Tryptophan derivative and preparation method thereof

Abstract

The embodiment of the invention relates to the technical field of synthesis of organic compounds, and particularly discloses a tryptophan derivative and a preparation method thereof, and the tryptophan derivative comprises the following raw materials: 4-methyl phenyl sulfonyl indole, 4-methyl-5-oxazolone and a proper amount of chiral catalyst. According to the embodiment of the invention, sulfuryl indole can be converted into a vinyl imine intermediate with unstable chemical properties after being treated by an alkaline reagent, and then 5-oxazolone is used as a nucleophilic reagent and is added onto the vinyl imine intermediate to synthesize the alpha, beta-substituted tryptophan derivative. According to the synthetic route provided by the embodiment of the invention, the raw materials are cheap and easy to obtain, the price is low, the reaction steps are simple, the conditions are mild, the yield is also greatly improved, the problems of harsh related synthetic reaction conditions and lower yield in the existing scheme for preparing the tryptophan derivative by adopting a chemical synthesis method are solved, and the synthetic route has a wide market prospect.

Description

Technical Field

[0001] This invention relates to the field of organic compound synthesis technology, specifically to a tryptophan derivative and its preparation method. Background Technology

[0002] With social development and technological progress, the application of tryptophan and its derivatives is becoming increasingly widespread. Tryptophan, as one of the essential amino acids for the human body, is mainly obtained through diet and cannot be synthesized by the body itself. Tryptophan derivatives exert various biological functions through different metabolic pathways and are widely used in the fields of medicine, biology, and chemistry.

[0003] Currently, methods for producing tryptophan and its derivatives include enzymatic methods, fermentation methods, and chemical synthesis methods. Among these, the chemical synthesis of tryptophan and its derivatives remains a hot research topic. For example, tryptophan can be synthesized using the phenylhydrazine method with α-cyanopropenal and phenylhydrazine as raw materials; using o-nitrotoluene and DMF-DMA (i.e., N,N-dimethylformamide dimethyl acetal) as raw materials, the key product 1-formyl-5-hydroxy-4-(2-nitrophenyl)-pyrrole-2,2-dicarboxylic acid ethyl ester is obtained through condensation and substitution reactions. This is then followed by condensation under room temperature hydrogenation catalysis to obtain 2-formamido-3-(3-indolyl)-2-ethoxycarbonylpropionate ethyl ester, which is then hydrolyzed to obtain... To obtain tryptophan; DL-tryptophan is obtained by combining 3-indolealdehyde and hydantoin as raw materials under alkaline conditions of acetic anhydride and sodium ethoxide, followed by catalytic hydrolysis; D-tryptophan is directly synthesized from D-glutamine using an asymmetric synthesis method through six steps; and a derivative with hydroxyl groups substituted by ethyl groups is obtained by reacting bromoethane in DMF (i.e., N,N-dimethylformamide) at a reaction temperature of 50-70℃ for several hours in the presence of alkaline reagents such as potassium carbonate.

[0004] However, the existing technical solutions mentioned above have the following drawbacks: the chemical synthesis methods for preparing tryptophan derivatives currently suffer from harsh reaction conditions and low yields, which are not conducive to large-scale industrial production. Therefore, it is particularly important to develop a new synthetic route for tryptophan derivatives. Summary of the Invention

[0005] The purpose of this invention is to provide a tryptophan derivative to address the problems of harsh reaction conditions and low yield in existing chemical synthesis methods for preparing tryptophan derivatives as described in the background.

[0006] To achieve the above objectives, the embodiments of the present invention provide the following technical solutions:

[0007] A tryptophan derivative having the structure shown in formula (1):

[0008]

[0009] Furthermore, the tryptophan derivative is prepared by reacting 4-methylphenylsulfonylindole as a raw material under alkaline conditions to obtain an intermediate and then proceeding with a ring-opening reaction.

[0010] Preferably, the intermediate has a structure as shown in formula (2):

[0011] .

[0012] Preferably, the raw materials for the tryptophan derivative include not only 4-methylphenylsulfonylindole, but also 4-methyl-5-oxazolone, and an appropriate amount of chiral catalyst.

[0013] Preferably, in the raw materials of the tryptophan derivative, the molar ratio of 4-methylphenylsulfonylindole to 4-methyl-5-oxazolone is 0.1-0.2:0.1.

[0014] More preferably, in the raw materials of the tryptophan derivative, the molar ratio of 4-methylphenylsulfonylindole to 4-methyl-5-oxazolone is 0.11:0.1.

[0015] Preferably, the chiral catalyst is a quinine-thiourea catalyst, selected from any of the following chemical formulas:

[0016] .

[0017] Another objective of this invention is to provide a method for preparing a tryptophan derivative, the method specifically comprising the following steps:

[0018] 1) Weigh 4-methylphenylsulfonylindole and 4-methyl-5-oxazolone in proportion and dissolve them in toluene. Add an appropriate amount of chiral catalyst under alkaline conditions and stir to react. Then perform chromatography to remove impurities and obtain the intermediate.

