Tetrahydro-beta-carboline derivative with optical activity and preparation method thereof

Abstract

The invention relates to a tetrahydro-beta-carboline derivative with optical activity and a preparation method thereof, and the preparation method comprises the following steps: S1, mixing D-tryptophan methyl ester hydrochloride with an organic solvent to obtain a mixed system; s2, adding an aldehyde compound into the mixed system to obtain a reaction system; s3, the reaction system is heated to reflux, a reaction is carried out under the reflux condition, the tetrahydro-beta-carboline derivative is obtained, and the tetrahydro-beta-carboline derivative is of a cis-configuration or a trans-configuration. According to the method, D-tryptophan methyl ester hydrochloride and an aldehyde compound are subjected to a reaction under the reflux condition, the tetrahydro-beta-carboline derivative with optical activity is obtained, the preparation method is simple, no catalyst needs to be used, the reaction condition is mild, the obtained reaction product is of a single cis-configuration or trans-configuration, and the method is suitable for industrial production. Column chromatography separation is not needed, and post-treatment is simple.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to an optically active tetrahydro-β-carboline derivative and a preparation method thereof. Background Art

[0002] In 1911, when the chemists Ame Pictet and Theodor Spengler from the University of Geneva studied the preparation of tetrahydroisoquinoline (THIQ) from phenethylamine and aldehyde in an acidic medium, they discovered the Pictet-Spengler reaction. This reaction is widely used in the preparation of nitrogen-containing heterocyclic compounds and is one of the important methods for preparing isoquinoline and indole alkaloids.

[0003] In 2004, the Jacobsen group first reported a method for preparing tetrahydro-β-carboline derivatives by organocatalytic asymmetric Pictet-Spengler reaction. However, this reaction needs to be carried out at low temperature (-78 °C), and the operation is relatively cumbersome.

[0004] In 2006, Muthukrishnan et al. reported an article "Pictet-Spengler Cyclization in Room Temperature Ionic Liquid: A Convenient Access to Tetrahydroβ-Carbolines" in J. Heterocyclic Chem., constructing tetrahydro-β-carboline through ionic liquid-catalyzed Pictet-Spengler reaction. The reaction conditions are mild and the reaction time is shortened. However, this method has no selectivity and gives racemic products.

[0005] In 2013, the research group of Professor Shi from East China University of Science and Technology reported a method for highly selective synthesis of tetrahydro-β-carboline in Tetrahedron: Asymmetry, achieving efficient conversion of 14 substrates. However, this method still has certain limitations and is not fully applicable to some special substrates.

[0006] The patent application with publication number US8546421B1 reported a tetrahydro-β-carboline intermediate obtained through a trifluoroacetic acid-catalyzed Pictet-Spengler reaction. The disadvantages are that trifluoroacetic acid is used as a catalyst, column chromatography separation is required, the post-treatment is troublesome, the solvent consumption is large, and it is not suitable for large-scale industrial production.

[0007] Therefore, it has become an urgent technical problem to provide a preparation method of tetrahydro-β-carboline derivatives that does not require the use of any catalyst, has a simple method, mild reaction conditions, and the product is easy to separate. Summary of the Invention

[0008] To solve the above problems existing in the prior art, the present invention provides an optically active tetrahydro-β-carboline derivative and a preparation method thereof. The technical problems to be solved by the present invention are achieved through the following technical solutions:

[0009] The first aspect of the present invention provides a preparation method of an optically active tetrahydro-β-carboline derivative, comprising the following steps:

[0010] S1: Mix D-tryptophan methyl ester hydrochloride with an organic solvent to obtain a mixed system;

[0011] S2: Add an aldehyde compound to the mixed system to obtain a reaction system;

[0012] S3: Heat the reaction system to reflux and carry out the reaction under reflux conditions to obtain a tetrahydro-β-carboline derivative, and the tetrahydro-β-carboline derivative is in a cis configuration or a trans configuration.

[0013] In a specific embodiment, the structural formula of the aldehyde compound is as follows:

[0014]

[0015] Among them, R is selected from any one of aryl, substituted aryl, and heteroaryl.

[0016] In a specific embodiment, the aryl includes: phenyl, naphthyl, anthracenyl;

[0017] The substituted aryl includes: alkyl-substituted phenyl, alkoxy-substituted phenyl, phenyl-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, nitro-substituted phenyl, trifluoromethyl-substituted phenyl;

[0018] The heteroaryl includes: furyl, thienyl, pyridyl.

[0019] In a specific embodiment, the molar ratio of the D-tryptophan methyl ester hydrochloride to the aldehyde compound is 1:1 to 2.

[0020] In a specific embodiment, the organic solvent includes anhydrous acetonitrile.

[0021] In a specific embodiment, the reaction time in step S3 is 4 to 12 h.

[0022] In a specific embodiment, step S3 includes:

[0023] S301: Heat the reaction system to reflux and carry out the reaction under reflux conditions to obtain a product system;

[0024] S302: Perform vacuum filtration on the product system to obtain a filter cake;

[0025] S303: Wash the filter cake with anhydrous acetonitrile, perform drying after the washing is completed, and obtain an optically active tetrahydro-β-carboline derivative after drying.

[0026] The second aspect of the present invention provides an optically active tetrahydro-β-carboline derivative, which is prepared by the preparation method provided in the first aspect of the present invention. The structural formula of the tetrahydro-β-carboline derivative is shown as follows:

[0027]

[0028] Among them, R is selected from any one of aryl, substituted aryl, and heteroaryl;

[0029] The tetrahydro-β-carboline derivative is in a cis configuration or a trans configuration.

