CN110294740A - A kind of N- benzyl amino acid water solubility couroupitine A and its preparation method and application - Google Patents

Abstract

The invention discloses a water-soluble N-benzyl amino acid tryptamine, a preparation method and application thereof. The preparation method uses 2-bromomethyl-8-fluorotryptamine as a substrate, and connects various amino acids to improve the water solubility of tryptamine. 2-bromomethyl-8-fluorotryptamine is reacted with various amino acids in the presence of triethylamine and potassium iodide in an acetonitrile solvent, and the synthesized product is separated by column chromatography to obtain N-benzyl amino acid water-soluble tryptamine ketone. Most amino acids have good water solubility. The amino acid-modified tryptamine has enhanced water solubility, enhanced bioavailability and pharmacological activity, and has broad application prospects. Such tryptophan derivatives can be used for the treatment of pathological diseases with IDO-mediated tryptophan metabolic pathway, such as cancer, Alzheimer's disease, depression, cataract and the like. The content of the invention is simple in operation, mild in conditions and easy in industrial production.

Description

A kind of N-benzyl amino acid water-soluble tryptamine and its preparation method and application

technical field

The invention belongs to the field of medicinal chemistry, and relates to N-benzyl amino acid water-soluble tryptamine and a preparation method and application thereof.

Background technique

Tryptamine is an indolequinazoline alkaloid, a yellow needle-like crystal. It was originally extracted from blue-producing plants such as Malan, Polygonum, and Isatis as well as the fermentation broth of a few microorganisms. With the increase of people's demand for tryptamine, the artificial synthesis of tryptamine is particularly important. Tryptamine compounds have high antibacterial, anti-inflammatory, anti-malarial, anti-Leishmania, anti-Mycobacterium tuberculosis and anti-tumor activities, and tryptamine compounds have the characteristics of low toxicity and few side effects.

In recent years, studies have found that tryptamine derivatives are a new type of IDO inhibitors. Indoleamine-2,3-dioxygenase (IDO) is the only rate-limiting enzyme other than the liver that can catalyze the metabolism of tryptophan along the kynurenine pathway. IDO participates in the regulation of T cell responses by degrading tryptophan to arrest T cell proliferation in the G1 phase. Based on this mechanism, IDO expressed in tumors mediates tumor immune escape. Antigen-presenting cells such as macrophages and IDO on dendritic cells can induce T cells' immune tolerance to tumor antigens by inhibiting the proliferation of T cells. Therefore, IDO is involved in the immune regulation of various physiology and diseases, is closely related to the pathogenesis of various diseases, and has been confirmed to be the target of major diseases such as Alzheimer's disease, depression, cataract, and cancer.

The water solubility of drug molecules has a great influence on their absorption in the human body. Drug molecules with low water solubility limit drug absorption and reduce the bioavailability of orally administered drugs. In order to improve the water solubility of drug molecules, pharmacologists improve the water solubility of compounds by modifying their structures, such as introducing water-soluble groups. Most amino acids are soluble in water, and all amino acids are soluble in strong acids or bases. Various amino acids are connected in the compound to achieve the purpose of increasing the water solubility of the drug molecule.

Amino acids are one of the many biologically active macromolecules that build biological organisms, and are the basic materials for building cells and repairing tissues. Amino acids are used by the body to make antibody proteins to fight bacterial and viral infections, hemoglobin to transport oxygen, and enzymes and hormones to maintain and regulate metabolism. Amino acids are the main substances for the production of sperm and egg cells, and an indispensable prerequisite for the synthesis of neural mediators. Amino acids provide energy for the body and brain activity. Amino acid derivatives such as 1-methyltryptophan, as a competitive IDO1 inhibitor, entered clinical trials in 2007. Therefore, we tried to link amino acids to tryptophan to improve the water solubility of tryptamine and at the same time improve its IDO inhibitory activity.

