A method for preparing dipeptide-2

Abstract

This invention provides a method for preparing dipeptide-2, the specific steps of which include amino protection of L-valine with 2-(trimethylsilyl)ethoxycarbonyl, condensation reaction of the product with L-tryptophan benzyl ester, deprotection to remove 2-(trimethylsilyl)ethoxycarbonyl, removal of benzyl group under palladium on carbon hydrogenation, and purification. This method belongs to the field of organic synthesis technology. This invention uses 2-(trimethylsilyl)ethoxycarbonyl as the amino acid protecting group, which can precisely and specifically protect the amino group, simplifying the operation steps for amino acid protection. Furthermore, the conditions are simple to control and easy to implement. Simultaneously, the condensation reaction generates a dipeptide intermediate, laying a good product foundation for subsequent preparation steps of dipeptide-2. In addition, the process of this invention is rapid, the operation steps are simple and clear, and the reagents used are readily available and inexpensive, making it very suitable for large-scale industrial production and providing a new synthetic route for the preparation of dipeptide-2.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and specifically relates to a method for preparing dipeptide-2. Background Technology

[0002] Dipeptide-2 is an important ingredient in cosmetics. Composed of two standard amino acids—valine and tryptophan—its unique structure gives it the ability to act as a highly effective skin conditioner, effectively improving skin condition. Dipeptide-2 is widely used in eye care products such as eye creams to help reduce puffiness and dark circles. Furthermore, its structure is similar to that of lipids in the epidermis, thus it is considered a natural skin moisturizing factor (NMF), maintaining the integrity of the intercellular structure of epidermal cells, preventing skin irritation, and promoting skin regeneration.

[0003] In existing technologies, dipeptide-2 can be prepared through biosynthesis. For example, one study discovered a novel method using histagged protein ligase from recombinant Actinobacillus pleuropneumoniae (APP) serotype 1 strain 4074. At 37°C and in a pH 8 buffer solution, L-valine and L-tryptophan were reacted enzymatically for 16 hours to successfully synthesize dipeptide-2. Chemical synthesis methods have also been used to prepare dipeptide-2. For instance, one study used carboxybenzyloxycarbonyl (Cbz)-protected valine as a starting material, followed by activation with bis(pentafluorophenyl) carbonate. The activated valine then reacted with the sodium salt of tryptophan to generate a Cbz-protected dipeptide-2 intermediate. Finally, the Cbz protecting group was removed through catalytic hydrogenolysis to obtain the final product, dipeptide-2. In addition, patent CN113929734A reports another method for synthesizing dipeptide-2. This method first protects valine with phthalic anhydride to obtain phthaloylvaline, which then reacts with thionyl chloride to generate phthaloylvaline chloride. Next, it reacts with N-hydroxysuccinimide to obtain an activated ester, phthaloylvaline succinimide. This activated ester then reacts with tryptophan to generate phthaloylvaline tryptophan. Finally, by removing the phthaloyl group, dipeptide-2 is obtained. Patent CN 114634547A also reports a method for synthesizing dipeptide-2, which uses valine and triphosgene as raw materials to synthesize an intermediate, which is then reacted with tryptophan under alkaline conditions to synthesize dipeptide-2.

[0004] Several reported methods face challenges when applied to large-scale industrial production, primarily due to high costs or overly demanding reaction conditions. For example, while enzyme-catalyzed reactions hold potential, their activity is susceptible to various factors such as temperature, pH, and substrate concentration, limiting the scale and efficiency of enzyme-catalyzed reactions and hindering their widespread application in large-scale industrial production. In the field of chemical synthesis, the dipeptide-2 synthesis method uses bis(pentafluorophenyl) carbonate to activate valine and requires catalytic hydrogenolysis to remove the Cbz protecting group; however, the reagents involved in this method are expensive, increasing production costs. Furthermore, the method described in patent CN113929734A uses thionyl chloride as a reagent, which generates large amounts of toxic sulfur dioxide gas during the reaction, causing environmental pollution and increasing safety risks during production. While patent CN114634547A simplifies the reaction steps, it uses large amounts of toxic triphosgene as a reagent, potentially posing a threat to human health and causing serious environmental pollution problems, thus also hindering large-scale industrial production. In summary, these methods all have certain limitations and challenges when applied to large-scale production. In view of the problems encountered in the current chemical synthesis of dipeptide-2, this invention aims to provide a new chemical method for the synthesis of dipeptide-2, and to provide a new solution for its application research and large-scale production. Summary of the Invention