[0019] 2) The intermediate obtained in step 1) is added to sodium methoxide and methanol under air-isolated conditions, and then the tryptophan derivative is obtained through a ring-opening reaction.

[0020] Preferably, in the method for preparing the tryptophan derivative, the alkaline condition is achieved by adjusting the alkaline environment using an alkaline reagent, wherein the alkaline reagent is selected from any one of potassium phosphate, sodium hydroxide, triethylamine, and potassium hydroxide.

[0021] In a further preferred embodiment, in the method for preparing the tryptophan derivative, the ring-opening reaction is carried out by adding sodium methoxide and methanol, first stirring the reaction at -20°C for 5 minutes, then stirring the reaction at room temperature for 25 minutes, then cooling to -20°C and quenching the reaction with a saturated ammonium chloride solution, followed by extraction, drying, and chromatography purification to obtain the tryptophan derivative.

[0022] Another objective of this invention is to provide a tryptophan derivative prepared using the above-described preparation method.

[0023] Compared with the prior art, the beneficial effects of the embodiments of the present invention are:

[0024] Compared to existing technologies, the tryptophan derivatives provided in this invention utilize the conversion of sulfonyl indole into a chemically unstable vinylimine intermediate after treatment with an alkaline reagent. Then, 5-oxazolone is used as a nucleophile to add to the vinylimine intermediate to synthesize α,β-substituted tryptophan derivatives. This provides a novel method for synthesizing α,β-substituted tryptophan derivatives. Compared to traditional synthetic routes, the synthetic route provided in this invention uses inexpensive and readily available raw materials, is inexpensive, has simple reaction steps, and mild conditions. Furthermore, it significantly improves the yield, solving the problems of harsh reaction conditions and low yields in existing chemical synthesis methods for preparing tryptophan derivatives. Moreover, the preparation method provided in this invention is simple; after screening different chiral catalysts, alkaline conditions, and solvent conditions, the reaction yield can reach 63%, indicating broad market prospects. Attached Figure Description

[0025] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention.

[0026] Figure 1 Product nuclear magnetic resonance provided in an embodiment of the present invention 1 H spectrum.

[0027] Figure 2 Product nuclear magnetic resonance provided in an embodiment of the present invention 13 C spectrum. Detailed Implementation

[0028] To make the technical problems, technical solutions, and beneficial effects of this invention clearer, the technical solutions in the embodiments of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the following embodiments will help those skilled in the art to further understand the embodiments of this invention, but do not limit the embodiments of this invention in any way. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the embodiments of this invention. These all fall within the protection scope of the embodiments of this invention.

[0029] The specific implementation of the present invention will be described in detail below with reference to specific embodiments.

[0030] First, it's important to clarify that tryptophan, also known as β-indoleylalanine, is an organic compound and one of the essential amino acids for the human body. It plays a crucial role in promoting the synthesis of serotonin and melatonin, regulating sleep and mood, and supporting protein synthesis, thus having a significant impact on the nervous system, digestive system, and growth and development. However, tryptophan is primarily obtained through dietary intake and cannot be synthesized by the body. It is commonly found in higher plants and can be used as a nutritional supplement for pregnant women, for treating niacin deficiency (pellagra), and as a sedative to regulate circadian rhythms and improve sleep. Tryptophan derivatives, as important biochemical reagents, exert various biological effects through different metabolic pathways, primarily involving neural regulation, metabolic control, and disease treatment, and are widely used in pharmaceutical, biological, and chemical research. Furthermore, many studies have shown that 1-methyltryptophan, as a tryptophan derivative and an IDO (indoleamine 2,3-dioxygenase) inhibitor, possesses antitumor activity and tumor chemotherapy effects. Therefore, researching the synthesis methods of tryptophan and its derivatives is of great significance. Although the applications of tryptophan and its derivatives are becoming increasingly widespread... However, current methods for producing tryptophan and its derivatives, including enzymatic methods, fermentation methods, and chemical synthesis, all have some shortcomings. Among these, chemical synthesis currently suffers from harsh reaction conditions, limited raw material sources, high costs, and low optical purity. Therefore, the chemical synthesis of tryptophan and its derivatives remains a hot research topic.

[0031] Secondly, it should be noted that tryptophan fermentation typically involves mutagenesis of bacterial strains to screen for strains capable of producing tryptophan. For example, AibaS produced optically pure tryptophan by continuously adding anthranilic acid to a 10% glucose medium. Studies on recombinant Escherichia coli revealed the relationship between bacterial growth, tryptophan synthesis, and inorganic salt concentrations, ultimately identifying the key inorganic salt components involved in tryptophan synthesis. However, this method suffers from complex metabolic pathways, involving multiple precursors (such as indole and serine) and complex metabolic flux regulation mechanisms. This leads to problems such as low production efficiency and poor robustness in the producing strains, and some strains require chemical synthesis, increasing production costs. Enzymatic synthesis utilizes specific enzyme-catalyzed reactions to synthesize tryptophan and its derivatives. For example, using D-amino acid transferase from Bacillus subtilis (which acts on D-amino acids but not L-amino acids), with indolepyruvate as the amino acceptor and D-Ala as the amino donor, D-tryptophan can be obtained with a yield of 8%-13%. This method has too low a yield and is not suitable for industrial production.