[0030] In a specific embodiment, the aryl includes: one of phenyl, naphthyl, and anthryl;

[0031] The substituted aryl includes: one of alkyl-substituted phenyl, alkoxy-substituted phenyl, phenyl-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, nitro-substituted phenyl, and trifluoromethyl-substituted phenyl;

[0032] The heteroaryl includes: one of furyl, thienyl, and pyridyl.

[0033] Compared with the prior art, the beneficial effects of the present invention:

[0034] The present invention reacts D-tryptophan methyl ester hydrochloride with an aldehyde compound under reflux conditions. The preparation method is simple, does not require the use of any catalyst, and the reaction conditions are mild; and after the reaction is completed, the components in the system are single, and column chromatography separation is not required, having the advantage that the product is easy to separate and the post-treatment is simple; at the same time, the reaction product prepared by this method is in a single cis configuration or trans configuration and has optical activity. Description of the Drawings

[0035] Figures 1a to 1b is the XRD single crystal structure diagram of the product obtained by using the preparation method provided in the embodiment of the present invention;

[0036] Figures 2a to 2n is the 1 HNMR spectrum of the product obtained by using the preparation method provided in the embodiment of the present invention;

[0037] Figures 3a to 3n is the 1 H- 11H NOESY spectrum Specific implementation mode

[0038] The present invention will be further described in detail below in conjunction with specific embodiments, but the implementation mode of the present invention is not limited thereto.

[0039] Embodiment 1

[0040] This embodiment provides a preparation method of an optically active tetrahydro-β-carboline derivative, which includes the following steps:

[0041] S1: Mix D-tryptophan methyl ester hydrochloride with an organic solvent to obtain a mixed system.

[0042] Specifically, the organic solvent includes anhydrous acetonitrile.

[0043] S2: Add an aldehyde compound to the mixed system to obtain a reaction system.

[0044] Specifically, the structural formula of the aldehyde compound is shown as follows:

[0045]

[0046] R is selected from any one of aryl, substituted aryl, and heteroaryl.

[0047] Specifically, aryl includes: phenyl, naphthyl, anthryl. Substituted aryl includes: alkyl-substituted benzene, alkoxy-substituted benzene, phenyl-substituted benzene, halogen-substituted benzene, cyano-substituted benzene, nitro-substituted benzene, trifluoromethyl-substituted benzene. Heteroaryl includes: furyl, thienyl, pyridyl.

[0048] Specifically, the molar ratio of D-tryptophan methyl ester hydrochloride to the aldehyde compound is 1:1 to 2.

[0049] S3: Heat the reaction system to reflux and carry out the reaction under reflux conditions to obtain an optically active tetrahydro-β-carboline derivative.

[0050] Specifically, step S3 includes:

[0051] S301: Heat the reaction system to reflux and carry out the reaction under reflux conditions to obtain a product system.

[0052] Specifically, place the reaction system in an oil bath heating environment, the oil bath temperature is 200 °C, heat the reaction system to reflux, and continuously stir. At this time, the temperature in the system is 90-100 °C, and the reaction is carried out under reflux stirring conditions for 4-12 h.

[0053] S302: Carry out vacuum filtration on the product system to obtain a filter cake.

[0054] Specifically, since the product is insoluble in anhydrous acetonitrile, the product system is a turbid liquid. After the reaction is completed, the product system is quickly subjected to vacuum filtration while it is still hot. The filter cake obtained by vacuum filtration is the crude product.

[0055] S303: Wash the filter cake with anhydrous acetonitrile, and perform drying after the washing is completed. After drying, an optically active tetrahydro-β-carboline derivative is obtained.

[0056] Specifically, wash the filter cake obtained by vacuum filtration with hot anhydrous acetonitrile at 50 °C, and perform vacuum drying after the washing is completed. After drying, an optically active tetrahydro-β-carboline derivative is obtained.

[0057] In this embodiment, the reaction general formula is as follows:

[0058]

[0059] Among them, the 1st C and the 3rd C are chiral carbons.

[0060] A preparation method of an optically active tetrahydro-β-carboline derivative provided in this embodiment reacts D-tryptophan methyl ester hydrochloride with an aldehyde compound under reflux conditions to obtain an optically active tetrahydro-β-carboline derivative. This preparation method is simple, does not require the use of any catalyst, the reaction conditions are mild, the reaction product obtained is a single cis configuration or trans configuration, does not require column chromatography separation, and the post-treatment is simple.

[0061] Example Two

[0062] This embodiment provides an optically active tetrahydro-β-carboline derivative, which is prepared by the preparation method provided in Embodiment 1 of the present invention, and the structural formula is as follows:

[0063]

[0064] Among them, R is selected from any one of aryl, substituted aryl, and heteroaryl; this tetrahydro-β-carboline derivative is in cis configuration or trans configuration. Specifically, aryl includes: phenyl, naphthyl, anthracenyl. Substituted aryl includes: alkyl-substituted benzene, alkoxy-substituted benzene, phenyl-substituted benzene, halogen-substituted benzene, cyano-substituted benzene, nitro-substituted benzene, trifluoromethyl-substituted benzene. Heteroaryl includes: furyl, thienyl, pyridyl.

