbled in for 40 minutes; when the starting material was completely consumed, methanol and dimethyl sulfide were added to quench the reaction; the reaction was warmed to 0°C and stirred for 15 minutes, then saturated aqueous sodium bicarbonate was added; the resulting reaction mixture was stirred at room temperature for 4 hours, extracted with dichloromethane, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure; compound 6 and its isomers were purified by silica gel column chromatography.

[0022] In the above scheme, the specific method of the fourth step is as follows:

[0023] Compound 6 and its isomers were dissolved in 1,4-dioxane, benzene hydrazine hydrochloride was added, followed by sulfuric acid; the resulting mixture was heated to 60°C and stirred for 12 hours; the reaction was quenched by adding saturated aqueous sodium bicarbonate solution; the mixture was extracted with ethyl acetate, and the combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure; compound 7 was purified by silica gel column chromatography.

[0024] In the above scheme, the specific method of the fifth step is as follows:

[0025] Compound 7 was dissolved in a mixture of dichloromethane and methanol, hydrazine hydrate was added at 0°C, the reaction was warmed to room temperature and stirred for 4 hours, quenched with water, and extracted with dichloromethane; the resulting organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the crude primary amine compound; the crude primary amine compound was dissolved in dichloromethane, N,N-diisopropylethylamine was added at 0°C, followed by methyl chloroformate; the reaction was warmed to room temperature and stirred for 1 hour, quenched with saturated aqueous ammonium chloride solution, and extracted with dichloromethane; the combined organic layers were washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure; the product 8 was purified by silica gel column chromatography.

[0026] Compound 8 was dissolved in tetrahydrofuran, and LiAlH4was added at 0°C; the reaction was heated to 70°C and stirred for 4 hours; the excess LiAlH4was quenched by gradually adding water, 15% aqueous sodium hydroxide solution, and water; the resulting suspension was filtered through a celite pad and rinsed with THF; the filtrate was extracted with ethyl acetate; the combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure; compound 9 was purified by silica gel column chromatography.

[0027] In the above scheme, the specific method of the sixth step is as follows:

[0028] Compound 9 is dissolved in chloroform, NCS is added at room temperature, the reaction is heated to 70 DEG C and continues to stir for 5 hours, sodium hydroxide aqueous solution is added to quench the reaction; the reaction is extracted with dichloromethane; the organic phase is combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure; compound 10 is obtained by purification through silica gel column chromatography.

[0029] In the above scheme, the specific method of the seventh step is as follows:

[0030] DIBAL-H is added to a DCM solution of compound 10 at room temperature and stirred for 15 hours, sodium potassium tartrate aqueous solution is added to quench the reaction and continue to stir for 30 minutes; transfer to a separatory funnel to separate the layers, the aqueous phase is extracted with DCM; the organic phase is combined, washed with water, dried with anhydrous MgSO4, and concentrated under reduced pressure; compound 11 is obtained by purification through column chromatography.

[0031] The alkaloid (-)-psychotriadine and its analog tetrahydropsychotradine synthesized by the synthetic method described above are used in LXRα and LXRβ transcriptional activation activity and treatment of Alzheimer's disease.

[0032] By the above technical solution, the synthetic method and application of the alkaloid (-)-psychotriadine and its analogs provided by the present application have the following beneficial effects:

[0033] The present application first completes the enantioselective total synthesis of the alkaloid (-)-psychotriadine and its analog tetrahydropsychotradine, and the total yield can reach 4.5%, compared with the existing 15-step racemate synthesis method, the present application can obtain the final product in nine steps, and the total yield is greatly improved.

[0034] The method of the present application has a kilogram-scale amplification capacity, and can solve the "drug source bottleneck" problem of natural samples and their homologues in future drug research.

[0035] The present application verifies that (-)-psychotriadine and tetrahydropsychotradine have certain LXRα and LXRβ transcriptional activation activity through Luciferase reporter gene experiments, and have potential anti-Alzheimer's disease treatment effects. BRIEF DESCRIPTION OF DRAWINGS

[0036] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed to be used in the embodiment or prior art description will be briefly introduced below.

