Preparation method of amino acid derivative
By reacting sulfoxide chloride with N-formylalanine and tetrahydrofuran, the environmental pollution and by-product generation problems caused by phosgene in the prior art were solved, and the preparation of amino acid derivatives with high purity and high yield was achieved, reducing the risk of environmental pollution in the production process.
Patent Information
- Application Number
- CN202410291970.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-03-14
- Publication Date
- 2025-03-07
AI Technical Summary
In the existing preparation methods for amino acid derivatives, phosgene is used to cause environmental pollution and by-product generation, affecting purity and yield.
The reaction of sulfoxide chloride with N-formylalanine and tetrahydrofuran was performed by slow warming and reflux reaction to produce amino acid derivatives, followed by vacuo concentration and petroleum ether crystallization to obtain the target product.
It improves the purity and yield of amino acid derivatives, reduces the risk of environmental pollution, and simplifies the treatment of three wastes, enhancing the reaction activity and selectivity.
Smart Images
Figure CN119569672A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of polypeptide synthesis, and in particular to a method for preparing an amino acid derivative. Background Art
[0002] N-carboxylic anhydrides of amino acids are commonly used in the synthesis of polypeptides; currently, methods for preparing amino acid derivatives such as N-carboxylic anhydrides generally involve reacting an amino acid or a salt thereof with phosgene in a solvent medium. Such reactions generally employ phosgene which is inert to other compounds in the reaction mixture; in addition, at least one olefinic double bond is oxidized to phosgene, diphosgene or triphosgene, in a solvent medium. It is noteworthy that such reactions occur at least partially in the presence of unsaturated organic compounds having one or more olefinic double bonds and having groups other than halogen atoms completely substituted on the remaining carbon atoms of the molecule.
[0003] In the process of generating N-carboxylic anhydride by reacting amino acids or their salts with phosgene, a considerable amount of HCl is produced. The HCl in the reaction medium may lead to the formation of chlorinated by-products, which affect the polymerization reaction of N-carboxylic anhydride. If these by-products remain in the N-carboxylic anhydride product, their purity and yield will be affected. In addition, phosgene is a highly dangerous chemical, which causes serious environmental pollution and is not conducive to mass production. Summary of the invention
[0004] In order to solve the technical problem that the existing method for preparing amino acid derivatives affects the purity and yield, the present application provides a method for preparing amino acid derivatives.
[0005] In order to achieve the above-mentioned purpose, the technical solution adopted in the present application is: a method for preparing an amino acid derivative, comprising the following steps: obtaining N-formylalanine and tetrahydrofuran, mixing and stirring the N-formylalanine and tetrahydrofuran, and cooling to obtain an initial mixed solution; obtaining thionyl chloride, adding thionyl chloride to the initial mixed solution, slowly heating it, and performing a reflux reaction, and after the reaction is completed, performing TLC detection to obtain a second-generation mixed solution; vacuum concentrating the second-generation mixed solution, adding petroleum ether, stirring and crystallizing to obtain a target product, and drying the target product to obtain an amino acid derivative.
[0006] As one of the optimized embodiments of the present invention, the mixing ratio of N-formylalanine and tetrahydrofuran is in the range of 1:7-1:8.
[0007] As one of the optimized implementation schemes of the present invention, N-formylalanine and tetrahydrofuran are mixed and stirred, and the temperature is lowered to obtain an initial mixed solution. Specifically, N-formylalanine and tetrahydrofuran are mixed and stirred according to a mixing ratio, and the temperature is controlled in the range of minus 9-minus 10°C to obtain an initial mixed solution.
[0008] As one of the optimized implementation schemes of the present invention, the mixing ratio of thionyl chloride to the initial mixed solution is in the range of 1:6-1:7.
[0009] As one of the optimized implementation schemes of the present invention, thionyl chloride is added to the initial mixed solution, the temperature is slowly raised, and a reflux reaction is carried out. After the reaction is completed, TLC detection is performed to obtain a second-generation mixed solution. Specifically, thionyl chloride is added to the initial mixed solution according to the mixing ratio, the temperature is slowly raised to 60-62° C., and a reflux reaction is carried out. After the reaction is completed, TLC detection is performed to determine whether the purity meets the standard. If it meets the standard, a second-generation mixed solution is obtained.
[0010] As one of the optimized implementation schemes of the present invention, if the purity does not meet the standard, continue to add thionyl chloride to react until the TLC detection meets the standard.
[0011] As one of the optimized implementation schemes of the present invention, vacuum concentration is performed based on the second-generation mixed liquid. Specifically, the second-generation mixed liquid is passed through a concentration bottle and vacuum concentrated based on a temperature range of 60°C-62°C.
[0012] Compared with the prior art, the present invention has the following beneficial effects: in the technical solution of the present application, the target product is synthesized by using thionyl chloride, a compound that is relatively friendly to the environment, which is beneficial to production and can also ensure the safety of production, that is, the use of phosgene and phosphorus pentachloride to prepare the target product is abandoned, and thionyl chloride with less toxicity is used, which has strong reactivity and selectivity in the reaction process, makes the treatment of three wastes simpler, reduces the risk of environmental pollution in the production process, and can reduce the generation of by-products by optimizing the production process, so that the purity and yield of the obtained target product are higher. BRIEF DESCRIPTION OF THE DRAWINGS
[0013] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For those skilled in the art, other drawings can be obtained based on these drawings without paying any creative labor.