[0065] An optically active tetrahydro-β-carboline derivative provided in this embodiment, this tetrahydro-β-carboline derivative is in a single cis configuration or trans configuration.

[0066] Example Three

[0067] Based on Example 1, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative, and the preparation method includes:

[0068] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) into a 250 mL three-necked flask. After stirring evenly, add 2.04 g (11 mmol) of compound 3a. Heat the reaction system to reflux and continuously stir. React for 6 h under the condition of reflux stirring. After the reaction ends, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain a grayish-white solid product 1a. The yield of this example is 53.4%. The reaction equation of this example is as follows:

[0069]

[0070] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3a is an aldehyde compound, and product 1a is a tetrahydro-β-carboline derivative. The XRD single crystal structure diagram of product 1a is as Figure 1a shown, and product 1a is in the trans configuration. From Figure 1a , 1 HNMR data and ESI-MS data, it can be proved that the structure of product 1a prepared in this example meets the requirements.

[0071] 1 HNMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.71 - 7.66 (m, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.29 - 7.18 (m, 3H), 7.04 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 6.78 - 6.72 (m, 1H), 5.66 (s, 1H), 3.72 - 3.66 (m, 1H), 3.62 (s, 3H), 3.12 (s, 1H), 3.08 (dd, J = 15.1, 4.8 Hz, 1H), 2.85 (dd, J = 14.9, 8.5 Hz, 1H).

[0072] ESI-MS (M + H) + m / z: 385.05.

[0073] Example 4

[0074] Based on Example 1, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative, and the preparation method includes:

[0075] In a 250 mL three-necked flask, 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) were added. After stirring evenly, 2.22 g (12 mmol) of compound 3b was added. The reaction system was heated to reflux and continuously stirred. The reaction was carried out for 6 h under reflux stirring. After the reaction, the system was a turbid liquid. It was quickly filtered under reduced pressure while it was hot, and the filter cake was washed with hot anhydrous acetonitrile and then dried in vacuo to obtain product 1b. The reaction equation for this example is as follows:

[0076]

[0077] In this example, compound 2 was D-tryptophan methyl ester hydrochloride, compound 3b was an aldehyde compound, product 1b was a tetrahydro-β-carboline derivative, and product 1b was in the cis configuration. The 1 HNMR spectrum of product 1b is as Figure 2a shown, 1 H- 1 The H- Figure 3a H NOESY spectrum is as Figure 2a 、 3a shown. From

[0078] 1 HNMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.46 (s, 1H), 7.77 - 7.71 (m, 2H), 7.57 (t, J = 6.5 Hz, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 5.99 (s, 1H), 4.75 (s, 1H), 3.85 (s, 3H), 3.38 - 3.34 (m, 1H), 3.34 - 3.26 (m, 1H).

[0079] ESI-MS (M + H) + m / z: 385.06.

[0080] Example 5

[0081] Based on Example 1, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative. This preparation method includes:

[0082] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.41 g (11 mmol) of compound 3c. Heat the reaction system to reflux and continue stirring. React for 6 h under reflux stirring conditions. After the reaction, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, wash the filter cake with hot anhydrous acetonitrile, and then dry it under vacuum to obtain product 1c. The reaction equation for this example is as follows:

[0083]

[0084] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3c is an aldehyde compound, product 1c is a tetrahydro-β-carboline derivative, and product 1c is in the cis configuration. The 1 HNMR spectrum of product 1c is as Figure 2b shown, 1 H- 1 The H- Figure 3b H NOESY spectrum is as Figure 2b , Figure 3b and ESI-MS data can prove that the structure of product 1c prepared in this example meets the requirements.

[0085] 1 HNMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.89 (s, 1H), 10.60 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.98 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.06 (s, 1H), 4.79 (s, 1H), 3.86 (s, 3H), 3.39 - 3.27 (m, 2H).

[0086] ESI-MS (M + H) + m / z: 332.30.

[0087] Example 6

[0088] Based on Example 1, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative, and this preparation method includes:

[0089] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.44 g (12 mmol) of compound 3d. Heat the reaction system to reflux and continue stirring. React for 6 h under reflux stirring conditions. After the reaction, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, wash the filter cake with hot anhydrous acetonitrile, and then dry it under vacuum to obtain product 1d. The reaction equation for this example is as follows:

[0090]

[0091] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3d is an aldehyde compound, product 1a is a tetrahydro-β-carboline derivative, and product 1d has a cis configuration. The 1 1H NMR spectrum of product 1d is as Figure 2c shown. 1 The H- 1 H NOESY spectrum is as Figure 3c shown. From Figure 2c , Figure 3c and ESI-MS data, it can be proved that the structure of product 1d prepared in this example meets the requirements.

[0092] 1 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.73 (s, 1H), 10.20 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.35 (d, J = 8.5 Hz, 3H), 7.29 (d, J = 8.0 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 5.90 (s, 1H), 4.77 (s, 1H), 3.85 (s, 3H), 3.37 - 3.25 (m, 2H), 2.35 (s, 3H).

[0093] ESI-MS (M + H) + m / z: 321.30.