[0005] Technical Problem to be Solved: To address the aforementioned technical problems, the present invention aims to provide a method for preparing dipeptide-2. The specific steps include amino protection of L-valine with 2-(trimethylsilyl)ethoxycarbonyl, condensation reaction of the product with L-tryptophan benzyl ester, deprotection to remove the 2-(trimethylsilyl)ethoxycarbonyl, debenzylation under catalytic hydrogenolysis, and filtration purification. This method belongs to the field of organic synthesis technology. The present invention uses 2-(trimethylsilyl)ethoxycarbonyl as the amino acid protecting group, which can precisely and specifically protect the amino group, simplifying the operation steps for amino acid protection. Furthermore, the conditions are simple to control and easy to implement. Simultaneously, the condensation reaction generates a dipeptide intermediate, laying a good product foundation for subsequent preparation steps of dipeptide-2. In addition, the process of the present invention is rapid, the operation steps are simple and clear, and the reagents used are readily available and inexpensive, making it very suitable for large-scale industrial production and providing a new synthetic route for the preparation of dipeptide-2.

[0006] Technical solution: A method for preparing dipeptide-2, comprising the following steps:

[0007] S1. 2-(trimethylsilyl)ethoxycarbonylL-valine was prepared by amino protection of L-valine with 2-(trimethylsilyl)ethoxycarbonyl;

[0008] S2,2-(trimethylsilyl)ethoxycarbonylL-valine and L-tryptophan benzyl ester undergo a condensation reaction to generate 2-(trimethylsilyl)ethoxycarbonylL-valine-L-tryptophan benzyl ester.

[0009] S3. L-Valyl L-Tryptophan benzyl ester was prepared by deprotecting 2-(trimethylsilyl)ethoxycarbonyl-L-valine-L-tryptophan benzyl ester with a deprotecting agent.

[0010] S4.L-valine-L-tryptophan benzyl ester was hydrolyzed under palladium-carbon hydrogenation conditions to prepare dipeptide-2; the synthetic reaction formula is as follows.

[0011]

[0012] Furthermore, the amino protection method in step S1 is as follows: the amino group of L-valine is protected by a substance containing 2-(trimethylsilyl)ethoxycarbonyl in reaction solvent A, and then triethylamine is added and the mixture is treated at room temperature for 36-48 hours.

[0013] Furthermore, the molar ratio of L-valine, the substance containing 2-(trimethylsilyl)ethoxycarbonyl, and triethylamine is 1.0:(1.1-1.3):(1.5-2); the reaction solvent A is a composition of 1,4-dioxane and water.

[0014] Furthermore, the condensation reaction in step S2 is performed as follows: using 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine as condensing agents, 2-(trimethylsilyl)ethoxycarbonyl L-valine and L-tryptophan benzyl ester are reacted in reaction solvent B at room temperature for 6-12 hours.

[0015] Furthermore, the molar ratio of 2-(trimethylsilyl)ethoxycarbonyl L-valine, L-tryptophan benzyl ester, 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine is 1.0:(1.0-1.3):(1.2-1.5):(3.0-3.5).

[0016] Furthermore, the reaction solvent B includes, but is not limited to, dichloromethane, 1,2-dichloroethane, and tetrahydrofuran.

[0017] Furthermore, the deprotecting agents in step S3 include, but are not limited to, tetrabutylammonium fluoride, tetramethylammonium fluoride, and tetraethylammonium fluoride.

[0018] Furthermore, the amount of the deprotecting agent added is 2-4 times the molar mass of 2-(trimethylsilyl)ethoxycarbonyl L-valine-L-tryptophan benzyl ester.

[0019] Furthermore, the specific method of hydrolysis in step S4 is as follows: using palladium on carbon as a debenzylating agent, L-valine-L-tryptophan benzyl ester is reacted at room temperature for 12-24 hours and then filtered and purified to obtain dipeptide-2.

