A method for synthesizing chiral n-alkyl amino acid derivatives

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of chiral N-alkyl amino acid derivatives. The synthesis method is improved on the basis of the synthesis method of chiral N-alkyl amino acid derivatives in the prior art, has mild reaction conditions, high yield, is beneficial to industrial large-scale production, and solves the amplification effect of the synthesis method in the prior art.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing chiral N-alkyl amino acid derivatives. Background Technology

[0002] Amino acids, as the basic building blocks of peptides and proteins, are among the most fundamental substances constituting organic organisms. In recent years, with the deepening research into the roles of amino acids, peptides, and proteins in life activities, and the expanding applications of amino acids in various fields such as pharmaceuticals and food processing, the study of synthetic methods for amino acid derivatives has become of great significance. Optically pure N-alkyl-α-amino acids are important components of many physiologically and pharmacologically active natural products and drugs. In particular, N-alkyl amino acid fragments play a crucial role in the spatial conformation and physiological activity of peptide molecules. For example, N-alkylation can inhibit isomer formation by restricting the flexibility of the peptide molecule's backbone; N-alkylation modifications may alter the biological activity of peptides, thereby affecting the interaction between peptide molecules and receptors; the introduction of alkyl groups onto the nitrogen atom of amino acids can also affect the stability of proteases or increase the resistance of peptides and their analogues to protease degradation. Furthermore, N-alkyl-α-amino acids are frequently used to construct various catalysts and transition metal ligands for efficient catalysis of various reactions. For these reasons, research on synthetic methods for highly optically active N-alkyl-α-amino acids is of great importance.

[0003] To date, numerous studies have reported on the synthesis of N-alkyl amino acids. Conventional synthetic methods mainly include direct N-alkylation, reductive amination, and indirect N-alkylation (through ring-opening after generating an oxazolidinone intermediate). Direct alkylation has been used for a long time, often employing NaH or potassium carbonate as a base, with iodomethane or dimethyl sulfate as preferred alkylating agents. However, this method inevitably generates a certain degree of carboxyl alkylation, requiring subsequent hydrolysis to obtain the exposed carboxyl group. Since alkaline hydrolysis of amino acid esters can lead to racemization, further purification is necessary to obtain highly optically active products, resulting in low atom utilization. Furthermore, most of the reported methods are at the laboratory scale-up stage, posing certain risks for large-scale production.

[0004] The method of reacting amino acid feedstocks with aldehydes followed by reductive amination is also a commonly used N-alkylation method, especially since it yields some N-alkylated products with unique structures. This method avoids the formation of carboxyl alkylation byproducts, but it requires expensive reducing agents such as NaBH3CN or NaBH(OAc)3, making post-processing complex, and reported yields are low, hindering industrial-scale production. Indirect methods often involve condensing the substrate with formaldehyde to form a ring, followed by reduction using a triethylsilane / trifluoroacetic acid system to obtain the target product. This method can be applied to the N-alkylation of most amino acids, but the cyclization reaction, especially the reductive ring-opening reaction, requires a large amount of strong acid (generally at least 5.0 equivalents), resulting in significant waste generation, increasing production costs, and greatly limiting the possibility of industrial-scale production.

[0005] The above method is a general approach for amino acid N-alkylation, with high applicability. To date, only one chiral study of the amino acid N-alkylation process has been reported (J. Org. Chem. 2009, 74, 8425–8427), the mechanism of which is as follows:

[0006]

[0007] This literature describes the use of Boc- or Cbz-protected valine (1) as a raw material, THF as a solvent, NaH as a base, and iodomethane as an alkylating agent to obtain optically pure N-alkylated product 2a. Specifically, when cesium carbonate is used as a base, only O-alkylated product (9) is generated; however, when the phase transfer catalyst 15-crown-5 is added, N- and O-dialkylated products (8) are obtained. Therefore, they proposed the above reaction mechanism: due to its unique oxyphilicity, the Na atom combines with the carboxyl group to form a complex equivalent to a tight ion pair, occupying the carboxyl reaction site, thus causing alkylation to occur only selectively on the N atom, while avoiding racemization of the O-methylated product in an alkaline system. However, this report is only at the laboratory scale-up stage and requires the use of large amounts of iodomethane (8.0 equivalents) and NaH (10 equivalents), exhibiting a significant scale-up effect, extremely low atom utilization, and greatly increasing the cost of post-treatment waste, which is highly unfavorable for industrial-scale production. Summary of the Invention

[0008] The purpose of this invention is to solve the problems of significant scale-up effects and incomplete reactions or low ee values ​​of reaction products in existing methods for synthesizing chiral N-alkyl amino acid derivatives under alkaline conditions.