[0037] Figure 1Schematic diagram of the influence of compounds 10 and 11 disclosed in the embodiments of the present application on the LXRα / LXRβ protein transcriptional activity. DETAILED DESCRIPTION

[0038] The technical solutions in the embodiments of the present application will be clearly and completely described in combination with the drawings in the embodiments of the present application.

[0039] The present application provides a synthetic method and application of alkaloid (-)-psychotriadine and analogues thereof, and the specific embodiments are as follows:

[0040]

[0041] The method comprises the following steps:

[0042] (1) Taking known compound 1 and compound 2 as starting materials, a chiral intermediate 3 is synthesized through Meerwein-Eschenmoser-Claisen rearrangement; after removing the Boc protecting group, an oxidized indole compound 4 is obtained, and the specific method is as follows:

[0043] Under nitrogen protection, a dry 500 mL round-bottom flask is added with compound 1 (8.54 g, 29.46 mmol, 1.67 eq) and Molecular sieves (4.0 g). After adding dichloromethane (DCM, 200 mL), the solution is cooled to 0 ℃ in an ice water bath. After adding triethylene diamine (DABCO, 1.98 g, 17.68 mmol, 1.0 eq) and N-chlorosuccinimide (NCS, 4.33 g, 32.40 mmol, 1.83 eq) to the reaction system, stirring is performed for 2 h, then compound 2 (4.054 g, 17.68 mmol, 1.0 eq, 91% ee) and methanesulfonic acid (MsOH, 0.58 mL, 8.84 mmol, 0.5 eq) are added, the reaction system is raised to room temperature and continues to be stirred for 20 h. The reaction solution is filtered through diatomite, and washed with DCM (50 mL). The combined filtrate is concentrated under reduced pressure to obtain the crude product oxidized indole 3.

[0044] The crude product oxidized indole 3 is dissolved in DCM (200 mL) and cooled to 0 ℃ in an ice water bath, and trifluoroacetic acid (TFA, 20 mL) is added. After stirring at room temperature for 6 h, NaOH aqueous solution is added under ice bath condition to adjust pH>7 (monitored by pH test paper). Extraction is performed with DCM (3×30 mL). The combined organic phase is dried over anhydrous MgSO4, and purified by column chromatography (gradient elution with DCM / MeOH 30:1 to 5:1) to obtain compound 4 (2.95 g, 40% overall yield based on compound 2) as a white solid.

[0045] The nuclear magnetic hydrogen spectrum data, nuclear magnetic carbon spectrum data and high resolution data of compound 4 are as follows:

[0046] R f = 0.25 (DCM / MeOH = 6 / 1).

[0047] 1 HNMR (400 MHz, CDC13) δ 7.66 (td, J = 5.2, 2.1 Hz, 2H), 7.60 (dd, J = 5.5, 3.0 Hz, 2H), 7.10 (d, J = 6.4 Hz, 1H), 6.96 (t, J = 7.7 Hz, 1H), 6.83 - 6.75 (m, 2H), 5.73 - 5.57 (m, 1H), 5.32 (ddd, J = 15.2, 10.0, 1.7 Hz, 1H), 3.49 - 3.37 (m, 2H), 2.53 - 2.41 (m, 3H), 2.38 (t, J = 7.8 Hz, 1H), 2.35 (s, 3H), 2.14 - 2.04 (m, 1H), 1.75 (d, J = 6.4 Hz, 3H), 1.40 (dt, J = 13.4, 6.5 Hz, 1H), 0.97 - 0.86 (m, 1H).

[0048] 13 CNMR (100 MHz, CDC13) δ 181.4, 167.9, 141.8, 133.7, 132.0, 130.6, 129.9, 128.6, 128.0, 124.1, 123.0, 122.1, 110.4, 54.8, 49.6, 48.5, 35.8, 34.2, 34.1, 28.6, 18.3.

[0049] HRMS calcd. for C 25 H 28 N3O3 + [M+H] + : 418.2125. Found: 418.2130.