SUMMARY OF THE INVENTION

The purpose of the present invention is to overcome the shortcomings of the prior art, and provide a kind of N-benzyl amino acid water-soluble tryptamine and its preparation method and application. The invention modifies the tryptamine to synthesize the N-benzyl amino acid water-soluble tryptamine. The preparation method has simple operation, mild conditions and easy industrial production.

To achieve the above object, the technical scheme adopted in the present invention is:

Using 2-bromomethyl-8-fluorotryptamine as the substrate, various amino acids are connected to improve the water solubility of tryptamine. 2-Bromomethyl-8-fluorotryptamine is reacted with various amino acids in the presence of triethylamine and potassium iodide in acetonitrile solvent, and the synthesized products are separated by column chromatography to obtain N-benzyl amino acid water-soluble tryptamine ketone.

Further, a kind of N-benzyl amino acid water-soluble tryptamine shown in formula A, the general formula of the compound is as follows:

Wherein, R is proline, tryptophan, cysteine, histidine, aspartic acid.

The structures of compounds of formula A include:

The preparation method of described N-benzyl tryptophan water-soluble tryptophan: according to the following route:

Including: oxidizing 5-methylisatin to 5-methylisatinic anhydride, then reacting with 5-fluoroisatin in the presence of triethylamine, refluxing in acetonitrile solvent, filtering and washing to obtain 2-methyl-8 -Fluorotryptamine. 2-Methyl-8-fluorotryptamine was reacted with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in carbon tetrachloride (CCl ₄ ) solvent under reflux, and concentrated to obtain 2-Bromomethyl-8-fluorotryptamine. 2-Bromomethyl-8-fluorotryptamine in acetonitrile (CH ₃ CN) solvent, adding amino acid ester, potassium iodide (KI) and triethylamine (Et ₃ N) to react at room temperature, spin dry and separate by column chromatography , to obtain 2-(amino acid ester methyl)-8-fluorotryptamine. Finally, 2-(amino acid ester methyl)-8-fluorotryptamine is hydrolyzed in methanol and aqueous solution of sodium hydroxide to obtain 2-(amino acid methyl)-8-fluorotryptamine; wherein:

The molar ratio of 5-methylisatin and m-chloroperoxybenzoic acid is: 1:(1～2);

And/or, the molar ratio of 5-methylisatinic anhydride, 5-fluoroisatin and triethylamine is: 1:(1～2):(3～5);

And/or, the molar ratio of 2-methyl-8-fluorotryptamine, NBS and azobisisobutyronitrile is: 1:(1.2～1.5):(0.1～0.5);

And/or, the molar ratio of 2-bromomethyl-8-fluorotryptamine, amino acid ester, potassium iodide and triethylamine is: 1:(1～2):(0.12～0.2):(3～5);

And/or, the molar ratio of 2-(N-amino acid ester methyl)-8-fluorotryptamine to sodium hydroxide is: 1:(3-5).

And/or, the preparation method of described N-benzyl amino acid tryptamine, comprises the following steps:

a. Synthesis of 5-methylisatinic anhydride

Suspend 5-methylisatin in dry dichloromethane, add m-chloroperoxybenzoic acid at 0°C, and stir at room temperature for 2-4 hours; after TLC detects the completion of the reaction, filter the orange solid obtained by the reaction, and use Wash with ethyl acetate to obtain 5-methylisatinic anhydride;

b. Synthesis of 2-methyl-8-fluorotryptamine

Suspend 5-methylisatinic anhydride and 5-fluoroisatin in dry acetonitrile solvent, add triethylamine, heat and stir at 82-90°C for 4-4.5 hours, cool to room temperature, filter, and wash the filter cake with methanol , to obtain 2-methyl-8-fluorotryptamine;

c. Synthesis of 2-bromomethyl-8-fluorotryptamine

Add 2-methyl-8-fluorotryptamine to dry carbon tetrachloride, then add a mixture of NBS and AIBN, under nitrogen protection, heat to 80 ℃ ~ 85 ℃, stir and reflux for 4 ~ 18 hours, TLC After the detection reaction is completed, spin dry and separate by column chromatography to obtain yellow 2-bromomethyl-8-fluorotryptamine;