[0094] Example 7

[0095] Based on Example 1, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative, and this preparation method includes:

[0096] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 2.57 g (13 mmol) of compound 3e. Heat the reaction system to reflux and continue stirring. React for 6 h under reflux stirring conditions. After the reaction, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, wash the filter cake with hot anhydrous acetonitrile, and then dry it under vacuum to obtain product 1e. The reaction equation for this example is as follows:

[0097]

[0098] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3e is an aldehyde compound, product 1e is a tetrahydro-β-carboline derivative, and product 1e is in the trans configuration. The 1 1H NMR spectrum of product 1e is as shown in Figure 2d shown. The 1 1H- 1 1H NOESY spectrum of product 1e is as shown in Figure 3d shown. From the Figure 2d , Figure 3d and ESI-MS data, it can be proved that the structure of product 1e prepared in this example meets the requirements.

[0099] 1 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.02 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.46 - 7.37 (m, 3H), 7.33 (d, J = 8.1 Hz, 1H), 7.22 (s, 1H), 7.19 - 7.10 (m, 3H), 7.10 - 7.03 (m, 4H), 6.01 (s, 1H), 4.56 - 4.46 (m, 1H), 3.52 (dd, J = 16.0, 5.5 Hz, 1H), 3.22 (dd, J = 15.9, 8.1 Hz, 1H).

[0100] ESI-MS (M + H) + m / z: 399.30.

[0101] Example 8

[0102] Based on Example 1, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative, which includes:

[0103] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.36 g (13 mmol) of compound 3f. Heat the reaction system to reflux and continue stirring. React for 6 h under reflux stirring conditions. After the reaction is completed, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain product 1f. The reaction equation of this example is as follows:

[0104]

[0105] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3f is an aldehyde compound, product 1f is a tetrahydro-β-carboline derivative, and product 1f is in the cis configuration. The 1 1H NMR spectrum of product 1f is as Figure 2e shown, 1 the 1 1H- Figure 3e H NOESY spectrum is as Figure 2e 、 Figure 3e shown. It can be proved by

[0106] 1 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.67 (s, 1H), 10.17 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 8.1 Hz, 1H), 7.15 - 7.10 (m, 1H), 7.06 (t, J = 7.4 Hz, 1H), 5.89 (s, 1H), 4.79 (s, 1H), 3.85 (s, 3H), 3.37 (d, J = 5.0 Hz, 1H), 3.32 - 3.25 (m, 1H), 2.39 (s, 3H).

[0107] ESI-MS (M + H) + m / z: 321.16.

[0108] Example 9

[0109] Based on Example 1, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative. The method for preparing an optically active tetrahydro-β-carboline derivative provided in this example includes:

[0110] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.82 g (11 mmol) of compound 3g. Heat the reaction system to reflux and continue stirring. React for 6 h under reflux stirring conditions. After the reaction is completed, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, wash the filter cake with hot anhydrous acetonitrile, and then dry it under vacuum to obtain 1 g of the product. The reaction equation for this example is as follows:

[0111]

[0112] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3g is an aldehyde compound, product 1g is a tetrahydro-β-carboline derivative, and product 1g is in the cis configuration. The 1 1H NMR spectrum of product 1g is as Figure 2f shown, 1 H- 1 H NOESY spectrum of product 1g is as Figure 3f shown. From Figure 2f , Figure 3f and ESI-MS data, it can be proved that the structure of product 1g prepared in this example meets the requirements.

[0113] 1 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.76 (s, 1H), 10.39 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.08 - 7.04 (m, 1H), 6.77 (d, J = 1.8 Hz, 2H), 6.67 (t, J = 2.1 Hz, 1H), 5.87 (s, 1H), 4.75 (s, 1H), 3.86 (s, 3H), 3.78 (s, 6H).

[0114] ESI-MS (M + H) + m / z: 367.17

[0115] Example Ten

[0116] Based on Example One, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative, which includes:

[0117] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.40 g (10.5 mmol) of compound 3h. Heat the reaction system to reflux and continue stirring. React for 6 h under reflux stirring conditions. After the reaction is completed, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain product 1h. The reaction equation of this example is as follows:

[0118]

[0119] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3h is an aldehyde compound, product 1h is a tetrahydro-β-carboline derivative, and product 1h is in the trans configuration. The 1 1H NMR spectrum is as Figure 2g shown, 1 H- 1 H NOESY spectrum is as Figure 3g shown. From Figure 2g , Figure 3g and ESI-MS data, it can be proved that the structure of product 1h prepared in this example meets the requirements.

[0120] 1 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.92 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 9.2 Hz, 2H), 7.13 (td, J = 8.1, 1.3 Hz, 2H), 7.09 - 7.03 (m, 1H), 5.90 (s, 1H), 4.48 (dd, J = 7.6, 5.8 Hz, 1H), 3.77 (s, 3H), 3.54 (dd, J = 16.0, 5.5 Hz, 1H), 3.23 (dd, J = 15.9, 7.9 Hz, 1H), 2.24 (d, J = 10.2 Hz, 6H).

[0121] ESI-MS (M + H) + m / z: 335.17.

[0122] Example 11

[0123] Based on Example 1, this example provides a preparation method of an optically active tetrahydro-β-carboline derivative, and this preparation method includes:

[0124] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 2.01 g (11.5 mmol) of compound 3i. Heat the reaction system to reflux and continue stirring. React for 6 h under reflux stirring conditions. After the reaction, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, wash the filter cake with hot anhydrous acetonitrile, and then dry it under vacuum to obtain product 1i. The reaction equation of this example is as follows:

[0125]

[0126] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3i is an aldehyde compound, product 1i is a tetrahydro-β-carboline derivative, and product 1i is in the cis configuration. The 1 HNMR spectrum is as shown in Figure 2h shown. 1 The H- 1 H NOESY spectrum is as shown in Figure 3h shown. From Figure 2h , Figure 3h and ESI-MS data, it can be proved that the structure of product 11 prepared in this example meets the requirements.