[0009] To address this need in the field, this application provides a method for synthesizing chiral N-alkyl amino acid derivatives.

[0010] On one hand, the present invention relates to a method for synthesizing a chiral N-alkyl amino acid derivative, comprising the following reaction steps:

[0011]

[0012] R1 is selected from methyl, isopropyl, phenyl, benzyl, or substituted aryl; R2 is selected from Boc or Cbz; and R3 is selected from C. 1-6 One of alkyl, substituted aryl, benzyl, allyl, benzyl and spirocycloalkyl;

[0013] Compound (2) was placed in a mixture containing THF and toluene and synthesized by alkylation to form compound (3);

[0014] In the mixture containing THF and toluene, the volume ratio of THF to toluene is 3:1 to 10:1.

[0015] Furthermore, in the method for synthesizing chiral N-alkyl amino acid derivatives provided by the present invention, each equivalent of compound (2) is placed in a mixture containing THF and toluene at a concentration of 10 to 15V, and 2.0 to 5.0 equivalents of alkyl reagent and 2.0 to 5.0 equivalents of first base are added. After reacting for 8 to 12 hours, a reaction solution containing compound (3) is obtained.

[0016] Furthermore, in the method for synthesizing chiral N-alkyl amino acid derivatives provided by the present invention, the alkyl reagent is selected from at least one of iodomethane, dimethyl sulfate, bromoethane, 2-bromopropane, allyl bromide, or benzyl bromide;

[0017] The first alkali is selected from at least one of NaH, cesium carbonate, sodium methoxide, sodium tert-butoxide, or potassium tert-butoxide.

[0018] Furthermore, in the method for synthesizing chiral N-alkyl amino acid derivatives provided by the present invention, the extraction method of the compound of formula (3) includes: adding 3-10V of water to the reaction solution containing the compound of formula (3) to quench the reaction, concentrating and adjusting the pH to 1-2, extracting with ethyl acetate, drying and concentrating until the theoretical yield of the compound of formula (3) and the mass ratio of the concentrate are 1:1.1 to 1:1.5;

[0019] For every 1g of compound (3) in the theoretical yield, add 1.0 to 1.5 mL of n-hexane, stir and cool to -5 to 0°C, then slurry and filter to obtain compound (3).

[0020] Furthermore, in the method for synthesizing chiral N-alkyl amino acid derivatives provided by the present invention, the synthesis of the compound of formula (2) includes the following reaction steps:

[0021]

[0022] The compound of formula (1) was placed in a mixture containing THF and water to synthesize a reaction solution containing the compound of formula (2) by alkylation;

[0023] In the mixture containing THF and water, the volume ratio of THF to water is 1:1 to 1:1.5.

[0024] Furthermore, the method for synthesizing chiral N-alkyl amino acid derivatives provided by the present invention includes: placing each equivalent of compound (1) in a mixture containing THF and water at a concentration of 6 to 10 V, adding 2.0 to 3.0 equivalents of a second base, reacting until dissolved, adding 1.1 to 1.5 equivalents of an amino protecting agent, and reacting to obtain a reaction solution containing compound (2).

[0025] Furthermore, in the method for synthesizing chiral N-alkyl amino acid derivatives provided by the present invention, the second base is selected from at least one of NaOH, KOH, and LiOH.

[0026] Furthermore, in the method for synthesizing chiral N-alkyl amino acid derivatives provided by the present invention, the extraction method of the compound of formula (2) includes: concentrating the reaction solution containing the compound of formula (2), washing with toluene, adjusting the pH to 1-2, then extracting with ethyl acetate, drying and concentrating to obtain the compound of formula (2).

[0027] This invention addresses the problem of significant scale-up effects in existing methods for synthesizing chiral N-alkyl amino acid derivatives by improving reaction conditions. Therefore, this invention further seeks protection for the application of the above-described synthetic method in the industrial production of the compound of formula (3).