[0032] In addition, existing chemical synthesis methods use o-nitrotoluene and DMFDMA as raw materials, and through condensation and substitution reactions, yield the key product ethyl 1-formyl-5-hydroxy-4-(2-nitrophenyl)-pyrrole-2,2-dicarboxylate. This product is then condensed via room-temperature hydrogenation catalysis to obtain ethyl 2-formamido-3-(3-indolyl)-2-ethoxycarbonylpropionate, which is subsequently hydrolyzed to give tryptophan, with an overall yield of 64.5%. This reaction uses expensive raw materials, requires stringent process conditions, and produces difficult-to-separate byproducts, making it unsuitable for large-scale industrial production. An asymmetric synthesis method, using D-glutamine as a raw material, directly synthesizes the final product D-tryptophan through six steps. The specific synthetic route is as follows:

[0033]

[0034] The yield of the asymmetric synthesis method is only 12%, and the raw material D-glutamine is not easy to obtain, while the other raw materials are relatively expensive.

[0035] Therefore, in order to solve the problems of harsh reaction conditions and low yield in existing chemical synthesis methods for preparing tryptophan derivatives, this invention provides a tryptophan derivative, specifically an α,β-substituted tryptophan derivative, which has the structure shown in formula (1):

[0036]

[0037] Furthermore, the tryptophan derivative is prepared by reacting 4-methylphenylsulfonylindole under alkaline conditions to obtain an intermediate, followed by a ring-opening reaction. This synthetic route utilizes inexpensive and readily available raw materials, is cost-effective, involves simple reaction steps, operates under mild conditions, and significantly improves the yield.

[0038] Furthermore, the intermediate has a structure as shown in formula (2):

[0039]

[0040] Furthermore, since the intermediate is a chemically unstable vinylimine intermediate, α,β-substituted tryptophan derivatives can be synthesized by adding 5-oxazolone as a nucleophile to the vinylimine intermediate, referring to existing technologies.

[0041] Furthermore, the tryptophan derivative comprises the following raw materials: 4-methylphenylsulfonylindole, 4-methyl-5-oxazolone, and an appropriate amount of chiral catalyst.

[0042] As another preferred embodiment of the present invention, in the raw materials of the tryptophan derivative, the molar ratio of 4-methylphenylsulfonylindole to 4-methyl-5-oxazolone is 0.1-0.2:0.1.

[0043] More preferably, in the raw materials of the tryptophan derivative, the molar ratio of 4-methylphenylsulfonylindole to 4-methyl-5-oxazolone is 0.11:0.1.

[0044] As another preferred embodiment of the present invention, the chiral catalyst is specifically a quinine thiourea catalyst, selected from any one of the following chemical formulas (i.e., formula (a), formula (b), and formula (c)):

[0045]

[0046] Among them, the quinine thiourea catalysts corresponding to formulas (a), (b), and (c) are simply referred to as catalyst 1, catalyst 2, and catalyst 3.

[0047] This invention utilizes indole and p-toluenesulfonic acid as raw materials to first synthesize phenylsulfonyl indole; then, it reacts the phenylsulfonyl indole obtained in the first step with 5-oxazolone under alkaline, solvent, and specific temperature conditions to obtain an intermediate product; finally, it reacts the intermediate synthesized in the second step under alkaline conditions to open the ring and yield a tryptophan derivative. This synthetic route uses inexpensive and readily available raw materials, is inexpensive, has simple reaction steps, mild conditions, and significantly improves the yield.

[0048] In another preferred embodiment of the present invention, the alkaline condition is specifically adjusted to an alkaline environment using an alkaline reagent. For example, potassium phosphate can be added as the alkaline reagent, or it can be sodium hydroxide, triethylamine, potassium hydroxide, or other alkaline reagents such as calcium hydroxide, ammonia, sodium carbonate, sodium bicarbonate, and trisodium phosphate. Potassium phosphate is preferred here. In this embodiment of the present invention, sulfonyl indole (specifically 4-methylphenylsulfonyl indole) can be converted into a chemically unstable vinylimine intermediate after treatment with an alkaline reagent. Then, 5-oxazolone is used as a nucleophile to add to the vinylimine intermediate to synthesize α,β-substituted tryptophan derivatives.

[0049] This invention also provides a method for preparing a tryptophan derivative, the method comprising the following steps:

[0050] 1) Weigh 4-methylphenylsulfonylindole and 4-methyl-5-oxazolone in proportion and dissolve them in toluene. Add an appropriate amount of chiral catalyst under alkaline conditions and stir to react. Then perform chromatography to remove impurities and obtain the intermediate.

[0051] 2) The intermediate obtained in step 1) is added to sodium methoxide and methanol under air-isolated conditions (such as by introducing nitrogen to remove air, thereby isolating air), and then the tryptophan derivative is obtained through a ring-opening reaction.