[0020] Furthermore, the mass ratio of L-valine-L-tryptophan benzyl ester to palladium on carbon is 1.0:(0.1-0.2).

[0021] Beneficial effects:

[0022] 1. In the preparation method of dipeptide-2 of the present invention, 2-(trimethylsilyl)ethoxycarbonyl is used as the amino protecting group, which can firmly bind to the amino group of valine to form a stable amino acid derivative, thereby effectively protecting the amino group from interference by other reaction conditions. Moreover, the reaction conditions are relatively mild and easy to control, and will not trigger other unnecessary side reactions, achieving precise and specific protection of the amino group. At the same time, it greatly simplifies the preparation process of the protected amino acid, making it simple and easy to implement.

[0023] 2. This invention uses a benzyl ester derivative of another target amino acid, and the amino acid protected by 2-(trimethylsilyl)ethoxycarbonyl is used to prepare the dipeptide-2 intermediate by condensation reaction. This not only reduces the side reactions in the condensation reaction and improves the yield of the dipeptide-2 intermediate, but also has mild reaction conditions and simple operation, laying a good substrate foundation for the subsequent synthesis of dipeptide-2.

[0024] 3. In this invention, the removal of the amino protecting group yields a pure compound through simple operations, eliminating the need for cumbersome post-processing steps and optimizing the entire synthesis method. Furthermore, the removal of the benzyl group can be achieved through catalytic hydrogenolysis, yielding high-purity dipeptide-2. This successfully avoids the use of toxic chemical reagents and the generation of toxic gases. It features simple process, mild conditions, high yield, and low cost, fully embodying the concept of green chemistry. It not only provides a new solution for related application research on dipeptide-2 preparation but also offers a feasible path for future large-scale production, demonstrating broad application prospects. Attached Figure Description

[0025] Figure 1 The proton NMR spectrum of dipeptide-2 in Example 1;

[0026] Figure 2 The carbon spectrum of dipeptide-2 in Example 1 is shown. Detailed Implementation

[0027] The present invention will be further described below with reference to embodiments. These embodiments are illustrative of the present invention, but the present invention is not limited to these embodiments:

[0028] Example 1

[0029] A method for preparing dipeptide-2 includes the following steps:

[0030] S1. 20 mL of 1,4-dioxane, 20 mL of H2O, 20 mmol of L-valine (2.34 g), 22 mmol of 1-[2-(trimethylsilyl)ethoxycarbonyl]pyrrolidine-2,5-dione (5.7 g), and 30 mmol of triethylamine (4.2 mL) were added sequentially to a 100 mL flask. The mixture was then reacted at room temperature for 36 h. After the reaction was complete, saturated sodium bisulfate was added to the reaction system for acidification, followed by three extractions with 50 mL of ethyl acetate. The combined organic phase was washed once with 30 mL of saturated brine. The organic phase was then dried with anhydrous sodium sulfate, and the solvent was removed under vacuum to finally obtain 5.0 g of 2-(trimethylsilyl)ethoxycarbonyl L-valine, with a yield of 95%.

[0031] S2. Add 50 mL of dichloromethane, 19 mmol of 2-(trimethylsilyl)ethoxycarbonyl-L-valine (5.0 g), 19 mmol of L-tryptophan benzyl ester (5.6 g), and 22.8 mmol of [unspecified ingredient] sequentially to a 100 mL flask. 6-Chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU, 9.43 g) and 57 mmol N,N-diisopropylethylamine (DIPEA, 9.9 mL) were reacted at room temperature for 6 h. After the reaction, the solvent was evaporated under vacuum to obtain the crude product system. The crude product was diluted with 100 mL of ethyl acetate and washed successively with 15 mL of water, 15 mL of hydrochloric acid (1N aqueous solution), 15 mL of saturated sodium bicarbonate aqueous solution, and 15 mL of water, with each washing step repeated twice. The organic phase was then dried with anhydrous sodium sulfate, and the solvent was removed under vacuum. Finally, the product was purified by column chromatography (eluent: 30% ethyl acetate / petroleum ether) to obtain 9.1 g of 2-(trimethylsilyl)ethoxycarbonyl L-valine-L-tryptophan benzyl ester, with a yield of 89%.