[0127] 1 HNMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 10.57 (s, 1H), 7.80 (dd, J = 9.8, 5.2 Hz, 2H), 7.55 (dd, J = 13.4, 5.0 Hz, 2H), 7.29 (d, J = 8.1 Hz, 1H), 7.14 (t, J = 7.1 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.02 (s, 1H), 4.76 (s, 1H), 3.86 (s, 3H), 3.32 (dd, J = 24.0, 12.2 Hz, 2H).

[0128] ESI-MS (M + H)+ m / z: 375.20.

[0129] Example Twelve

[0130] Based on Example One, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative, and the preparation method includes:

[0131] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.99 g (12 mmol) of compound 3j. Heat the reaction system to reflux and continue stirring. React for 6 h under the condition of reflux stirring. After the reaction is completed, the system is a turbid liquid. Filter it quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it in vacuo to obtain product 1j. The reaction equation of this example is as follows:

[0132]

[0133] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3j is an aldehyde compound, product 1j is a tetrahydro-β-carboline derivative, and product 1j is in the trans configuration. The 1 1H NMR spectrum of product 1j is as Figure 2i shown, 1 H- 1 H NOESY spectrum of product 1j is as Figure 3i shown. From Figure 2i , Figure 3i and ESI-MS data, it can be proved that the structure of product 1j prepared in this example meets the requirements.

[0134] 1 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.93 (s, 1H), 9.97 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.18 - 7.12 (m, 1H), 7.09 - 7.03 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 8.3, 2.0 Hz, 1H), 5.95 (s, 1H), 4.47 (dd, J = 7.4, 6.0 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.54 (dd, J = 16.0, 5.6 Hz, 1H), 3.23 (dd, J = 15.8, 7.8 Hz, 1H).

[0135] ESI-MS (M + H) + m / z: 367.18.

[0136] Example Thirteen

[0137] Based on Example One, this example provides a preparation method of an optically active tetrahydro-β-carboline derivative, and this preparation method includes:

[0138] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.80 g (11 mmol) of compound 3k. Heat the reaction system to reflux and continue stirring. React for 6 h under reflux stirring conditions. After the reaction is completed, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain product 1k. The reaction equation of this example is as follows:

[0139]

[0140] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3k is an aldehyde compound, product 1k is a tetrahydro-β-carboline derivative, and product 1k is in the trans configuration. The 1 HNMR spectrum is as Figure 2j shown. 1 H- 1 H NOESY spectrum is as Figure 3j shown. From Figure 2j , Figure 3j and ESI-MS data, it can be proved that the structure of product 1k prepared in this example meets the requirements.

[0141] 1 HNMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.98 (s, 1H), 9.90 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.35 - 7.27 (m, 3H), 7.17 - 7.11 (m, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 5.95 (s, 1H), 4.49 - 4.38 (m, 1H), 3.95 (t, J = 6.5 Hz, 2H), 3.77 (s, 3H), 3.52 (dd, J = 16.0, 5.5 Hz, 1H), 3.22 (dd, J = 15.9, 8.2 Hz, 1H), 1.78 - 1.65 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).

[0142] ESI-MS (M + H) + m / z: 365.30.

[0143] Example 14

[0144] On the basis of Example 1, this example provides a preparation method of an optically active tetrahydro-β-carboline derivative, and this preparation method includes:

[0145] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) into a 250 mL three-necked flask. After stirring evenly, add 1.55 g (10.5 mmol) of compound 3l. Heat the reaction system to reflux and continue stirring. React for 6 h under the condition of reflux stirring. After the reaction is completed, the system is a turbid liquid. Filter it quickly under reduced pressure while it is hot, wash the filter cake with hot anhydrous acetonitrile, and then dry it under vacuum to obtain product 1l. The reaction equation of this example is as follows:

[0146]

[0147] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3l is an aldehyde compound, product 1l is a tetrahydro-β-carboline derivative, and product 1l has a cis configuration. The 1 1H NMR spectrum is as Figure 2k shown. 1 The H- 1 H NOESY spectrum is as Figure 3k shown. From Figure 2k , Figure 3k and ESI-MS data, it can be proved that the structure of product 1l prepared in this example meets the requirements.

[0148] 1 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.70 (s, 1H), 10.19 (s, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.1 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 5.92 (s, 1H), 4.76 (s, 1H), 3.84 (s, 3H), 2.97 (dt, J = 13.8, 6.9 Hz, 1H), 1.26 (s, 3H), 1.24 (s, 3H).

[0149] ESI-MS (M + H) + m / z: 349.20.

[0150] Example 15

[0151] On the basis of Example 1, this example provides a preparation method of an optically active tetrahydro-β-carboline derivative, and this preparation method includes:

[0152] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.59 g (10.5 mmol) of compound 3m. Heat the reaction system to reflux and continue stirring. React for 6 h under reflux stirring conditions. After the reaction is completed, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain product 1m. The reaction equation for this example is as follows:

[0153]

[0154] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3m is an aldehyde compound, product 1m is a tetrahydro-β-carboline derivative, and product 1m is in the cis configuration. The 1 HNMR spectrum of product 1m is as Figure 2l shown. 1 H- 1 The H- Figure 3l H NOESY spectrum is as Figure 2l 、 Figure 3l shown. It can be proved by

[0155] 1 and ESI-MS data that the structure of product 1m prepared in this example meets the requirements.