[0050] (2) Oxidation of indole compound 4 to construct piperidine ring to obtain compound 5 under the condition of Ti(O-iPr)4, the specific method is as follows:

[0051] To a solution of compound 4 (2.95 g, 7.07 mmol, 1.0 eq) in tetrahydrofuran (60 mL) was added titanium tetraisopropoxide (Ti(Oi-Pr)4, 6.3 mL, 21.22 mmol, 3.0 eq). The reaction was warmed to 130 °C for 20 h, cooled to room temperature and quenched with saturated aqueous potassium sodium tartrate (30 mL). After separation of the layers, the aqueous phase was extracted with ethyl acetate (EtOAc) (3 x 20 mL). The combined organic phases were washed with water (30 mL), saturated brine (30 mL), dried over anhydrous MgS04and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / EtOAc 1 : 1 to 1 :2 gradient elution) afforded compound 5 (1.75 g, 62% yield) as a yellow solid.

[0052] The nuclear magnetic hydrogen spectrum data, nuclear magnetic carbon spectrum data and high resolution data of compound 5 are as follows:

[0053] R f = 0.40 (petroleum ether / EtOAc = 1 / 2)

[0054] 1 HNMR (400 MHz, CDC13) δ 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 7.64 (dd, J = 5.5, 3.1 Hz, 2H), 7.26 (d, J = 7.6 Hz, 1H), 7.17 (td, J = 7.6, 1.3 Hz, 1H), 7.09 (d, J = 6.7 Hz, 1H), 6.95 (td, J = 7.4, 1.1 Hz, 1H), 5.45-5.33 (m, 1H), 4.78 (ddd, J = 15.1, 8.4, 1.7 Hz, 1H), 3.52-3.43 (m, 1H), 3.39-3.26 (m, 1H), 3.25-3.10 (m, 2H), 3.08 (s, 3H), 3.05-2.96 (m, 1H), 2.58-2.45 (m, 1H), 2.24-2.07 (m, 2H), 1.80-1.69 (m, 1H), 1.38 (dd, J = 6.5, 1.7 Hz, 3H).

[0055] 13 CNMR (100 MHz, CDC13) δ 176.6, 168.0, 136.9, 133.9, 132.1, 128.7, 128.1, 127.5, 123.2, 122.4, 121.6, 116.8, 54.8, 48.5, 41.9, 38.2, 36.5, 33.5, 26.3, 17.8.

[0056] HRMS calcd. for C 25 H 26 N3O2+ [M+H] + :400.2020.Found:400.2022.

[0057] (3) The double bond of compound 5 is cut off by oxidation to obtain aldehyde compound 6, and the specific method is as follows:

[0058] The DCM solution (40 mL) of compound 5 (1.722 g, 4.32 mmol, 1.0 eq) was cooled to -78°C, and ozone (O3) was introduced for 40 min. After the raw material was completely consumed, methanol (MeOH, 10 mL) and dimethyl sulfide (0.95 mL, 13.95 mmol, 3.0 eq) were added. The reaction was warmed to 0°C and stirred for 15 min, and then saturated NaHCO3 aqueous solution (40 mL) was added. Gradually warmed to room temperature and stirred for 4 h, after the layer was separated by a separatory funnel, the aqueous phase was extracted with DCM (3×20 mL). The combined organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure. Purified by column chromatography (gradient elution with DCM / MeOH 50:1 to 25:1), compound 6 and its isomer (1.13 g, total yield 68%, dr = 8:1) were obtained as a mixture.

[0059] The nuclear magnetic hydrogen spectrum data, nuclear magnetic carbon spectrum data and high resolution data of compound 6 are as follows:

[0060] R f = 0.40 (DCM / MeOH = 25 / 1)

[0061] 1 HNMR (400MHz, CDCl3) δ 9.04 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 5.5, 3.1 Hz, 2H), 7.69 (dd, J = 5.5, 3.0 Hz, 2H), 7.33-7.23 (m, 3H), 7.03 (td, J = 7.0, 2.0 Hz, 1H), 3.72-3.61 (m, 1H), 3.40-3.31 (m, 1H), 3.30-3.15 (m, 3H), 3.10 (s, 3H), 2.37-2.18 (m, 4H).