[0028] Compared with the prior art, the present invention has the following beneficial effects or advantages:

[0029] This invention increases the solubility of dianionic salts in heterogeneous reactions by adding toluene as a mixed solvent, thereby increasing the concentration of reactants exposed in the system and expanding the contact area between reactants. This significantly improves the reaction rate for scale-up reactions, effectively resolving the scale-up effect problem of the original reaction. This invention provides a method for synthesizing chiral N-alkyl amino acid derivatives that is more suitable for large-scale industrial production due to its readily available and inexpensive raw materials, mild reaction conditions, high selectivity, low equipment requirements, simple operation, high overall yield, and low environmental impact. Attached Figure Description

[0030] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0031] Figure 1 The results were obtained by comparing the proportions of the products.

[0032] Figure 2 The NMR spectra are representative of the compounds.

[0033] Figure 3 The chiral LC spectrum of the representative compound.

[0034] Figure 4 This is a diagram representing the appearance of the compound.

[0035] Figures 2-4 The representative compound in is Detailed Implementation

[0036] The technical solution of the present invention will be described below with reference to the embodiments. However, the present invention is not limited to the following embodiments.

[0037] To enable those skilled in the art to better understand and implement the technical solutions of the present invention, the present invention will be further described below in conjunction with specific embodiments and accompanying drawings. However, the embodiments described are not intended to limit the present invention.

[0038] Unless otherwise specified, the experimental and detection methods described in the following embodiments are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0039] Comparative Example

[0040] This comparative example provides experimental preparation of a method for synthesizing chiral N-alkyl amino acid derivatives.

[0041] Following the preparation method provided in J. Org. Chem. 2009, 74, 8425–8427, the experimental results obtained are as follows: Figure 1 As shown.

[0042] Through relevant experiments, this comparative example found that the preparation method provided in J. Org. Chem. 2009, 74, 8425–8427 is reproducible in the laboratory and applicable to substrates with the "phenylalanine skeleton". Further optimization of the reaction conditions revealed that the amounts of relevant reactants could be significantly reduced: iodomethane could be reduced to 2.0 equivalents, and NaH to 3.0 equivalents. However, the reaction exhibits a significant scale-up effect, such as… Figure 1 As shown.

[0043] When the reaction was scaled up from 5g to 50g, the reaction rate slowed down significantly; extending the reaction time continued the reaction, but the ee value decreased significantly. That is, the preparation method provided in J.Org.Chem.2009,74,8425–8427, under alkaline conditions, leads to a decrease in the product ee value (from >99.5% to 95%) when the reaction time is extended, while reducing the reaction time results in incomplete reaction.

[0044] Example 1

[0045] This embodiment provides a preparative experiment of a method for synthesizing chiral N-alkyl amino acid derivatives.

[0046] Compound 3 was synthesized from readily available and inexpensive compound 1 via a combination of protection, alkylation, and deprotection reactions. The synthetic route is as follows:

[0047]

[0048] The compound of formula (1) (1 mol, 1 equivalent) was dissolved in a mixture of 4V THF and 6V water. NaOH (2.0 equivalent) was added with stirring, and the temperature was controlled at 25°C. The mixture was stirred until the system was completely dissolved. The corresponding amino protecting agent (1.1 equivalent) was added. After stirring overnight, the reaction solution was directly concentrated (to remove most of the THF). The aqueous phase was then washed twice with toluene (single volume: 2V). The pH of the aqueous phase was adjusted to 1 with hydrochloric acid, followed by extraction twice with ethyl acetate (single volume: 5V). The organic phase was dried and concentrated to obtain compound 2, which was directly used in the next reaction (yield 100%).

[0049] The compound of formula (2) (1 mol, 1 equivalent) was dissolved in 10V solvent (THF:toluene = 3:1), and iodomethane (2.0 equivalent) was added. The temperature was controlled at 0℃, and alkali (NaH, 2.0 equivalent) was slowly added. After the addition was complete, the temperature was controlled at 0℃ and stirred for 8h. 3V water was added to the reaction system to quench the reaction, and the reaction solution was directly concentrated (to remove most of the organic solvent). The pH of the system was adjusted to 1 by adding hydrochloric acid to the aqueous phase, and then extracted twice with ethyl acetate (single volume: 5V). The organic phase was dried and concentrated to a product:concentrate = 1g:1.1g. Hexane (product:hexane = 1g:1.0mL) was added at room temperature, and the mixture was stirred and cooled to -5℃. The mixture was slurried for 1h and filtered to obtain the target compound of formula (3). The experimental results are shown in groups #1 to #4 and #9 in Table 1.