Synthesis of d. N-benzyl amino acid ester tryptamine

2-Bromomethyl-8-fluorotryptamine, potassium iodide, triethylamine and various amino acid esters (proline/tryptophan/cysteine/histidine/aspartic acid) ester) was added to acetonitrile, and the reaction was stirred at room temperature for 2 to 5 hours. TLC detected that the reaction was completed, the solvent was evaporated under reduced pressure, and the mixture was separated by column chromatography. Obtain yellow N-benzyl amino acid ester tryptamine;

Synthesis of e.N-benzyl amino acid tryptamine

N-benzyl amino acid ester tryptamine was added to the methanol and water mixture of sodium hydroxide, mixed and stirred at room temperature for 4 to 5 hours, TLC detected the completion of the reaction, water was added, the methanol was spin-dried, and the remaining liquid was poured into hydrochloric acid , adjusted to pH=5～6, extracted with chloroform, combined the organic layers, dried with anhydrous sodium sulfate, filtered and concentrated to obtain N-benzyl amino acid tryptamine.

Further, in step a, the mol ratio of 5-methylisatin and m-chloroperoxybenzoic acid is: 1:(1～2);

And/or, in step b, the molar ratio of 5-methylisatinic anhydride to 5-fluoroisatin and triethylamine is: 1:(1～2):(3～5);

And/or, in step c, the molar ratio of 2-methyl-8-fluorotryptamine to N-bromosuccinimide and azobisisobutyronitrile is: 1:(1.2～1.5):( 0.1～0.5);

And/or, in step d, the molar ratio of 2-bromomethyl-8-fluorotryptamine, amino acid ester, potassium iodide and triethylamine is: 1:(1～2):(0.12～0.2):(3 ~5);

And/or, in step e, the molar ratio of 2-(N-benzyl amino acid ester)-8-fluorotryptamine to sodium hydroxide is: 1:(3-5).

An application of the above-mentioned N-benzyl amino acid water-soluble tryptophan derivative in the preparation of a medicine for preventing and/or treating a disease with pathological characteristics of IDO-mediated tryptophan metabolic pathway.

Since most amino acids have good water solubility, amino acid-modified tryptamine has enhanced water solubility, enhanced bioavailability and pharmacological activity, and has broad application prospects. Such tryptophan derivatives can be used for the treatment of pathological diseases with IDO-mediated tryptophan metabolic pathway, such as cancer, Alzheimer's disease, depression, cataract and the like. The content of the invention is simple in operation, mild in conditions and easy in industrial production.

Detailed ways

The present invention is further described below with reference to the examples. Unless otherwise specified, the reagents or raw materials involved in the following examples are all commercially available.

Implementation Case 1

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, and heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.3 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Data representation:

¹ HNMR (600MHz, Chloroform-d) δ 8.63 (dd, J=8.8, 4.0Hz, 1H), 8.33 (d, J=1.8Hz, 1H), 8.01-7.89 (m, 2H), 7.57 (dd, J=6.5, 2.7Hz, 1H), 7.47 (td, J=8.6, 2.8Hz, 1H), 4.12 (d, J=13.5Hz, 1H), 3.70 (s, 4H), 3.38 (t, J=7.6 Hz, 1H), 3.04(s, 1H), 2.46(d, J＝9.8Hz, 1H), 2.17(d, J＝10.2Hz, 1H), 2.01(td, J＝11.7, 10.5, 5.0Hz, 1H) ^The ,126.14,123.85,122.37,118.67(d,J＝7.6Hz),111.02(d,J＝24.4Hz),64.34,57.01,52.25,50.85,28.30,22.20.