[0062] 13 CNMR (100MHz, CDCl3) δ 200.7, 174.4, 167.9, 134.1, 132.0, 129.4, 123.3, 122.2, 122.1, 117.5, 52.1, 50.4, 48.0, 38.2, 35.8, 32.9, 19.5.

[0063] HRMScalcd.forC 23 H 22 N3O3+ [M+H] + : 388.1656. Found: 388.1663.

[0064] (4) Compound 6 and phenylhydrazine undergo Fischer indole formation, Plancher rearrangement to give the seven-membered ring product 7, in detail as follows:

[0065] To a solution of compound 6 and its isomers (1.130 g, 2.90 mmol, 1.0 eq) in 1,4-dioxane (60 mL) was added phenylhydrazine hydrochloride (PhNHNH2·HCl, 1.05 g, 7.26 mmol, 2.5 eq) and sulfuric acid (H2SO4, 0.6 mL). The mixture was heated to 60 °C and stirred for 12 h. After reaction, the mixture was quenched with saturated aqueous NaHCO3solution (50 mL). The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous MgSO4and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / EtOAc 1:1 to 1:3 gradient elution) gave compound 7 (695 mg, 52% yield) as a yellow solid.

[0066] The NMR data of compound 7 is as follows:

[0067] R f = 0.17 (petroleum ether / EtOAc = 1 / 2)

[0068] 1 HNMR (400 MHz, CDC13) δ 8.10 (s, 1H), 7.75 (dd, J = 5.5, 3.0 Hz, 2H), 7.65 (dd, J = 5.5, 3.0 Hz, 2H), 7.58 (d, J = 7.3 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.29 - 7.21 (m, 3H), 7.17 - 7.02 (m, 3H), 4.79 (t, J = 13.2 Hz, 1H), 3.63 - 3.50 (m, 2H), 3.39 (ddd, J = 13.8, 9.5, 5.8 Hz, 1H), 3.30 (s, 3H), 3.26 - 3.12 (m, 1H), 3.02 (ddd, J = 14.4, 5.5, 3.2 Hz, 2H), 2.77 (ddd, J = 14.1, 9.7, 5.8 Hz, 1H).

[0069] 13CNMR (101 MHz, CDC13) δ 173.5, 167.9, 135.0, 134.5, 134.1, 131.9, 129.7, 128.9, 123.2, 122.7, 122.4, 121.5, 119.9, 117.9, 117.2, 111.1, 110.6, 55.8, 49.5, 40.3, 37.9, 34.1, 23.5.

[0070] HRMS calcd for C 29 H 25 N4O2 + [M+H] + : 461.1972. Found: 461.1972.

[0071] (5) The Phth protecting group of compound 7 was converted to methyl ester protecting group to obtain compound 8, and the ester group was further reduced to methyl to obtain compound 9, the specific method is as follows:

[0072] To the mixture of compound 7 (690 mg, 1.50 mmol, 1.0 eq) in DCM (20 mL) and MeOH (10 mL) was added hydrazine hydrate (N2H4-H2O, 1.7 mL, 29.99 mmol, 20.0 eq). Stirring at room temperature for 4 h, the reaction was quenched with water (10 mL). Extracted with DCM (3 x 10 mL). The combined organic phase was washed with water (20 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain a mixture.

[0073] To the DCM solution (25 mL) of the above mixture was added N, N-diisopropyl ethylamine (DIPEA, 0.34 mL, 1.96 mmol, 1.5 eq) and methyl chloroformate (ClCOOMe, 0.12 mL, 1.57 mmol, 1.2 eq) at 0 °C. Stirring at room temperature for 1 h, quenched with saturated aqueous NH4Cl solution (10 mL). Extracted with DCM (3 x 10 mL). The combined organic phase was washed with water (20 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. Purified by column chromatography (DCM / MeOH 100:1 by volume), to obtain the product 8 (481 mg, yield 95%) as a white solid.