[0156] ESI-MS (M+H) + m / z: 352.30.

[0157] Example XVI

[0158] Based on Example I, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative, and this preparation method includes:

[0159] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.74 g (12 mmol) of compound 3n. Heat the reaction system to reflux and continuously stir. React for 6 h under reflux stirring conditions. After the reaction is completed, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain product 1n. The reaction equation of this example is as follows:

[0160]

[0161] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3n is an aldehyde compound, product 1n is a tetrahydro-β-carboline derivative, and product 1n is in the cis configuration. The 1 1H NMR spectrum is as Figure 2m shown, 1 H- 1 H NOESY spectrum is as Figure 3m shown. From Figure 2m , Figure 3m and ESI-MS data, it can be proved that the structure of product 1n prepared in this example meets the requirements.

[0162] 1 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.86 (s, 1H), 10.53 (s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.3 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.08 (s, 1H), 4.80 (d, J = 4.9 Hz, 1H), 3.85 (s, 3H), 3.38 - 3.28 (m, 2H).

[0163] ESI-MS (M + H) + m / z: 375.12.

[0164] Example XVII

[0165] Based on Example 1, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative, and this preparation method includes:

[0166] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.49 g (12 mmol) of compound 3o. Heat the reaction system to reflux and continue stirring. React for 6 h under reflux stirring conditions. After the reaction, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, wash the filter cake with hot anhydrous acetonitrile, and then dry it under vacuum to obtain product 1o. The reaction equation of this example is as follows:

[0167]

[0168] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3o is an aldehyde compound, product 1o is a tetrahydro-β-carboline derivative, and product 1o is in the cis configuration. The 1 1H NMR spectrum of product 1o is as Figure 2n shown, 1 H- 1 H NOESY spectrum is as Figure 3n shown. From Figure 2n , Figure 3n and ESI-MS data, it can be proved that the structure of product 1o prepared in this example meets the requirements.

[0169] 1 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 10.70 (s, 1H), 10.25 (s, 1H), 7.62 - 7.49 (m, 3H), 7.37 (t, J = 8.8 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.1 Hz, 1H), 7.06 (t, J = 7.1 Hz, 1H), 5.97 (s, 1H), 4.79 (s, 1H), 3.86 (s, 3H), 3.35 - 3.19 (m, 2H).

[0170] ESI-MS (M + H) + m / z: 325.13.

[0171] Example 18

[0172] Based on Example 1, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative, which includes:

[0173] A method for preparing an optically active tetrahydro-β-carboline derivative provided in this example includes:

[0174] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.77 g (13 mmol) of compound 3p. Heat the reaction system to reflux and continue stirring. React for 6 h under reflux stirring conditions. After the reaction is completed, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain product 1p. The reaction equation of this example is as follows:

[0175]

[0176] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3p is an aldehyde compound, product 1p is a tetrahydro-β-carboline derivative, and product 1p is in the trans configuration. From 1 the HNMR data and ESI-MS data, it can be proved that the structure of product 1p prepared in this example meets the requirements.

[0177] 1 HNMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.77 (s, 1H), 9.70 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.32 (dd, J = 8.4, 4.4 Hz, 3H), 7.17 - 7.11 (m, 1H), 7.10 - 7.04 (m, 1H), 7.01 (d, J = 8.8 Hz, 2H), 5.95 (s, 1H), 4.49 - 4.37 (m, 1H), 3.78 (s, 3H), 3.50 (dd, J = 16.1, 5.5 Hz, 1H), 3.20 (dd, J = 16.0, 8.5 Hz, 1H).

[0178] ESI-MS (M + H) + m / z: 337.14

[0179] Example XIX

[0180] Based on Example 1, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative, and this preparation method includes:

[0181] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.91 g (10.5 mmol) of compound 3q. Heat the reaction system to reflux and continue stirring. React for 6 h under reflux stirring conditions. After the reaction is completed, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain product 1q. The reaction equation of this example is as follows:

[0182]

[0183] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3q is an aldehyde compound, product 1q is a tetrahydro-β-carboline derivative, and product 1q is in the cis configuration. From 1 the HNMR data and ESI-MS data, it can be demonstrated that the structure of product 1q prepared in this example meets the requirements.

[0184] 1 HNMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.71 (s, 1H), 10.24 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.77 - 7.72 (m, 2H), 7.59 (dd, J = 11.1, 8.2 Hz, 3H), 7.52 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.3 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.1 Hz, 1H), 7.06 (t, J = 7.1 Hz, 1H), 6.00 (s, 1H), 4.82 (s, 1H), 3.86 (s, 3H), 3.36 - 3.23 (m, 2H).

[0185] ESI-MS (M + H) + m / z: 383.30.

[0186] Example 20

[0187] Based on Example 1, this example provides a method for preparing an optically active tetrahydro-β-carboline derivative, and this preparation method includes:

[0188] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile ACN to a 250 mL three-necked flask. After stirring evenly, add 2.03 g (13 mmol) of compound 3r. Heat the reaction system to reflux and continue stirring. React for 6 h under the condition of reflux stirring. After the reaction is completed, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain product 1r. The reaction equation of this example is as follows:

[0189]

[0190] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3r is an aldehyde compound, and product 1r is a tetrahydro-β-carboline derivative. The XRD single crystal structure diagram of product 1r is as Figure 1b shown, and product 1r is in the trans configuration. From1 The HNMR data and ESI-MS data can prove that the structure of the product 1r prepared in this example meets the requirements.