Example 2

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered, washed with (5 mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, and heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.5 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Example 3

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered, washed with (5 mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, and heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.5 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Example 4

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, and heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.3 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Example 5

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.3 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Example 6

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.5 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Example 7

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.5 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Example 8

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.3 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Example 9

Step 1: Synthesis of 5-methylisatinic anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.3 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected that the reaction was complete, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.2 mL of sodium hydroxide solution (ω=8%, containing 14.8 mg of sodium hydroxide, or 0.3691 mmol) and 1 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, adjust to pH=5 to 6, and use (10mL×3) chloroform extraction, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow-brown product 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 10

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.5 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.3 mL of sodium hydroxide solution (ω=8%, containing 24.6 mg of sodium hydroxide, or 0.6151 mmol) and 1.5 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, and adjust to pH=5 to 6, Extract with (10 mL×3) chloroform, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-brown product, 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 11

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.5 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.2 mL of sodium hydroxide solution (ω=8%, containing 14.8 mg of sodium hydroxide, or 0.3691 mmol) and 1 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol, pour the remaining liquid into 1 mol/L hydrochloric acid, adjust to pH=5 to 6, and use (10mL×3) chloroform extraction, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow-brown product 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 12

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.3 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.3 mL of sodium hydroxide solution (ω=8%, containing 24.6 mg of sodium hydroxide, or 0.6151 mmol) and 1.5 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, and adjust to pH=5 to 6, Extract with (10 mL×3) chloroform, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-brown product, 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 13

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.3 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.2 mL of sodium hydroxide solution (ω=8%, containing 14.8 mg of sodium hydroxide, or 0.3691 mmol) and 1 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, adjust to pH=5 to 6, and use (10mL×3) chloroform extraction, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow-brown product 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 14

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.5 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.3 mL of sodium hydroxide solution (ω=8%, containing 24.6 mg of sodium hydroxide, or 0.6151 mmol) and 1.5 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, and adjust to pH=5 to 6, Extract with (10 mL×3) chloroform, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-brown product, 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 15

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.5 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.2 mL of sodium hydroxide solution (ω=8%, containing 14.8 mg of sodium hydroxide, or 0.3691 mmol) and 1 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol, pour the remaining liquid into 1 mol/L hydrochloric acid, adjust to pH=5 to 6, and use (10mL×3) chloroform extraction, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow-brown product 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 16

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 2293.5 mg (12.43 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.3 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.3 mL of sodium hydroxide solution (ω=8%, containing 24.6 mg of sodium hydroxide, or 0.6151 mmol) and 1.5 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, and adjust to pH=5 to 6, Extract with (10 mL×3) chloroform, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-brown product, 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 17

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, and heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.3 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.2 mL of sodium hydroxide solution (ω=8%, containing 14.8 mg of sodium hydroxide, or 0.3691 mmol) and 1 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, adjust to pH=5 to 6, and use (10mL×3) chloroform extraction, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow-brown product 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 18

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, and heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.5 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.3 mL of sodium hydroxide solution (ω=8%, containing 24.6 mg of sodium hydroxide, or 0.6151 mmol) and 1.5 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, and adjust to pH=5 to 6, Extract with (10 mL×3) chloroform, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-brown product, 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 19

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, and heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.5 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.2 mL of sodium hydroxide solution (ω=8%, containing 14.8 mg of sodium hydroxide, or 0.3691 mmol) and 1 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol, pour the remaining liquid into 1 mol/L hydrochloric acid, adjust to pH=5 to 6, and use (10mL×3) chloroform extraction, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow-brown product 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 20

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, and heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.3 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.3 mL of sodium hydroxide solution (ω=8%, containing 24.6 mg of sodium hydroxide, or 0.6151 mmol) and 1.5 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, and adjust to pH=5 to 6, Extract with (10 mL×3) chloroform, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-brown product, 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 21

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.3 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.2 mL of sodium hydroxide solution (ω=8%, containing 14.8 mg of sodium hydroxide, or 0.3691 mmol) and 1 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, adjust to pH=5 to 6, and use (10mL×3) chloroform extraction, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow-brown product 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 22

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.5 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.3 mL of sodium hydroxide solution (ω=8%, containing 24.6 mg of sodium hydroxide, or 0.6151 mmol) and 1.5 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, and adjust to pH=5 to 6, Extract with (10 mL×3) chloroform, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-brown product, 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 23