[0050] Example 2

[0051] This embodiment provides a preparative experiment of a method for synthesizing chiral N-alkyl amino acid derivatives.

[0052] Compound 3 was synthesized from readily available and inexpensive compound 1 via a combination of protection, alkylation, and deprotection reactions. The synthetic route is as follows:

[0053]

[0054] The compound of formula (1) (1 mol, 1 equivalent) was dissolved in a mixture of 3V THF and 3V water. KOH (2.5 equivalents) was added with stirring, and the temperature was controlled at 30°C. The mixture was stirred until the solution was clear. The corresponding amino protecting agent (1.3 equivalents) was added. After stirring overnight, the reaction solution was directly concentrated (to remove most of the THF). The aqueous phase was then washed twice with toluene (2V each time). The pH of the aqueous phase was adjusted to 1.5 with hydrochloric acid, followed by extraction twice with ethyl acetate (5V each time). The organic phase was dried and concentrated to obtain compound 2, which was directly used in the next reaction (yield 100%).

[0055] The compound of formula (2) (1 mol, 1 equivalent) was dissolved in 12V solvent (THF:toluene = 6:1), and bromoethane (3.0 equivalent) was added. The temperature was controlled at 3℃, and alkali (cesium carbonate, 3.5 equivalent) was slowly added. After the addition was complete, the temperature was controlled at 3℃ and stirred for 10h. The reaction was quenched with 6V water, and the reaction solution was directly concentrated (to remove most of the organic solvent). The pH of the aqueous phase was adjusted to 1.5 with hydrochloric acid, and then extracted twice with ethyl acetate (single volume: 5V). The organic phase was dried and concentrated to a product:concentrate = 1g:1.3g. Hexane (product:hexane = 1g:1.3mL) was added at room temperature, and the mixture was stirred and cooled to -3℃. The mixture was slurried for 1h and filtered to obtain the target compound of formula (3). The experimental results are shown in groups #5 to #6 in Table 1.

[0056] Example 3

[0057] This embodiment provides a preparative experiment of a method for synthesizing chiral N-alkyl amino acid derivatives.

[0058] Compound 3 was synthesized from readily available and inexpensive compound 1 via a combination of protection, alkylation, and deprotection reactions. The synthetic route is as follows:

[0059]

[0060] The compound of formula (1) (1 mol, 1 equivalent) was dissolved in a mixture of 3.5 V THF and 4.9 V water. LiOH (3 equivalents) was added with stirring, and the temperature was controlled at 35 °C. The mixture was stirred until the system was completely dissolved. The corresponding amino protecting agent (1.5 equivalents) was added. After stirring overnight, the reaction solution was directly concentrated (to remove most of the THF). The aqueous phase was then washed twice with toluene (single volume: 2 V). The pH of the aqueous phase was adjusted to 2 with hydrochloric acid, followed by extraction twice with ethyl acetate (single volume: 5 V). The organic phase was dried and concentrated to obtain compound 2, which was directly used in the next reaction (yield 100%).

[0061] The compound of formula (2) (1 mol, 1 equivalent) was dissolved in 15V solvent (THF:toluene = 10:1), and benzyl bromide (5 equivalents) was added. The temperature was controlled at 5℃, and the base (sodium methoxide, 2 equivalents) was slowly added. After the addition was complete, the temperature was controlled at 5℃ and the mixture was stirred for 12h. 10V water was added to the reaction system to quench the reaction. The reaction solution was directly concentrated (to remove most of the organic solvent). The pH of the aqueous phase was adjusted to 2 with hydrochloric acid. Then, ethyl acetate was added to extract twice (single volume: 5V). The organic phase was dried and concentrated to a product:concentrate = 1g:1.5g. Hexane (product:hexane = 1g:1.5mL) was added at room temperature, and the mixture was stirred and cooled to 0℃. The mixture was slurried for 1h and filtered to obtain the target compound of formula (3). The experimental results are shown in groups #7 to #8 in Table 1.