[0052] Furthermore, the ring-opening reaction is the process by which a cyclic compound is converted into a chain structure by breaking chemical bonds. In specific embodiments of the present invention, after adding sodium methoxide and methanol, the reaction is carried out by stirring at -10°C to -30°C and at room temperature, then cooled to -10°C to -30°C and quenched with a saturated ammonium chloride solution, followed by extraction, drying, and chromatography purification to obtain the tryptophan derivative.

[0053] Preferably, the ring-opening reaction is a process in which a cyclic compound is converted into a chain structure by breaking chemical bonds. In this embodiment of the invention, after adding sodium methoxide and methanol, the reaction is stirred at -20°C for 5 minutes and at room temperature for 25 minutes, then cooled to -20°C and quenched with a saturated ammonium chloride solution, followed by extraction, drying, and chromatography purification to obtain the tryptophan derivative.

[0054] More preferably, the method for preparing the tryptophan derivative includes the following steps:

[0055] 1) Weigh a clean, dry 50 mL round-bottom flask. Using an analytical balance, weigh 0.037 g (0.11 mmol) of 4-methylphenylsulfonylindole, 0.017 g (0.1 mmol) of 4-methyl-5-oxazolone, and 0.023 g (0.1 mmol) of potassium phosphate. Add the weighed 4-methylphenylsulfonylindole and 4-methyl-5-oxazolone to the round-bottom flask. Pour 1 mL of toluene solution into the round-bottom flask to dissolve the 4-methylphenylsulfonylindole and 4-methyl-5-oxazolone in the toluene. Add potassium phosphate as a base and use a chiral quinine-thiourea catalyst. Add a magnetic stir bar to the round-bottom flask and fix it to a magnetic stirrer. Turn on the stirrer and heating switch, and maintain the reaction at 30°C for 2 hours while stirring. The reaction was analyzed by TLC to determine if it was complete. After the reaction was complete, the substance in the round-bottom flask was subjected to chromatography with ethyl acetate:petroleum ether = 1:5-1:20 as the eluent to remove impurities and obtain the intermediate product.

[0056] 2) Weigh 0.02 g (0.042 mmol) of the intermediate product from step 1) into a 15 mL round-bottom flask. Fix the round-bottom flask in a cryogenic reaction bath, seal the flask, and connect it to a nitrogen gas supply via a gas inlet tube. Purge the flask with nitrogen to purge air from the flask. Close the main nitrogen valve. Use a syringe to add 0.3 mL of sodium methoxide and 0.7 mL of methanol to the round-bottom flask, respectively. Turn on the cooling switch of the cryogenic reaction bath and cool to -20°C. Stir the reaction for 5 minutes. Then place the round-bottom flask in a magnetic stirring heating mantle and stir at room temperature for 25 minutes. Fix the round-bottom flask back in the cryogenic reaction bath and cool to -20°C. Quench the reaction with a saturated ammonium chloride solution. Extract using a separatory funnel, extracting three times with 10 mL of dichloromethane. Combine the organic layers and dry with sodium sulfate before filtration. The filtered product was subjected to a rotary evaporator to remove the remaining solvent, and then purified by silica gel column chromatography using ethyl acetate:petroleum ether = 1:4 as the eluent to obtain the tryptophan derivative.

[0057] This invention also provides a tryptophan derivative prepared using the above-described preparation method.

[0058] This invention also provides an application of the above-mentioned tryptophan derivative in the fields of medicine, biology, and chemistry. Of course, it is understood that the preparation method of the tryptophan derivative can also be used as a framework for the synthesis of other amino acids and their derivatives, which will not be elaborated upon here.

[0059] The following specific examples further illustrate the technical effects of the tryptophan derivatives and their preparation methods according to the present invention.

[0060] Example 1

[0061] A tryptophan derivative comprises the following raw materials: 4-methylphenylsulfonylindole, 4-methyl-5-oxazolone, and a suitable amount of chiral catalyst. The preparation method of the tryptophan derivative includes the following steps:

[0062] Step 1: Synthesis of 4-methylphenylsulfone indole

[0063] Prepare a saturated sodium bicarbonate solution and pour it into a small beaker. Set up the reaction apparatus, connecting a three-necked flask to a funnel via a gas delivery tube and placing it on the surface of the saturated sodium bicarbonate solution. Turn on the analytical balance, place a weighing paper on the balance, zero it, and weigh 0.42 g (3.2 mmol) of 2-methylindole into a 100 mL three-necked flask. Then weigh 0.56 g (3.6 mmol) of p-toluenesulfinic acid and 0.26 g (1.5 mmol) of p-toluenesulfonic acid into the three-necked flask. Measure 10 mL of ethyl acetate into the three-necked flask using a graduated cylinder, and then add a magnetic stir bar. Place the three-necked flask on a magnetic stirrer and turn on the stirrer to stir. Test a constant-pressure dropping funnel for leaks. Weigh 0.36g of p-methylbenzaldehyde into the funnel using a small beaker. Rotate the stopcock to allow the p-methylbenzaldehyde to drip into a three-necked flask. Stir at room temperature for 2.5-6 hours to allow the reaction to proceed fully, yielding a white solution. Extract the white solution three times with 20mL of dichloromethane. Pour off the upper layer of the white solution and combine them. Add anhydrous magnesium sulfate to the organic phase, dry, and filter to obtain a solution. Remove the solvent by vacuum filtration to obtain crystals. Heat ethyl acetate in a beaker to boiling. Pour the product into the boiling ethyl acetate solution. After dissolving, filter while hot to obtain a white solid. Wash the product with the filtrate. Allow it to cool naturally to obtain 4-methylphenylsulfone indole. The specific reaction formula is as follows.