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.5 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.2 mL of sodium hydroxide solution (ω=8%, containing 14.8 mg of sodium hydroxide, or 0.3691 mmol) and 1 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, adjust to pH=5 to 6, and use (10mL×3) chloroform extraction, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow-brown product 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 24

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 932.9 mg (5.650 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.3 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.3 mL of sodium hydroxide solution (ω=8%, containing 24.6 mg of sodium hydroxide, or 0.6151 mmol) and 1.5 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, and adjust to pH=5 to 6, Extract with (10 mL×3) chloroform, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-brown product, 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 25

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.3 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.2 mL of sodium hydroxide solution (ω=8%, containing 14.8 mg of sodium hydroxide, or 0.3691 mmol) and 1 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, adjust to pH=5 to 6, and use (10mL×3) chloroform extraction, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow-brown product 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 26

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.5 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.3 mL of sodium hydroxide solution (ω=8%, containing 24.6 mg of sodium hydroxide, or 0.6151 mmol) and 1.5 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, and adjust to pH=5 to 6, Extract with (10 mL×3) chloroform, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-brown product, 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 27

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.5 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.2 mL of sodium hydroxide solution (ω=8%, containing 14.8 mg of sodium hydroxide, or 0.3691 mmol) and 1 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, adjust to pH=5 to 6, and use (10mL×3) chloroform extraction, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow-brown product 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 28

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 3.92 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.3 mL of triethylamine and 92.2 mg (0.5569 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.3 mL of sodium hydroxide solution (ω=8%, containing 24.6 mg of sodium hydroxide, or 0.6151 mmol) and 1.5 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, and adjust to pH=5 to 6, Extract with (10 mL×3) chloroform, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-brown product, 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 29

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.3 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.2 mL of sodium hydroxide solution (ω=8%, containing 14.8 mg of sodium hydroxide, or 0.3691 mmol) and 1 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, adjust to pH=5 to 6, and use (10mL×3) chloroform extraction, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow-brown product 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 30

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 152.6 mg (0.8571 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 11.1 mg (0.0668 mmol) of potassium iodide, 0.5 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.3 mL of sodium hydroxide solution (ω=8%, containing 24.6 mg of sodium hydroxide, or 0.6151 mmol) and 1.5 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, and adjust to pH=5 to 6, Extract with (10 mL×3) chloroform, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-brown product, 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 31

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 11.7 mg (0.071 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.5 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.2 mL of sodium hydroxide solution (ω=8%, containing 14.8 mg of sodium hydroxide, or 0.3691 mmol) and 1 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, adjust to pH=5 to 6, and use (10mL×3) chloroform extraction, combined organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow-brown product 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Example 32

Step 1: Synthesis of 5-Methylisatinic Anhydride

1000.0 mg (6.213 mmol) of 5-methylisatin 1 was suspended in 20 mL of dry dichloromethane, 1146.7 mg (6.213 mmol) of m-chloroperoxybenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 4 hours; After the completion of the TLC detection reaction, the orange solid obtained from the reaction solution was filtered and washed with (5mL×3) ethyl acetate to obtain 5-methylisatinic anhydride 2;

Step 2: Synthesis of 2-methyl-8-fluorotryptamine

Suspend 1000.0 mg (5.650 mmol) of 5-methylisatinic anhydride 2 and 1865.8 mg (11.3 mmol) of 5-fluoroisatin in 10 mL of dry acetonitrile solvent, add 2.35 mL of triethylamine, heat and stir for 82~ Reflux at 90°C for 4-4.5 hours, cooled to room temperature, filtered, and the filter cake was washed with (5 mL×3) methanol to obtain a yellow-green solid, namely 2-methyl-8-fluorotryptamine 3;