[0074] The nuclear magnetic hydrogen spectrum data, nuclear magnetic carbon spectrum data and high resolution data of compound 8 are as follows:

[0075] R f = 0.49 (DCM / MeOH = 20 / 1)

[0076] 1HNMR (400 MHz, CDC13) δ 8.13 (s, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.30-7.23 (m, 3H), 7.15 (t, J = 6.9 Hz, 1H), 7.12-7.05 (m, 2H), 4.82 (t, J = 5.9 Hz, 1H), 4.72 (t, J = 13.6 Hz, 1H), 3.61 (s, 3H), 3.48 (dt, J = 15.4, 3.6 Hz, 1H), 3.37 (s, 3H), 3.17 (ddd, J = 17.2, 13.4, 4.1 Hz, 1H), 3.08-2.90 (m, 3H), 2.80 (dt, J = 12.5, 4.9 Hz, 1H), 2.49-2.38 (m, 1H).

[0077] 13 CNMR (100 MHz, CDC13) δ 174.6, 157.2, 135.0, 129.7, 129.4, 129.0, 122.7, 122.1, 121.5, 119.9, 118.0, 117.0, 111.1, 110.4, 56.0, 52.2, 49.4, 40.2, 40.1, 37.6, 23.6.

[0078] HRMS calcd. for C 23 H 25 N4O2 + [M+H] + : 389.1972. Found: 389.1969.

[0079] To a solution of LiAlH4(282 mg, 7.42 mmol, 6.0 eq) in tetrahydrofuran (THF) (25 mL) was added dropwise a solution of 8 (480 mg, 1.24 mmol, 1.0 eq) in THF at 0 °C. After stirring at 70 °C for 4 h, the excess LiAlH4was quenched by the addition of H2O (2.0 mL), 15% aqueous NaOH (2.0 mL) and H2O (10 mL) successively. The suspension was filtered through Celite and washed with THF (10 mL). The filtrate was separated into layers in a separatory funnel, and the aqueous phase was extracted with EA (3 x 10 mL). The combined organic phases were washed with water (10 mL), saturated brine (10 mL), dried over anhydrous MgS04and concentrated under reduced pressure. Purification by column chromatography (DCM / MeOH 5:1 by volume) gave the product 9 (362 mg, 85% yield) as a white solid.

[0080] The NMR data of compound 9, NMR data of compound 9, and high resolution data are as follows:

[0081] R f = 0.13 (DCM / MeOH = 6 / 1)

[0082] 1 HNMR (400 MHz, CDC13) δ 8.22 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 9.8 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.24 (dd, J = 7.5, 1.2 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.17-7.12 (m, 1H), 7.09 (t, J = 7.4 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 4.63 (t, J = 14.3 Hz, 1H), 3.71 (s, 1H), 3.46 (dt, J = 15.3, 3.5 Hz, 1H), 3.33 (s, 3H), 3.15 (ddd, J = 16.9, 13.2, 3.8 Hz, 1H), 3.01-2.92 (m, 1H), 2.86 (dd, J = 11.0, 8.5 Hz, 1H), 2.58 (d, J = 7.8 Hz, 2H), 2.27 (s, 3H), 2.20-2.11 (m, 1H).

[0083] 13 CNMR (100 MHz, CDC13) δ 174.9, 156.1, 136.2, 135.0, 130.1, 129.4, 128.9, 122.5, 121.6, 121.4, 119.8, 118.0, 117.2, 111.0, 110.8, 56.2, 49.6, 47.3, 39.7, 35.7, 27.0, 23.6.

[0084] HRMS calcd. for C 22 H 25 N4 + [M+H] + : 345.2074. Found: 345.2077.

[0085] (6) Compound 9 was reacted with NCS to give product (-)-psychotriadine via a skeletal rearrangement reaction. The specific method is as follows:

[0086] To a solution of compound 9 (360 mg, 1.05 mmol, 1.0 eq) in CHCI3(30 mL) was added N-chlorosuccinimide (NCS, 154 mg, 1.15 mmol, 1.1 eq). The temperature was raised to 70 °C and stirred for 5 h, quenched by the addition of aqueous NaOH (10 mL) and continued stirring for 20 min. Transferred to a separatory funnel and the layers were separated, the aqueous phase was extracted with DCM (3 x 10 mL). The combined organic phases were washed with water (20 mL) and dried over anhydrous MgS04before being concentrated under reduced pressure. Purified by column chromatography (DCM / MeOH 50:1 to 20:1 by volume) to give the final product (-)-psychotriadine (256 mg, 72% yield) as a white solid, which is compound 10.