[0191] 1 HNMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.44 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.05 (dd, J = 11.0, 4.0 Hz, 1H), 7.00 (dd, J = 10.9, 3.9 Hz, 1H), 6.89 (s, 1H), 6.11 (s, 1H), 3.76 - 3.69 (m, 1H), 3.60 (s, 3H), 3.18 (dd, J = 12.2, 7.4 Hz, 1H), 3.13 (dd, J = 15.1, 4.8 Hz, 1H), 2.90 (dd, J = 14.9, 8.8 Hz, 1H).

[0192] ESI-MS (M + H) + m / z: 357.19.

[0193] Example 21

[0194] On the basis of Example 1, this example provides a preparation method of an optically active tetrahydro-β-carboline derivative, and the preparation method includes:

[0195] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile ACN into a 250 mL three-necked flask. After stirring evenly, add 1.93 g (11 mmol) of compound 3s. Heat the reaction system to reflux and continuously stir. React for 6 h under the condition of reflux stirring. After the reaction is completed, the system is a turbid liquid. Quickly carry out vacuum filtration while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain the product 1s. The reaction equation of this example is as follows:

[0196]

[0197] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3s is an aldehyde compound, product 1s is a tetrahydro-β-carboline derivative, and product 1s is in the cis configuration. 1 The HNMR data and ESI-MS data can prove that the structure of the product 1s prepared in this example meets the requirements.

[0198] 1 HNMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 10.74 (s, 1H), 7.87 (d, J = 1.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 11.1, 4.0 Hz, 1H), 7.05 (t, J = 7.1 Hz, 1H), 6.34 (s, 1H), 5.06 (s, 1H), 3.86 (s, 3H), 3.38 (d, J = 4.8 Hz, 2H).

[0199] ESI-MS (M + H) + m / z: 375.20.

[0200] Example 22

[0201] On the basis of Example 1, this example provides a preparation method of an optically active tetrahydro-β-carboline derivative, and this preparation method includes:

[0202] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.93 g (11 mmol) of compound 3t. Heat the reaction system to reflux and continue stirring. React under reflux stirring conditions for 6 h. After the reaction is completed, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain product 1t. The reaction equation of this example is as follows:

[0203]

[0204] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3t is an aldehyde compound, product 1t is a tetrahydro-β-carboline derivative, and product 1t is in the trans configuration. 1 It can be proved by the HNMR data and ESI-MS data that the structure of product 1t prepared in this example meets the requirements.

[0205] 1HNMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.31 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.06 (t, J = 7.3 Hz, 1H), 7.00 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.71 (s, 1H), 3.70 (s, 1H), 3.64 (s, 3H), 3.24 (s, 1H), 3.10 (dd, J = 15.1, 4.8 Hz, 1H), 2.88 (dd, J = 14.9, 8.0 Hz, 1H).

[0206] ESI-MS (M+H) + m / z: 375.06.

[0207] Example 23

[0208] On the basis of Example 1, this example provides a preparation method of an optically active tetrahydro-β-carboline derivative, and the preparation method includes:

[0209] Add 2.54 g (10 mmol) of compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.63 g (12 mmol) of compound 3u. Heat the reaction system to reflux and continue stirring. React for 6 h under the condition of reflux stirring. After the reaction is completed, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain product 1u. The reaction equation of this example is as follows:

[0210]

[0211] In this example, compound 2 is D-tryptophan methyl ester hydrochloride, compound 3u is an aldehyde compound, product 1u is a tetrahydro-β-carboline derivative, and product 1u is in the cis configuration. From 1 The HNMR data and ESI-MS data can prove that the structure of product 1u prepared in this example meets the requirements.

[0212] 1HNMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 10.49 (s, 1H), 10.10 (s, 1H), 7.55 - 7.48 (m, 2H), 7.45 - 7.40 (m, 1H), 7.25 (dd, J = 18.4, 8.1 Hz, 2H), 7.10 (t, J = 7.2 Hz, 1H), 7.04 (t, J = 7.5 Hz, 2H), 6.26 (s, 1H), 4.95 (s, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.38 - 3.33 (m, 2H).

[0213] ESI-MS (M + H) + m / z: 373.30.

[0214] Example Twenty-Four

[0215] On the basis of Example 1, this example provides a preparation method of an optically active tetrahydro-β-carboline derivative, and this preparation method includes:

[0216] Add 2.54 g (10 mmol) of Compound 2 and 80 mL of anhydrous acetonitrile (ACN) to a 250 mL three-necked flask. After stirring evenly, add 1.46 g (13 mmol) of Compound 3v. Heat the reaction system to reflux and continue stirring. React for 6 h under the condition of reflux stirring. After the reaction is completed, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain Product 1v. The reaction equation of this example is as follows:

[0217]

[0218] In this example, Compound 2 is D-tryptophan methyl ester hydrochloride, Compound 3v is an aldehyde compound, Product 1v is a tetrahydro-β-carboline derivative, and Product 1v is in the cis configuration. 1 It can be proved by the HNMR data and ESI-MS data that the structure of Product 1v prepared in this example meets the requirements.