Step 3: Synthesis of 2-bromomethyl-8-fluorotryptamine

200.0 mg (0.7143 mmol) of 2-methyl-8-fluorotryptamine 3 was added to 20 mL of dry carbon tetrachloride, followed by 190.7 mg (1.071 mmol) of NBS and 58.8 mg (0.357 mmol) of AIBN The mixture was heated to 80-85°C under nitrogen protection, stirred and refluxed for 4-18 hours, TLC detected the completion of the reaction, spin-dried, and separated by column chromatography (dichloromethane) to obtain yellow 2-bromomethyl-8 - Fluorotryptamine 4;

Step 4: Synthesis of 2-(N-proline methyl ester methyl)-8-fluorotryptamine

Suspend 200 mg (0.5569 mmol) of 2-bromomethyl-8-fluorotryptamine 4 in 10 mL of acetonitrile, then add 18.5 mg (0.1114 mmol) of potassium iodide, 0.3 mL of triethylamine and 184.5 mg (1.11 mmol) of Proline methyl ester hydrochloride, reacted at room temperature for 2 to 5 hours, TLC detected the completion of the reaction, evaporated the solvent under reduced pressure to obtain a dark green solid, separated and purified by column chromatography (dichloromethane:methanol=90:1), The yellow product, 2-(N-proline methyl ester methyl)-8-fluorotryptamine 5, was obtained.

Step 5: Synthesis of 2-(N-prolinemethyl)-8-fluorotryptamine

Mix 50 mg (0.1229 mmol) of 2-(proline methyl ester methyl)-8-fluorotryptamine 5 with 0.3 mL of sodium hydroxide solution (ω=8%, containing 24.6 mg of sodium hydroxide, or 0.6151 mmol) and 1.5 mL of methanol, mix and stir at room temperature for 4 to 5 hours, TLC detects the completion of the reaction, add 1 mL of water, spin the methanol to dryness, pour the remaining liquid into 1 mol/L hydrochloric acid, and adjust to pH=5 to 6, Extract with (10 mL×3) chloroform, combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-brown product, 2-(N-prolinemethyl)-8-fluorotryptamine 6;

Regarding the inhibitory activity of compounds 5 and 6 on IDO1 enzyme, the specific embodiments are as follows:

Determination of IC ₅₀ of IDO1 Enzyme Level by Compounds 5 and 6

Example 33

The construction of the plasmid containing human IDO gene, expression in E. coli, purification and purification were carried out according to the method reported by Littlejohn et al. The inhibitory activity of the compounds against IDO was detected by the method described in the literature. The standard reaction mixture (0.5 mL) contained 100 mM potassium phosphate buffer (PH=6.5), 40 mM ascorbic acid, 200 μg/mL catalase, 20 μM methylene blue and 0.05 μM rhIDO enzyme. This standard reaction mixture was added to a solution containing a defined concentration of L-tryptophan and the test sample. The reaction was carried out at 37 °C for 30 min, then stopped, 200 μL of 30% (w/v) trichloroacetic acid was added, heated at 65 °C for 15 min, centrifuged at 1200 rpm for 10 min, and the supernatant was transferred to a microplate, Mix with 100 μL of 2% (w/v) p-(dimethylamino)benzaldehyde in acetic acid. The yellow pigment produced by kynurenine was measured spectrally at 492 nm, and the result was calculated using _IC50 calculation software.

Determination of IC ₅₀ of Compounds 5 and 6 on IDO1 at Cellular Level

Example 34

HeLa cells in logarithmic growth phase were taken, digested with 0.25% trypsin for 3 min, and resuspended in DMEM medium (containing 10% FBS). Count the cells with a hemocytometer, dilute the cells to 1.25×10 ⁵ /mL in DMEM medium, add 200 μL of cell suspension to a 96-well plate to make the seeding cell density reach 25,000 cells/well, and culture the cells at 37°C Incubate overnight in the box for 12h to make the cells fully adherent. Aspirate and discard the supernatant of the medium, replace with fresh medium, add 100ng/mL recombinant human interferon gamma and different concentrations of inhibitors, set the Blank group (no cells), the Control group (no drug addition) and the drug addition group, continue After incubation for 24h, the concentration range of the dosing group was set at about 100 times the _IC50 . Take the 96-well plate out of the incubator, transfer 100 μL of the supernatant to a 1.5 mL EP tube, add 10 μL of TCA to stop the reaction, vortex to mix, and incubate in a 50°C water bath for 30 min. Then centrifuge at 13000rpm for 10min, take 100μL of supernatant and transfer it to a new ELISA plate, add 100μL of p-diaminobenzaldehyde (2% in acetic acid), and detect the absorbance at 492nm with a microplate reader using Graphpadprism Software processes the data.