[0087] The nuclear magnetic hydrogen spectrum data, nuclear magnetic carbon spectrum data and high resolution data of compound 10 are as follows:

[0088] R f = 0.38 (DCM / MeOH = 20 / 1)

[0089] 1 HNMR (400 MHz, CDCI3) δ 7.26 (d, J = 7.7 Hz, 2H), 7.10 (ddd, J = 7.6, 7.5, 1.6 Hz, 2H), 6.72 - 6.61 (m, 4H), 3.61 - 3.47 (m, 4H), 3.25 (s, 6H), 2.89 (ddd, J = 14.2, 11.6, 7.4 Hz, 2H), 1.51 (ddd, J = 14.2, 5.1, 1.6 Hz, 2H).

[0090] 13 CNMR (100 MHz, CDCI3) δ 176.3, 153.4, 136.2, 128.8, 121.7, 120.5, 117.5, 51.3, 49.3, 38.3, 33.2.

[0091] [a] D 20 = -43.74 (c 0.33, CH2CI2)

[0092] HRMS calcd. for C 22 H 23 N4 + [M + H] + : 343.1917. Found: 343.1924.

[0093] (7) The alkaloid (-)-psychotriadine (10) was reduced by diisobutylaluminum hydride (DIBAL-H) to give the analogue tetrahydropychotriadine (11). The procedure is as follows:

[0094] To a solution of the product psychotriadine (100 mg, 0.292 mmol, 1.0 equiv) in DCM (10 mL) was added diisobutylaluminum hydride (DIBAL-H, 1.95 mL, 2.92 mmol, 10.0 equiv, 1.5 M in toluene) at room temperature and stirred for 15 h, quenched by the addition of aqueous sodium potassium tartrate (10 mL) and stirred for another 30 min. The layers were separated in a separatory funnel and the aqueous phase was extracted with DCM (3 x 10 mL). The combined organic phases were washed with water (20 mL) and dried over anhydrous MgS04before being concentrated under reduced pressure. The final product (-)-tetrahydropychotriadine (39.4 mg, 39% yield) was obtained as a white solid, compound 11, after purification by column chromatography.

[0095] The NMR hydrogen spectrum data, NMR carbon spectrum data and high resolution data of compound 11 are as follows:

[0096] R f = 0.32 (DCM / MeOH = 4 / 1)

[0097] 1 HNMR (400 MHz, CDC13) δ 7.54 (d, J = 7.6 Hz, 2H), 6.74 (td, J = 7.6, 1.3 Hz, 2H), 6.39 (td, J = 7.5, 1.1 Hz, 2H), 6.32 (d, J = 7.7 Hz, 2H), 4.23 (s, 2H), 3.43 (td, J = 12.2, 3.2 Hz, 2H), 2.75-2.68 (m, 2H), 2.58 (s, 6H), 2.33-2.25 (m, 2H), 1.87 (dt, J = 13.6, 3.1 Hz, 2H).

[0098] 13 CNMR (151 MHz, CDC13) δ 148.5, 127.2, 125.1, 118.2, 109.7, 87.3, 45.8, 45.6, 43.0, 32.0.

[0099] M.p. = 152-155 °C

[0100] [a] D 25 = -123.15 (c 0.28, MeOH)

[0101] HRMScalcd.forC 22 H 27 N4 + [M+H] + :347.2230.Found:347.2225.

[0102] Investigation of the LXR Transcriptional Activation Activity of the Products (-)-psychotriadine and tetrahydropsychotriadine

[0103] 1. Experimental materials and methods

[0104] 1.1 Cell culture

[0105] Hek293T cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS, Gibco, Australia) at 37°C and 5% CO2.