[0064] .

[0065] Experimental Step 2: Synthesis of 4-methyl-5-oxazolone

[0066] Measure 30 mL of water into a beaker and place it in a heating mantle to heat to 75°C, adding water continuously during heating. Weigh 0.62 g (7 mmol, 1 equiv) of alanine and 0.56 g (14 mmol, 2 equiv) of sodium hydroxide into a 100 mL three-necked flask. Measure 30 mL of 75°C water into the three-necked flask using a graduated cylinder and add a stir bar. Secure the apparatus to a magnetic stirrer and turn on the stirrer to allow the reaction to proceed fully. Weigh 1.08 g (7.7 mmol, 1.1 equiv) of benzoyl chloride into a small beaker and pour it into a pre-tested, leak-proof constant-pressure dropping funnel. Rotate the stopcock of the constant-pressure dropping funnel to allow the benzoyl chloride to drip into the three-necked flask dropwise over 30 minutes. After the dripping is complete, continue stirring for 30 minutes. Cool the three-necked flask to 0°C in an ice bath. Acidify the reaction solution by adding 2 mol / L hydrochloric acid dropwise to adjust the pH to 1-2. The acidified reaction solution was then extracted with ethyl acetate. The reaction solutions were combined, dried over anhydrous sodium sulfate, and filtered. Most of the ethyl acetate was removed from the filtrate using a rotary evaporator. Using hexane:ethyl acetate in a ratio of 8:2, and adding 10% methanol / dichloromethane as the eluent, the solution was purified by silica gel column chromatography to obtain 1.5 g of N-benzoyl-DL-alanine with a yield of 91%. The specific reaction formula is as follows.

[0067] .

[0068] Anhydrous acetic anhydride was poured into a three-necked flask, and the prepared N-benzoyl-DL-alanine (1 equiv) was added. A magnetic stir bar was added, and a thermometer sleeve was inserted. The three-necked flask was placed in a heating mantle, and the heating and stirring switches were turned on to raise the temperature in the three-necked flask to 75°C. The reaction was carried out for 1 hour. Thin-layer chromatography (TLC) was used to determine whether the N-benzoyl-DL-alanine reaction was complete. After the liquid in the three-necked flask cooled, it was concentrated using a rotary evaporator to remove most of the residual acetic acid and acetic anhydride. The obtained solid was diluted with 30 mL of ethyl acetate, and then washed three times with 20 mL of saturated sodium bicarbonate solution. After filtration, the aqueous phase was extracted three times with 20 mL of ethyl acetate, and the aqueous phases were combined. The solid was dried over anhydrous sodium sulfate, filtered, and then filtered under reduced pressure to obtain a brownish-yellow solid (4-methyl-5-oxazolone) in a Buchner funnel. Because the product was impure, it was recrystallized. A saturated solution of 4-methyl-5-oxazolone was prepared by heating. Using dichloromethane-petroleum as a solvent, the solution was filtered while hot to remove insoluble substances. After cooling, the filtrate was filtered again, washed, and dried. A white solid was finally obtained. The specific reaction formula is as follows.

[0069] .

[0070] Step 3: Asymmetric Michael Addition Reaction

[0071] Take a clean, dry 50 mL round-bottom flask and weigh out 0.037 g (0.11 mmol) of 4-methylphenylsulfonylindole, 0.017 g (0.1 mmol) of 4-methyl5-oxazolone, and 0.023 g (0.1 mmol) of potassium phosphate using an analytical balance. Add the weighed 4-methylphenylsulfonylindole and 4-methyl5-oxazolone to the round-bottom flask. Pour 1 mL of toluene solution into the round-bottom flask to dissolve the 4-methylphenylsulfonylindole and 4-methyl5-oxazolone in the toluene. Add potassium phosphate as a base and use a chiral quinine thiourea catalyst. Add a magnetic stir bar to the round-bottom flask and fix it to a magnetic stirrer. Turn on the stirrer and heating switch and maintain the reaction at 30°C for 2 hours while stirring. The reaction was analyzed by TLC to determine if it was complete. After the reaction was complete, the substance in the round-bottom flask was subjected to chromatography with ethyl acetate:petroleum ether = 1:5-1:20 as the eluent to remove impurities and obtain the intermediate product. The specific reaction formula is as follows.

[0072] .