Using the above method, with INCB024360 (Epacadostat) as a positive control, the IDO1 inhibitory activities of compounds 5 and 6 were determined. The IDO1 enzyme inhibitory activities and Hela cell inhibitory activities of compounds 5 and 6 synthesized in the above examples are as follows:

<u>Compounds</u> <u>IC₅₀(nM)(IDO1 enzyme)</u> <u>IC₅₀(nM)(Hela cells)</u> <u>INCB024360</u> <u>92.46</u> <u>4.86</u> <u>Compound 5</u> <u>457.5</u> <u>669.2</u> <u>Compound 6</u> <u>553.1</u> <u>3756</u>

The foregoing description of the embodiments is provided to facilitate understanding and use of the present invention by those of ordinary skill in the art. It will be apparent to those skilled in the art that various modifications to these embodiments can be readily made, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above-described embodiments. Improvements and modifications made by those skilled in the art according to the principles of the present invention without departing from the scope of the present invention should all fall within the protection scope of the present invention.

Claims (11)

1. a N-benzyl amino acid water-soluble tryptamine, is characterized in that, described compound general formula is as follows: 2. N-benzyl amino acid water-soluble tryptamine according to claim 1, characterized in that: R is proline, tryptophan, cysteine, histidine or aspartic acid. 3. N-benzyl amino acid water-soluble tryptamine according to claim 1, is characterized in that, the structure of compound shown in formula A is as follows: 4. a preparation method of N-benzyl amino acid tryptamine, it is characterized in that: take 2-bromomethyl-8-fluorotryptamine as a substrate, connect amino acid, to improve the water solubility of tryptamine; 2 -Bromomethyl-8-fluorotryptamine in acetonitrile solvent, in the presence of triethylamine and potassium iodide, react with various amino acids, the synthesized products are separated by column chromatography to obtain N-benzyl amino acid water-soluble tryptamine ketone . 5. the preparation method of N-benzyl amino acid tryptamine according to claim 4, is characterized in that, according to following route: 6. according to the preparation method of the described N-benzyl amino acid tryptamine of claim 4, it is characterized in that, comprising: 5-methyl isatin is oxidized to 5-methyl through m-chloroperoxybenzoic acid (m-CPBA) Isatoic anhydride, then reacted with 5-fluoroisatin in the presence of triethylamine, refluxed in acetonitrile solvent, filtered and washed to obtain 2-methyl-8-fluorotryptamine; 2-methyl-8-fluorochrome The amine ketone is refluxed with N-bromosuccinimide (NBS) and azobisisobutyronitrile (AIBN) in carbon tetrachloride solvent, and concentrated to obtain 2-bromomethyl-8-fluorotryptamine; 2-Bromomethyl-8-fluorotryptamine in acetonitrile solvent, adding amino acid ester, potassium iodide and triethylamine to react at room temperature, spin dry, and separate by column chromatography to obtain 2-(amino acid ester methyl)-8- Fluorotryptamine; Finally, 2-(amino acid ester methyl)-8-fluorotryptamine is hydrolyzed in methanol and aqueous solution of sodium hydroxide to obtain 2-(amino acid methyl)-8-fluorotryptamine. 7. according to the preparation method of the described N-benzyl amino acid tryptamine of claim 6, it is characterised in that, The molar ratio of 5-methylisatin and m-chloroperoxybenzoic acid is: 1:(1～2); And/or, the molar ratio of 5-methylisatinic anhydride, 5-fluoroisatin and triethylamine is: 1:(1～2):(3～5); And/or, the molar ratio of 2-methyl-8-fluorotryptamine, NBS and azobisisobutyronitrile is: 1:(1.2～1.5):(0.1～0.5); And/or, the molar ratio of 2-bromomethyl-8-fluorotryptamine, amino acid ester, potassium iodide and triethylamine is: 1:(1～2):(0.12～0.2):(3～5); And/or, the molar ratio of 2-(N-amino acid ester methyl)-8-fluorotryptamine to sodium hydroxide is: 1:(3-5). 