[0106] 1.2 LXRα / β Dual Luciferase Reporter Assay (Luciferase)

[0107] Hek293T cells were seeded in 48-well plates at a density of 5*10 ^4 cells per well. When the cell density reached 50%, TATA-Luc (50 ng / well) and Renilla (5 ng / well) were transfected into the cells using PEI, and Gal4-DBD-LXRα-LBD (20 ng / well) was added in the LXRα group and Gal4-DBD-LXRβ-LBD (20 ng / well) was added in the LXRβ group. After 4 hours of transfection, complete medium containing 20% FBS without penicillin / streptomycin (P / S) was added to avoid potential cell damage caused by P / S during the transfection process. After 6 hours, the cells were treated with different concentrations of positive drug T0901317 and compounds 10 and 11. After 24 hours, the fluorescence intensity was measured using a dual luciferase reporter assay kit (Promega, E1960).

[0108] 2. Experimental results and conclusions

[0109] The experimental results are shown in Table 1 Figure 1As shown, compounds 10 and 11 can activate the transcription of LXRα / LXRβ protein at the same efficiency at the concentration of 20 μM, being potential LXR dual subtype agonists. Cholesterol metabolism disorder and neuroinflammation are closely related to Alzheimer's disease, and the LXR-ABCA1 / APOE pathway is the core hub connecting cholesterol metabolism, Aβ pathology and neuroinflammation in AD, and LXR has been considered as a potential target for the development of drugs for treating Alzheimer's disease (AD). Therefore, LXRα / β dual subtype agonist compounds 10 and 11 with novel structure are expected to be used as lead compounds for the development of anti-Alzheimer's disease drugs.

[0110] The above description of disclosed embodiments enables one of ordinary skill in the art to make or use the application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein can be applied to other embodiments without departing from the spirit or scope of the application. Thus, the present application is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for the synthesis of the alkaloid (-)-psychotriadine and analogues thereof, characterized in that, The method comprises the following steps: First, chiral intermediate 3 is synthesized by Meerwein-Eschenmoser-Claisen rearrangement reaction with compound 1 and compound 2 as starting materials; then, after removing the Boc protecting group, the oxidized indole compound 4 is obtained; Second, the piperidine ring of the oxidized indole compound 4 is constructed to obtain compound 5 under the condition of Ti(O-iPr)4; Third, the double bond of compound 5 is cut off by oxidation to obtain aldehyde compound 6; Fourth, compound 6 and phenylhydrazine undergo Fischer indole synthesis and Plancher rearrangement reaction to obtain seven-membered ring compound 7; Fifth, the Phth protecting group of compound 7 is converted into a methyl ester protecting group to obtain compound 8, and the ester group is further reduced to obtain compound 9; Sixth, compound 9 reacts with NCS to obtain compound 10, i.e. alkaloid (-)-psychotriadine, through skeleton rearrangement reaction; Seventh, compound 10 is reduced by diisobutylaluminum hydride to obtain compound 11, i.e. analog tetrahydropsychotradine; The specific reaction process is as follows:

2. The process for the synthesis of alkaloid (-)-psychotriadine and its analogues as claimed in claim 1 wherein, The specific method of the first step is as follows: add known compound 1 and Molecular sieve, add dichloromethane and cool to 0°C, then add DABCO, then add NCS, stir at 0°C for 2h, add compound 2 and methanesulfonic acid, gradually increase the temperature of the reaction to room temperature, and react at room temperature for 24h, filter the reaction liquid with a sand core funnel containing diatomite, rinse with DCM, collect the filtrate and concentrate in vacuum to obtain the crude product, oxidized indole compound 3; The crude product of the oxidized indole compound 3 is dissolved in DCM and cooled to 0 DEG C, then trifluoroacetic acid is added, the reaction is warmed to room temperature and stirred for 6 hours; the reaction is quenched by adding sodium hydroxide aqueous solution at 0 DEG C; the mixture is transferred to a separatory funnel, extracted with DCM, and the combined organic phase is dried over anhydrous magnesium sulfate and purified by column chromatography to obtain compound 4.