[0032] S3. 20 mL of tetrahydrofuran, 17 mmol of 2-(trimethylsilyl)ethoxycarbonyl L-valine-L-tryptophan benzyl ester (9.1 g), and 34 mL of 1 M tetrabutylammonium fluoride (TBAF) in THF solution were added sequentially to a 100 mL flask. The mixture was then reacted at 60 °C for 12 h. After the reaction was completed, the solvent was removed under vacuum to obtain the crude product. The crude product was then dissolved in 100 mL of ethyl acetate and washed twice with 20 mL of water. The organic phase was then dried with anhydrous sodium sulfate and the solvent was removed under vacuum to finally obtain 5.9 g of L-valine-L-tryptophan benzyl ester, with a yield of 88%.

[0033] S4. 15.0 mmol L-valine-L-tryptophan benzyl ester (5.9 g) was dissolved in 40 mL methanol. Then, 0.59 g of palladium / carbon catalyst (10% loaded on carbon, water content approximately 55%) was added to the reaction system, and the reaction was started by bubbling hydrogen gas for 15 minutes. The reaction continued for 12 h under a continuous hydrogen atmosphere. After the reaction was completed, the catalyst was removed by filtration to obtain a methanol solution. The solvent was removed under vacuum, and then recrystallized to obtain 4.1 g of dipeptide-2 white solid with a yield of 90%.

[0034] Depend on Figure 1 As can be seen, the 1H NMR spectrum data of dipeptide-2 in Example 1 are as follows: 1 HNMR (400MHz, C2D6OS) δ = 10.89 (s, 1H), 8.26 (d, J = 7.0H, 1H), 7.56 (d, J = 7.8Hz, 1H), 7.31 (d , J=8.0Hz, 1H), 7.17 (d, J=1.7Hz, 1H), 7.03 (t, J=7.5Hz, 1H), 6.94 (t, J=7.4Hz, 1H), 4.86 (s, 1H), 4.43 (d, J=5.4Hz, 1H), 3.32 (d, J=4.9Hz, 1H), 3.21 (dd, J=14.6, 4.9Hz, 1H), 3.07 (dd, J= 14.6, 7.4Hz, 1H), 2.03 (dd, J=12.1, 6.7Hz, 1H), 0.88 (d, J=6.9H, 1H), 0.79 (d, J=6.8Hz, 1H).

[0035] Depend on Figure 2 As can be seen, the carbon NMR spectrum data of dipeptide-2 in Example 1 are as follows: 13CNMR (100MHz, C2D6OS) δ = 174.1, 170.7, 136.2, 127.7, 123.7, 120.8, 118.6, 118.2, 111.3, 110.7, 58.6, 54.2, 30.6, 27.8, 22.0, 19.1, 17.2.

[0036] Example 2

[0037] A method for preparing dipeptide-2 includes the following steps:

[0038] S1. 20 mL of 1,4-dioxane, 20 mL of H2O, 20 mmol of L-valine (2.34 g), 24 mmol of 1-[2-(trimethylsilyl)ethoxycarbonyl]pyrrolidine-2,5-dione (6.2 g), and 40 mmol of triethylamine (5.6 mL) were added sequentially to a 100 mL flask. The mixture was then reacted at room temperature for 24 h. After the reaction was complete, saturated sodium bisulfate was added to the reaction system for acidification, followed by three extractions with 50 mL of ethyl acetate. The combined organic phase was washed once with 30 mL of saturated brine. The organic phase was then dried with anhydrous sodium sulfate, and the solvent was removed under vacuum to finally obtain 5.07 g of 2-(trimethylsilyl)ethoxycarbonyl L-valine, with a yield of 97%.