[0073] Step 4: Synthesis of tryptophan derivatives

[0074] Weigh 0.02 g (0.042 mmol) of the intermediate product obtained in step three and add it to a 15 mL round-bottom flask. Fix the round-bottom flask in a cryogenic reaction bath, seal the flask, and connect it to a nitrogen gas system using a gas inlet tube. Purge the flask with nitrogen to remove air from the flask. Close the main nitrogen valve and use a syringe to add 0.3 mL of sodium methoxide and 0.7 mL of methanol to the round-bottom flask, respectively. Turn on the cooling switch of the cryogenic reaction bath and cool to -20°C, stirring for 5 minutes. Then place the round-bottom flask in a magnetic stirring heating mantle and stir at room temperature for 25 minutes. Next, fix the round-bottom flask in the cryogenic reaction bath and cool to -20°C, quenching the reaction with a saturated ammonium chloride solution. Extract using a separatory funnel, extracting three times with 10 mL of dichloromethane. Combine the organic layers and dry with sodium sulfate before filtration. The filtered product was subjected to a rotary evaporator to remove the remaining solvent, followed by purification by silica gel column chromatography using ethyl acetate:petroleum ether = 1:4 as the eluent. The tryptophan derivative could then be obtained via a ring-opening reaction. The specific reaction formula is as follows.

[0075]

[0076] Furthermore, in this embodiment of the invention, the chiral quinine thiourea catalyst (i.e., catalyst 2) is:

[0077]

[0078] The specific synthetic route for catalyst 2 is as follows:

[0079] .

[0080] Experiments revealed that 4-methylphenylsulfonylindole reacts with 4-methyl-5-oxazolone in an asymmetric Michael addition reaction at 30°C, using potassium phosphate, toluene, and the chiral quinine thiourea catalyst, yielding a 97% ee value, an 82:18 dr value, and a 63% yield.

[0081] In this embodiment of the invention, the intermediate product obtained in step three is characterized to obtain nuclear magnetic resonance (NMR) results. 1 H-spectroscopy and nuclear magnetic resonance 13 The C-spectrum is as follows: Figure 1 and Figure 2 As shown.

[0082] The results show that the intermediate product is a white solid with a melting point of 127-128℃.

[0083] Nuclear magnetic resonance 1 H spectrum (400 MHz, CDCl3): δ 7.62-7.60 (d,J = 6 Hz,2H),7.43-7.26 (m,10H),7.12-6.99 (m,4H),5.59 (s,1H),4.30-4.23 (q,J = 6 Hz,4H),3.87 (s,2H),3.57(s,2H),1.32-1.28 (t,J = 6 Hz,6H);

[0084] Nuclear magnetic resonance 13 C-spectrum (100 MHz, CDCl3): δ = 182.15, 159.17, 136.64, 136.24, 135.37, 133.30, 132.36, 129.65, 128.86, 128.74, 128.68, 128.62, 128.31, 127.83, 126.01, 120.97, 119.55, 110.12, 73.85, 50.89, 23.18, 20.82, 12.43;

[0085] Therefore, it can be deduced that the intermediate product is:

[0086]

[0087] Furthermore, since the intermediate is a chemically unstable vinylimine intermediate, α,β-substituted tryptophan derivatives can be synthesized by adding 5-oxazolone as a nucleophile to the vinylimine intermediate, referring to existing technologies.

[0088] Example 2

[0089] A tryptophan derivative, compared to Example 1, except that the chiral quinine thiourea catalyst is:

[0090]

[0091] Everything else is the same as in Example 1.

[0092] The chiral quinine thiourea catalyst was prepared by weighing 2 g (6 mmol) of (s)-9-aminoquinine and 1.9 g (7 mmol) of 3,5-(bis(trifluoromethyl)phenyl)isothiocyanate into a 250 mL three-necked flask; dissolving the substrate in 30 mL of tetrahydrofuran as a solvent, and adding a magnetic stir bar. The three-necked flask was placed in a magnetic stirring heating mantle, the stirring switch was turned on, and stirring was performed at room temperature. TLC was used to determine if the substrate had reacted completely. After complete reaction, the mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was dried with magnesium sulfate, filtered, and then dried under vacuum. The product was then evaporated under reduced pressure using a rotary evaporator, and separated by column chromatography using ethyl acetate:petroleum ether at a volume ratio of 1:20 as the eluent. The chiral quinine thiourea catalyst was obtained as catalyst 1. The specific synthetic route is as follows:

[0093]

[0094] It should also be noted that the synthesis of catalyst 1 is basically the same as the chiral quinine thiourea catalyst in Example 1, except that the raw materials are different.

[0095] Example 3

[0096] A tryptophan derivative, compared to Example 1, except that the chiral quinine thiourea catalyst is:

[0097]

[0098] Everything else is the same as in Example 1.

[0099] The chiral quinine thiourea catalyst was prepared by weighing 0.2 g (0.62 mmol) of quinineamine into a 50 mL round-bottom flask and adding 20 mL of dichloromethane to dissolve the quinineamine. A magnetic stir bar was added to the round-bottom flask, and the flask was fixed to a magnetic stirrer. The stirrer was turned on and stirred. Then, 0.202 g (0.75 mmol) of 3,5-(bis(trifluoromethyl)phenyl isothiocyanate) was weighed and slowly added to the round-bottom flask. The reaction was stirred at room temperature, and TLC was used to determine whether the reaction was complete. The resulting solution was filtered under reduced pressure, dried, and dissolved in dichloromethane. Chromatography was performed using methanol:dichloromethane = 1:30 as the eluent to obtain the chiral quinine thiourea catalyst as catalyst 3.