[0062] The experimental results of Examples 1 to 3 are shown in Table 1.

[0063] Table 1: Experimental Results

[0064]

[0065] When substituent R2 = Boc and R3 = methyl, chirality is well preserved during the reaction (ee > 99.0%), with slight differences in yield (R1 = methyl, yield = 95%; R1 = isopropyl, yield = 85%; R1 = phenyl, yield = 87%; R1 = benzyl, yield = 91%), presumably due to steric hindrance of the R1 group. When R1 = benzyl and R2 = Boc, the yield varies due to differences in the reactivity of the alkyl reagent (R3 = ethyl, yield = 85%; R3 = isopropyl, yield = 77%; R3 = allyl, yield = 82%; R3 = benzyl, yield = 75%), but chirality is well preserved (ee > 99.0%). Finally, when R1 = benzyl, R2 = Cbz, and R3 = methyl, the yield reaches 93%, and chirality is well preserved. Figure 3 (ee>99.5%).

[0066] As described above, the present invention can be well implemented. The above embodiments are merely descriptions of preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, all changes and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the protection scope defined by the present invention.

Claims

1. A chiral N A method for synthesizing alkyl amino acid derivatives, characterized in that, The reaction steps include the following: ； R1 is selected from methyl, isopropyl, phenyl, and benzyl; R2 is selected from Boc or Cbz; and R3 is selected from C. 1-6 One of alkyl, benzyl, or allyl; Compound (2) was placed in a mixture containing THF and toluene and synthesized by alkylation to form compound (3); In the mixture containing THF and toluene, the volume ratio of THF to toluene is 3:1 to 10:1; Each equivalent of compound (2) is placed in a mixture containing THF and toluene at a concentration of 10-15V, and 2.0-5.0 equivalents of an alkyl reagent and 2.0-5.0 equivalents of a first base are added. After reacting for 8-12 hours, a reaction solution containing compound (3) is obtained. The first alkali is selected from at least one of NaH, cesium carbonate, sodium methoxide, sodium tert-butoxide, or potassium tert-butoxide.

2. The synthesis method according to claim 1, characterized in that, The alkyl reagent is selected from at least one of iodomethane, dimethyl sulfate, bromoethane, 2-bromopropane, allyl bromide, or benzyl bromide.

3. The synthesis method according to claim 1, characterized in that, The extraction method of the compound of formula (3) includes: adding 3~10V of water to the reaction solution containing the compound of formula (3) to quench the reaction, concentrating and adjusting the pH to 1~2, extracting with ethyl acetate, drying and concentrating until the theoretical yield of the compound of formula (3) and the mass ratio of the concentrate are 1:1.1~1:1.5; For every 1g of compound (3) in the theoretical yield, add 1.0~1.5mL of n-hexane, stir and cool to -5~0℃, then slurry and filter to obtain compound (3).

4. The synthesis method according to claim 1, characterized in that, The synthesis of the compound of formula (2) includes the following reaction steps: The compound of formula (1) was placed in a mixture containing THF and water to synthesize a reaction solution containing the compound of formula (2) by alkylation; In the mixture containing THF and water, the volume ratio of THF to water is 1:1 to 1:1.

5.

5. The synthesis method according to claim 4, characterized in that, include: Each equivalent of compound (1) is placed in a mixture of 6-10V containing THF and water, and 2.0-3.0 equivalents of a second base are added. The mixture is reacted until dissolved, and 1.1-1.5 equivalents of an amino protecting agent are added. The reaction is then carried out to obtain a reaction solution containing compound (2).

6. The synthesis method according to claim 5, characterized in that, The second alkali is selected from at least one of NaOH, KOH, and LiOH.

7. The synthesis method according to claim 4, characterized in that, The extraction method of the compound of formula (2) includes: concentrating the reaction solution containing the compound of formula (2), washing with toluene, adjusting the pH to 1-2, then extracting with ethyl acetate, drying and concentrating to obtain the compound of formula (2).

8. The application of the synthesis method according to any one of claims 1 to 7 in the industrial production of compound (3).

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