[0039] S2. Add 60 mL of dichloromethane, 19.4 mmol of 2-(trimethylsilyl)ethoxycarbonyl L-valine (5.0 g), 19.4 mmol of L-tryptophan benzyl ester (5.7 g), and 23.3 mmol of [unspecified ingredient] to a 100 mL flask in sequence. 6-Chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU, 9.6 g) and 58.2 mmol N,N-diisopropylethylamine (DIPEA, 10.1 mL) were reacted at room temperature for 7 h. After the reaction, the solvent was evaporated under vacuum to obtain the crude product system. The crude product was diluted with 100 mL of ethyl acetate and washed successively with 15 mL of water, 15 mL of hydrochloric acid (1N aqueous solution), 15 mL of saturated sodium bicarbonate aqueous solution, and 15 mL of water, with each washing step repeated twice. The organic phase was then dried with anhydrous sodium sulfate, and the solvent was removed under vacuum. Finally, the product was purified by column chromatography (eluent: 30% ethyl acetate / petroleum ether) to obtain 9.5 g of 2-(trimethylsilyl)ethoxycarbonyl L-valine-L-tryptophan benzyl ester, with a yield of 91%.

[0040] S3. Add 30 mL of tetrahydrofuran, 17.6 mmol of 2-(trimethylsilyl)ethoxycarbonyl L-valine-L-tryptophan benzyl ester (9.5 g), and 53 mL of 1 M tetrabutylammonium fluoride (TBAF) in THF solution to a 200 mL flask. Then react the mixture at 60 °C for 6 h. After the reaction is complete, remove the solvent under vacuum to obtain the crude product. Dissolve the crude product in 100 mL of ethyl acetate and wash twice with 20 mL of water. Then dry the organic phase with anhydrous sodium sulfate and remove the solvent under vacuum to finally obtain 6.2 g of L-valine-L-tryptophan benzyl ester, with a yield of 89%.

[0041] S4. 15.7 mmol L-valine-L-tryptophan benzyl ester (6.2 g) was dissolved in 50 mL methanol. Then, 0.62 g of palladium / carbon catalyst (10% loaded on carbon, water content approximately 55%) was added to the reaction system, and the reaction was started by bubbling hydrogen gas for 15 minutes. The reaction continued for 14 h under a continuous hydrogen atmosphere. After the reaction was completed, the catalyst was removed by filtration to obtain a methanol solution. The solvent was removed under vacuum, and then recrystallized to obtain 4.2 g of dipeptide-2 white solid, with a yield of 88%.

[0042] Example 3

[0043] A method for preparing dipeptide-2 includes the following steps:

[0044] S1. 20 mL of 1,4-dioxane, 20 mL of H2O, 20 mmol of L-valine (2.34 g), 24 mmol of 1-[2-(trimethylsilyl)ethoxycarbonyl]pyrrolidine-2,5-dione (6.2 g), and 30 mmol of triethylamine (4.2 mL) were added sequentially to a 100 mL flask. The mixture was then reacted at room temperature for 36 h. After the reaction was complete, saturated sodium bisulfate was added to the reaction system for acidification, followed by three extractions with 50 mL of ethyl acetate. The combined organic phase was washed once with 30 mL of saturated brine. The organic phase was then dried with anhydrous sodium sulfate, and the solvent was removed under vacuum to finally obtain 4.9 g of 2-(trimethylsilyl)ethoxycarbonyl L-valine, with a yield of 94%.

[0045] S2. Add 60 mL of dichloromethane, 18.8 mmol of 2-(trimethylsilyl)ethoxycarbonyl L-valine (4.9 g), 20.7 mmol of L-tryptophan benzyl ester (6.1 g), and 22.6 mmol of [unspecified ingredient] to a 100 mL flask in sequence. 6-Chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU, 9.3 g) and 56.4 mmol N,N-diisopropylethylamine (DIPEA, 9.8 mL) were reacted at room temperature for 7 h. After the reaction, the solvent was evaporated under vacuum to obtain the crude product system. The crude product was diluted with 100 mL of ethyl acetate and washed successively with 15 mL of water, 15 mL of hydrochloric acid (1N aqueous solution), 15 mL of saturated sodium bicarbonate aqueous solution, and 15 mL of water, with each washing step repeated twice. The organic phase was then dried with anhydrous sodium sulfate, and the solvent was removed under vacuum. Finally, the product was purified by column chromatography (eluent: 30% ethyl acetate / petroleum ether) to obtain 9.2 g of 2-(trimethylsilyl)ethoxycarbonyl L-valine-L-tryptophan benzyl ester, with a yield of 91%.