[0100] The specific synthetic route is as follows:

[0101] .

[0102] Example 4

[0103] In this embodiment, in order to test the catalytic effect of different catalysts, the method in Example 1 was followed, and experiments were conducted in three groups using catalyst 1, catalyst 2 and catalyst 3 respectively, to study the effect of different catalysts on the reaction rate.

[0104] Specifically, by controlling the reaction temperature at 30℃, experiments were conducted using catalysts 1, 2, and 3 as three groups to study the effect of different catalysts on the reaction rate. The results of the effects of different catalysts on the reaction are shown in Table 1. As can be seen from Table 1, catalyst 3 had the highest yield, but its enantioselectivity was -87, and the product obtained was not the target product, which did not meet the experimental requirements. Combining the enantioselectivity and diastereoselectivity, catalyst 2 showed the best catalytic efficiency, even though the yield of catalyst 2 was lower than that of catalyst 1.

[0105] Table 1 Effect of different catalysts on the reaction

[0106] Group Catalyst types Yield (%) dr ee(%) 1 Catalyst 1 60 69:31 95 2 Catalyst 2 52 79:21 97 3 Catalyst 3 64 57:43 -87

[0107] Example 5

[0108] In this embodiment, in order to detect the effect of different alkaline conditions on the reaction, the method in Example 1 was followed, and comparative experiments were conducted using four bases: potassium phosphate, sodium hydroxide, triethylamine, and potassium hydroxide.

[0109] Specifically, the reaction temperature was controlled at 30℃, and catalyst 2 was used to catalyze the reaction. Comparative experiments were conducted using four bases: potassium phosphate, sodium hydroxide, triethylamine, and potassium hydroxide, to study the effect of different bases on the reaction rate. The results of the effects of different bases on the reaction are shown in Table 2. Combining the yield and enantioselectivity, the conclusion is that, comparing the data of triethylamine as an organic base with that of the inorganic base potassium phosphate in Table 2, the inorganic base yields and enantioselectivity are higher. Potassium hydroxide, sodium hydroxide, and potassium phosphate are all inorganic bases; potassium phosphate has the weakest basicity but the highest diastereoselectivity and single optical activity, making it the optimal base choice even though the yield is not high.

[0110] Table 2 Effect of different bases on the reaction

[0111] Group alkali Yield (%) dr ee(%) 1 potassium phosphate 63 82:18 97 2 Sodium hydroxide 50 71:29 91 3 Triethylamine 31 62:38 49 4 potassium hydroxide 72 70:30 92

[0112] Example 6

[0113] In this embodiment, in order to detect the effect of different solvent conditions on the reaction, the method in Example 1 was followed, and comparative experiments were conducted using toluene, benzene, chloroform, and dichloromethane respectively.

[0114] Specifically, the reaction temperature was controlled at 30℃, and catalyst 2 was used for catalysis. Comparative experiments were conducted using toluene, benzene, chloroform, and dichloromethane to study the effect of different solvents on the reaction rate. The results of the effects of different solvents on the reaction are shown in Table 3. From the perspective of solvent polarity, chloroform showed the strongest polarity, but also the lowest enantioselectivity and yield. Weaker polarity resulted in better yield, diastereoselectivity, and enantioselectivity. From the perspective of solvent solubility, stronger solubility led to worse yield, diastereoselectivity, and enantioselectivity; toluene again showed the highest yield and the highest single optical activity value. Therefore, toluene was chosen as the optimal solvent.

[0115] Table 3 Effect of different solvents on the reaction

[0116] Group solvent Yield (%) dr ee(%) 1 Toluene 63 82:18 97 2 benzene 60 82:18 97 3 chloroform 40 73:27 80 4 dichloromethane 44 80:20 95

[0117] Based on the above results, it can be seen that the embodiments of the present invention utilize the conversion of sulfonyl indole into a chemically unstable vinylimine intermediate after treatment with an alkaline reagent, and then use 5-oxazolone as a nucleophile to add to the vinylimine intermediate to synthesize α,β-substituted tryptophan derivatives. This provides a new method for synthesizing α,β-substituted tryptophan derivatives, enriching the synthetic routes for α,β-substituted tryptophan derivatives and solving the problems of harsh reaction conditions and low yields in existing chemical synthesis methods for preparing tryptophan derivatives. Moreover, the preparation method provided by the embodiments of the present invention is simple. Based on screening different chiral catalysts, alkaline conditions, and solvent conditions, experiments showed that the reaction of 4-methylphenylsulfonyl indole with 4-methyl-5-oxazolone at 30°C, catalyst 2, potassium phosphate, and toluene yields a 97% ee value, an 82:18 dr value, and a 63% yield, indicating broad market prospects.