8. the preparation method of N-benzyl amino acid tryptamine according to claim 4, is characterized in that synthetic route is as follows: 9. the preparation method of N-benzyl amino acid tryptamine ketone according to claim 4, is characterized in that, comprises the following steps: a. Synthesis of 5-methylisatinic anhydride Suspend 5-methylisatin in dry dichloromethane, add m-chloroperoxybenzoic acid at 0°C, and stir at room temperature for 2-4 hours; after TLC (thin layer chromatography) detects the completion of the reaction, filter the reaction to obtain The orange solid was washed with ethyl acetate to give 5-methylisatinic anhydride; b. Synthesis of 2-methyl-8-fluorotryptamine Suspend 5-methylisatinic anhydride and 5-fluoroisatin in dry acetonitrile solvent, add triethylamine, heat and stir at 82-90℃ for 4-4.5 hours, cool to room temperature, filter, and wash the filter cake with methanol , to obtain 2-methyl-8-fluorotryptamine; c. Synthesis of 2-bromomethyl-8-fluorotryptamine Add 2-methyl-8-fluorotryptamine to dry carbon tetrachloride, then add a mixture of NBS and AIBN, under nitrogen protection, heat to 80 ℃ ~ 85 ℃, stir and reflux for 4-18 hours, TLC After the detection reaction is completed, spin dry and separate by column chromatography to obtain yellow 2-bromomethyl-8-fluorotryptamine; Synthesis of d. N-benzyl amino acid ester tryptamine 2-Bromomethyl-8-fluorotryptamine, potassium iodide, triethylamine and various amino acid esters (proline/tryptophan/cysteine/histidine/aspartic acid) ester) was added to acetonitrile, and the reaction was stirred at room temperature for 2 to 5 hours. TLC detected that the reaction was completed, the solvent was evaporated under reduced pressure, and the mixture was separated by column chromatography. Obtain yellow N-benzyl amino acid ester tryptamine; Synthesis of e.N-benzyl amino acid tryptamine N-benzyl amino acid ester tryptamine was added to the methanol and water mixture of sodium hydroxide, mixed and stirred at room temperature for 4-5 hours, TLC detected the reaction completion, added water, spin-dried methanol, and poured the remaining liquid into hydrochloric acid , adjusted to pH=5～6, extracted with chloroform, combined the organic layers, dried with anhydrous sodium sulfate, filtered and concentrated to obtain N-benzyl amino acid tryptamine. 10. according to the preparation method of the described N-benzyl amino acid tryptamine of claim 9, it is characterized in that: In step a, the mol ratio of 5-methylisatin and m-chloroperoxybenzoic acid is: 1:(1～2); And/or, in step b, the molar ratio of 5-methylisatinic anhydride to 5-fluoroisatin and triethylamine is: 1:(1～2):(3～5); And/or, in step c, the molar ratio of 2-methyl-8-fluorotryptamine to N-bromosuccinimide and azobisisobutyronitrile is: 1:(1.2～1.5):( 0.1～0.5); And/or, in step d, the molar ratio of 2-bromomethyl-8-fluorotryptamine, amino acid ester, potassium iodide and triethylamine is: 1:(1～2):(0.12～0.2):(3 ~5); And/or, in step e, the molar ratio of 2-(N-benzyl amino acid ester)-8-fluorotryptamine to sodium hydroxide is: 1:(3-5). 11. A N-benzyl amino acid water-soluble tryptophan derivative described in any one of claims 1 to 3 is prepared to prevent and/or treat a disease with the pathological characteristics of IDO-mediated tryptophan metabolic pathway application in medicines.