[0046] S3. 20 mL of tetrahydrofuran, 17.1 mmol of 2-(trimethylsilyl)ethoxycarbonyl L-valine-L-tryptophan benzyl ester (9.2 g), and 34.2 mL of 1 M tetrabutylammonium fluoride (TBAF) THF solution were added sequentially to a 100 mL flask. The mixture was then reacted at 60 °C for 12 h. After the reaction was completed, the solvent was removed under vacuum to obtain the crude product. The crude product was then dissolved in 100 mL of ethyl acetate and washed twice with 20 mL of water. The organic phase was then dried with anhydrous sodium sulfate and the solvent was removed under vacuum to finally obtain 6.0 g of L-valine-L-tryptophan benzyl ester, with a yield of 86%.

[0047] S4. 14.7 mmol L-valine-L-tryptophan benzyl ester (6.0 g) was dissolved in 40 mL methanol, and then 0.6 g palladium / carbon catalyst (10% loaded on carbon, water content approximately 55%) was added to the reaction system. The reaction was started by bubbling hydrogen gas for 15 minutes. The reaction continued for 12 h under a continuous hydrogen atmosphere. After the reaction was completed, the catalyst was removed by filtration to obtain a methanol solution. The solvent was removed under vacuum, and then recrystallized to obtain 4.0 g dipeptide-2 white solid with a yield of 89%.

[0048] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any person skilled in the art can make many possible variations and modifications to the technical solutions of the present invention, or modify them into equivalent embodiments, without departing from the spirit and technical essence of the present invention. Therefore, any simple modifications, equivalent substitutions, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention, without departing from the content of the technical solutions of the present invention, shall still fall within the scope of protection of the present invention.

Claims

1. A method for preparing dipeptide-2, characterized in that, Includes the following steps: S1. 2-(trimethylsilyl)ethoxycarbonyl L-valine is prepared by amino protection of L-valine using a 2-(trimethylsilyl)ethoxycarbonyl group. The amino protection method is as follows: the amino group of L-valine is protected in reaction solvent A using a substance containing a 2-(trimethylsilyl)ethoxycarbonyl group, followed by treatment with triethylamine at room temperature for 36-48 hours. The molar ratio of L-valine, the substance containing a 2-(trimethylsilyl)ethoxycarbonyl group, and triethylamine is 1.0:(1.1-1.3):(1.5-2). The reaction solvent A is a composition of 1,4-dioxane and water. S2,2-(trimethylsilyl)ethoxycarbonylL-valine and L-tryptophan benzyl ester undergo a condensation reaction to generate 2-(trimethylsilyl)ethoxycarbonylL-valine-L-tryptophan benzyl ester; the condensation reaction is carried out using 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine as condensing agents, and 2-(trimethylsilyl)ethoxycarbonylL-valine reacts with... L-Tryptophan benzyl ester was reacted in reaction solvent B at room temperature for 6-12 h; the molar ratio of 2-(trimethylsilyl)ethoxycarbonyl L-valine, L-Tryptophan benzyl ester, 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine was 1.0:(1.0-1.3):(1.2-1.5):(3.0-3.5); the reaction solvent B was dichloromethane. S3. 2-(trimethylsilyl)ethoxycarbonyl-L-valine-L-tryptophan benzyl ester was deprotected using a deprotecting agent to prepare L-valine-L-tryptophan benzyl ester; the deprotecting agent was tetrabutylammonium fluoride. The amount of the deprotecting agent added is 2-4 times the molar mass of 2-(trimethylsilyl)ethoxycarbonyl L-valine-L-tryptophan benzyl ester; S4. L-valine-L-tryptophan benzyl ester was hydrolyzed under palladium carbon hydrogenation conditions to obtain dipeptide-2; the specific method of hydrolysis was as follows: using palladium carbon as a debenzylation reagent, L-valine-L-tryptophan benzyl ester was reacted at room temperature for 12-24 h and purified by filtration to obtain dipeptide-2; the mass ratio of L-valine-L-tryptophan benzyl ester to palladium carbon was 1.0:(0.1-0.2).

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