[0118] It should be noted that indole possesses specific physiological activity in medicine, and many indole derivatives are novel and highly efficient pharmaceutical intermediates that can be used to synthesize antihypertensive drugs, fluoxetine, antipyretic analgesics, etc. For example, the indole derivative reserpine is a commonly used antihypertensive drug. In recent years, the development of indole derivatives in the field of tryptophan has also been gradually discovered by chemists. Tryptophan is mainly used as a nutritional supplement for the human body, and the development of other applications of tryptophan is currently a research direction for many researchers. In this invention, indole with a 4-methylphenylsulfone functional group introduced at position 3 is used as a substrate and reacted with 4-methyl5-oxazolone at 30°C. After treatment with methanol and sodium methoxide, α,β-substituted tryptophan derivatives are obtained. In the embodiments of this invention, the catalyst, base, and reaction solvent are used as variables to study the effects of different conditions on the product yield, dr value, and ee value. The experimental data show that when the reaction temperature is 30°C, the product with the highest ee value and the best yield is obtained when catalyst 2 is used as the catalyst, potassium phosphate is used as the inorganic base, and toluene is used as the solvent. Therefore, it is understandable that the preparation method of tryptophan derivatives provided in the embodiments of the present invention can also be used as a concept for the synthesis of other amino acids and their derivatives. By utilizing sulfonyl indole and other substances that can be converted into chemically unstable intermediates after treatment with alkaline reagents, and then adding nucleophilic reagents to vinylimine intermediates to synthesize tryptophan derivatives.

[0119] The preferred embodiments of the present invention have been described in detail above, outlining the basic principles, main features, and advantages of the invention. However, those skilled in the art should understand that the embodiments of the present invention are not limited to the above-described embodiments. The embodiments and descriptions in the specification are merely preferred examples of the present invention and are not intended to limit the invention. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the embodiments of the present invention. It is neither necessary nor possible to exhaustively describe all embodiments here. However, obvious changes or modifications derived therefrom are still within the protection scope of the embodiments of the present invention.

Claims

1. A tryptophan derivative, characterized in that, The tryptophan derivative has the structure shown in formula (1): ; Furthermore, the tryptophan derivative is prepared by reacting 4-methylphenylsulfonylindole as a raw material under alkaline conditions to obtain an intermediate and then proceeding with a ring-opening reaction.

2. The tryptophan derivative according to claim 1, characterized in that, The intermediate has a structure as shown in formula (2): 。 3. The tryptophan derivative according to claim 2, characterized in that, The tryptophan derivative comprises the following raw materials: 4-methylphenylsulfonylindole, 4-methyl-5-oxazolone, and a suitable chiral catalyst.

4. The tryptophan derivative according to claim 3, characterized in that, In the raw materials for the tryptophan derivative, the molar ratio of 4-methylphenylsulfonylindole to 4-methyl-5-oxazolone is 0.1-0.2:0.

1.

5. The tryptophan derivative according to claim 4, characterized in that, In the raw materials for the tryptophan derivative, the molar ratio of 4-methylphenylsulfonylindole to 4-methyl-5-oxazolone is 0.11:0.

1.

6. The tryptophan derivative according to claim 5, characterized in that, The chiral catalyst is a quinine-thiourea catalyst, specifically selected from any of the following chemical formulas: 。 7. A method for preparing a tryptophan derivative as described in any one of claims 1-6, characterized in that, Includes the following steps: 1) Weigh 4-methylphenylsulfonylindole and 4-methyl-5-oxazolone in proportion and dissolve them in toluene. Add a chiral catalyst under alkaline conditions and stir to react. Then perform chromatography to remove impurities and obtain the intermediate. 2) The intermediate obtained in step 1) is added to sodium methoxide and methanol under air-isolated conditions, and then the tryptophan derivative is obtained through a ring-opening reaction.

8. The method for preparing the tryptophan derivative according to claim 7, characterized in that, In the preparation method of the tryptophan derivative, the alkaline condition is achieved by adjusting the alkaline environment using an alkaline reagent, wherein the alkaline reagent is selected from any one of potassium phosphate, sodium hydroxide, triethylamine, and potassium hydroxide.

9. The method for preparing the tryptophan derivative according to claim 7, characterized in that, In the preparation method of the tryptophan derivative, the ring-opening reaction is carried out by adding sodium methoxide and methanol, first stirring the reaction at -10°C to -30°C, then stirring the reaction at room temperature, then cooling the temperature to -10°C to -30°C and quenching the reaction with a saturated ammonium chloride solution, and then extracting, drying and chromatographic purification to obtain the tryptophan derivative.

10. The method for preparing the tryptophan derivative according to claim 9, characterized in that, In the preparation method of the tryptophan derivative, the ring-opening reaction is carried out by adding sodium methoxide and methanol, stirring the reaction at -20°C for 5 minutes, stirring the reaction at room temperature for 25 minutes, cooling the temperature to -20°C and quenching the reaction with a saturated ammonium chloride solution, and then extracting, drying and chromatographic purification to obtain the tryptophan derivative.

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