[0219] 1HNMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 10.88 (s, 1H), 10.42 (s, 1H), 7.80 (d, J = 4.8 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 2.8 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.22 (dd, J = 5.0, 3.6 Hz, 1H), 7.17 - 7.13 (m, 1H), 7.09 - 7.05 (m, 1H), 6.32 (s, 1H), 4.77 (s, 1H), 3.86 (s, 3H), 3.37 (dd, J = 15.6, 4.4 Hz, 1H), 3.28 - 3.17 (m, 1H).

[0220] ESI-MS (M+H) + m / z: 313.12.

[0221] Example Twenty-Five

[0222] On the basis of Example 1, this example provides a preparation method of an optically active tetrahydro-β-carboline derivative, and this preparation method includes:

[0223] Add 2.54 g (10 mmol) of Compound 2 and 80 mL of anhydrous acetonitrile (ACN) into a 250 mL three-necked flask. After stirring evenly, add 1.38 g (13 mmol) of Compound 3w. Heat the reaction system to reflux and continue stirring. React under reflux stirring conditions for 6 h. After the reaction ends, the system is a turbid liquid. Filter quickly under reduced pressure while it is hot, and wash the filter cake with hot anhydrous acetonitrile and then dry it under vacuum to obtain Product 1w. The reaction equation of this example is as follows:

[0224]

[0225] In this example, Compound 2 is D-tryptophan methyl ester hydrochloride, Compound 3w is an aldehyde compound, Product 1w is a tetrahydro-β-carboline derivative, and Product 1w is in the cis configuration. 1 It can be proved by the HNMR data and ESI-MS data that the structure of Product 1w prepared in this example meets the requirements.

[0226] 1HNMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.78 (s, 1H), 10.26 (s, 1H), 7.62 - 7.45 (m, 6H), 7.30 (d, J = 8.0 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.09 - 7.03 (m, 1H), 5.95 (s, 1H), 4.77 (d, J = 5.2 Hz, 1H), 3.85 (s, 3H), 3.37 - 3.25 (m, 2H).

[0227] ESI-MS (M + H) + m / z: 307.18.

[0228] The above content is a further detailed description of the present invention in combination with specific preferred embodiments. It cannot be determined that the specific implementation of the present invention is only limited to these descriptions. For those of ordinary skill in the technical field to which the present invention pertains, without departing from the concept of the present invention, several simple deductions or substitutions can be made, which should all be regarded as belonging to the protection scope of the present invention.

Claims

1. A method for preparing an optically active tetrahydro-β-carboline derivative, characterized in that, It includes the following steps: S1: Mix D-tryptophan methyl ester hydrochloride with an organic solvent to obtain a mixed system; S2: Add an aldehyde compound to the mixed system to obtain a reaction system; S3: Heat the reaction system to reflux and carry out the reaction under reflux conditions to obtain a tetrahydro-β-carboline derivative, and the tetrahydro-β-carboline derivative is in a cis configuration or a trans configuration.

2. The preparation method of an optically active tetrahydro-β-carboline derivative according to claim 1, characterized in that, The structural formula of the aldehyde compound is as follows: Wherein, R is selected from any one of aryl, substituted aryl, and heteroaryl.

3. The preparation method of an optically active tetrahydro-β-carboline derivative according to claim 2, characterized in that, The aryl includes: one of phenyl, naphthyl, and anthracenyl; The substituted aryl includes: one of alkyl-substituted phenyl, alkoxy-substituted phenyl, phenyl-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, nitro-substituted phenyl, and trifluoromethyl-substituted phenyl; The heteroaryl includes: one of furyl, thienyl, and pyridyl.

4. The preparation method of an optically active tetrahydro-β-carboline derivative according to claim 1, characterized in that, The molar ratio of the D-tryptophan methyl ester hydrochloride to the aldehyde compound is 1:1 to 2.

5. The preparation method of an optically active tetrahydro-β-carboline derivative according to claim 1, characterized in that, The organic solvent includes anhydrous acetonitrile.

6. The preparation method of an optically active tetrahydro-β-carboline derivative according to claim 1, characterized in that, The reaction time in step S3 is 4 to 12 h.

7. The preparation method of an optically active tetrahydro-β-carboline derivative according to claim 1, characterized in that, Step S3 includes: S301: Heat the reaction system to reflux and carry out the reaction under reflux conditions to obtain a product system; S302: Carry out vacuum filtration on the product system to obtain a filter cake; S303: Wash the filter cake with anhydrous acetonitrile, and after washing, carry out drying to obtain an optically active tetrahydro-β-carboline derivative.

8. An optically active tetrahydro-β-carboline derivative, characterized in that, Prepared by the preparation method according to any one of claims 1 to 7, and the structural formula of the tetrahydro-β-carboline derivative is as follows: Wherein, R is selected from any one of aryl, substituted aryl, and heteroaryl; The tetrahydro-β-carboline derivative is in a cis configuration or a trans configuration.

9. An optically active tetrahydro-β-carboline derivative according to claim 8, characterized in that, The aryl includes: one of phenyl, naphthyl, and anthracenyl; The substituted aryl includes: one of alkyl-substituted phenyl, alkoxy-substituted phenyl, phenyl-substituted phenyl, halogen-substituted phenyl, cyano-substituted phenyl, nitro-substituted phenyl, and trifluoromethyl-substituted phenyl; The heteroaryl includes: one of furyl, thienyl, and pyridyl.

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