3. The process for synthesis of alkaloid (-)-psychotriadine and its analogues as claimed in claim 1, wherein, The specific method of the second step is as follows: Compound 4 is dissolved in tetrahydrofuran, Ti(O-iPr)4 is added at room temperature, the reaction is warmed to 130 DEG C and stirred for 20 hours; after the reaction is completed, it is cooled to room temperature, quenched with saturated potassium sodium tartrate solution, extracted with ethyl acetate, the combined organic layers are washed with water and saturated brine respectively, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure; finally, compound 5 is obtained by silica gel column chromatography.

4. The process for synthesis of alkaloid (-)-psychotriadine and its analogues as claimed in claim 1, wherein, The specific method of the third step is as follows: Compound 5 is dissolved in dichloromethane and cooled to -78 DEG C, and ozone is passed in for 40 minutes; after the starting material is completely consumed, methanol and dimethyl sulfide are added to quench the reaction; the reaction is warmed to 0 DEG C, stirred for 15 minutes, then saturated sodium bicarbonate aqueous solution is added; the obtained reaction system is stirred at room temperature for 4 hours, extracted with dichloromethane, and the organic phase is combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure; compound 6 and its isomers are obtained by silica gel column chromatography.

5. The process for synthesis of alkaloid (-)-psychotriadine and its analogues as claimed in claim 1, wherein, The specific method of the fourth step is as follows: Compound 6 and its isomers are dissolved in 1,4-dioxane, phenylhydrazine hydrochloride is added, then sulfuric acid is added; the obtained mixture is heated to 60 DEG C and stirred for 12 hours; the reaction is quenched by adding saturated sodium bicarbonate aqueous solution; extracted with ethyl acetate, the combined organic layers are washed with water and saturated brine respectively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure; compound 7 is obtained by silica gel column chromatography.

6. The process for synthesis of alkaloid (-)-psychotriadine and its analogues as claimed in claim 1, wherein, The specific method of the fifth step is as follows: Compound 7 was dissolved in a mixture of dichloromethane and methanol, hydrazine hydrate was added at 0°C, the reaction was warmed to room temperature and stirred for 4 hours, the reaction was quenched with water and extracted with dichloromethane; the organic phase was combined, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude primary amine compound; the crude primary amine compound was dissolved in dichloromethane, N, N-diisopropyl ethylamine was added at 0°C, followed by the addition of methyl chloroformate; the reaction was warmed to room temperature and stirred for 1 hour, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane; the combined organic layers were washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure; the product 8 was purified by silica gel column chromatography; Compound 8 was dissolved in THF, LiAlH4was added at 0°C, the reaction was heated to 70°C and stirred for 4 hours; the excess LiAlH4was quenched by the stepwise addition of water, 15% aqueous sodium hydroxide solution and water; the resulting suspension was filtered through a celite pad and rinsed with THF; extracted with ethyl acetate; the combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure; compound 9 was purified by silica gel column chromatography.

7. The process for synthesis of alkaloid (-)-psychotriadine and its analogues as claimed in claim 1, wherein, The specific method of the sixth step is as follows: Compound 9 was dissolved in chloroform, NCS was added at room temperature, the reaction was heated to 70°C and stirred for 5 hours, the reaction was quenched with aqueous sodium hydroxide solution; the reaction was extracted with dichloromethane; the organic phase was combined, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure; compound 10 was purified by silica gel column chromatography.

8. The process for synthesis of alkaloid (-)-psychotriadine and its analogues as claimed in claim 1, wherein, The specific method of the seventh step is as follows: Compound 10 was dissolved in DCM, DIBAL-H was added at room temperature and stirred for 15 hours, the reaction was quenched with aqueous sodium potassium tartrate solution and stirred for 30 minutes; it was transferred to a separatory funnel and separated into layers, the aqueous phase was extracted with DCM; the combined organic phases were washed with water, dried over anhydrous MgSO4and concentrated under reduced pressure; compound 11 was purified by column chromatography.

9. The use of alkaloid (-)-psychotriadine and its analog tetrahydropsychotradine synthesized by the synthetic method of any one of claims 1-8 in LXRα and LXRβ transcriptional activation activity and the treatment of Alzheimer's disease.

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