[0014] Figure 1 1 is a flow chart of the steps of the method for preparing the amino acid derivatives provided in the first embodiment of the present invention. DETAILED DESCRIPTION
[0015] In order to make the purpose, technical solution and advantages of the embodiments of the present application clearer, the technical solution in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. The components of the embodiments of the present application described and shown in the drawings here can be arranged and designed in various different configurations.
[0016] Therefore, the following detailed description of the embodiments of the present application provided in the accompanying drawings is not intended to limit the scope of the present application for which protection is sought, but merely represents selected embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present application.
[0017] It should be noted that similar reference numerals and letters denote similar items in the following drawings, and therefore, once an item is defined in one drawing, further definition and explanation thereof is not required in subsequent drawings.
[0018] In the description of this application, it should be noted that if the terms "center", "up", "down", "left", "right", "vertical", "horizontal", "inside", "outside", etc. appear, the orientation or position relationship indicated is based on the orientation or position relationship shown in the drawings, or the orientation or position relationship in which the product of the application is usually placed when in use. It is only for the convenience of describing this application and simplifying the description, and does not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operate in a specific orientation, and therefore cannot be understood as a limitation on this application. In addition, if the terms "first", "second", etc. appear in the description of this application, they are only used to distinguish the description and cannot be understood as indicating or implying relative importance.
[0019] In addition, if the terms "horizontal" or "vertical" appear in the description of this application, it does not mean that the components are required to be absolutely horizontal or suspended, but can be slightly tilted. For example, "horizontal" only means that its direction is more horizontal than "vertical", and does not mean that the structure must be completely horizontal, but can be slightly tilted.
[0020] In the description of this application, it should also be noted that, unless otherwise clearly specified and limited, the terms "set", "install", "connect", and "connect" should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection, or it can be indirectly connected through an intermediate medium, or it can be the internal connection of two components. For ordinary technicians in this field, the specific meanings of the above terms in this application can be understood according to specific circumstances.
[0021] See also Figure 1The first embodiment of the present invention provides a method for preparing an amino acid derivative, comprising the following steps:
[0022] Step S1: obtaining N-formylalanine and tetrahydrofuran, mixing and stirring the N-formylalanine and tetrahydrofuran, and cooling the mixture to obtain an initial mixed solution;
[0023] Step S2: obtaining thionyl chloride, adding thionyl chloride to the initial mixed solution, slowly heating it, and performing a reflux reaction, and after the reaction is completed, performing TLC detection to obtain a second-generation mixed solution;
[0024] Step S3: vacuum concentrate the second-generation mixed solution, add petroleum ether and stir to crystallize to obtain the target product, and dry the target product to obtain an amino acid derivative.
[0025] It is to be noted that the amino acid derivatives described in this embodiment involve N-carboxycyclic acid anhydrides (NCA), which is an important organic compound and an important intermediate for the synthesis of L-amino acids. It is used to synthesize a variety of drugs and can also be used to synthesize polymer materials and bioactive molecules through polymerization reactions. Among them, L-Ala-NCA prepared from N-formylalanine is used to prepare α-amino acids.
[0026] It can be explained that L-Ala-NCA is prepared based on N-formylalanine, tetrahydrofuran and other related solvents, wherein Ala refers to alanine, which is a non-polar amino acid; NCA is an amide bond connected to the side chain of alanine, which can stabilize the peptide chain structure; L-Ala-NCA is one of the important raw materials for synthesizing polypeptides and can be used to study amino acid biosynthesis, enzyme catalysis and other fields.
[0027] N-formylalanine (N-For) is a very important amino acid derivative. It is used in protein synthesis and biological activity research. It can protect the amino acid side chain from chemical and biological degradation and improve the stability of synthetic proteins.
[0028] Tetrahydrofuran (THF) is an organic compound with good solubility and polarity. It can be mixed with organic solvents such as water, alcohol, and ether, but it is prone to chemical reactions when in contact with inorganic substances such as acids and alkalis. It has strong chemical activity and is prone to addition, oxidation, reduction and other reactions.
[0029] Sulfur chlorides are a class of organic compounds with a sulfoxide group (-SO-) and a chlorine atom (-Cl). In organic synthesis, sulfur chloride, as an intermediate, can be further converted into other organic compounds through substitution, addition, oxidation and other reactions. Although it is toxic, the toxicity is relatively low. Compared with the preparation of the target product by phosgene and phosphorus pentachloride, sulfur chloride makes the preparation and processing of the target product simpler and reduces the environmental impact.
[0030] It can be understood that in the technical solution of the present application, the target product is synthesized by using the environmentally friendly compound thionyl chloride, which is conducive to production and can also ensure the safety of production. That is, the use of phosgene and phosphorus pentachloride to prepare the target product is abandoned, and thionyl chloride with less toxicity is used. It has strong reactivity and selectivity in the reaction process, making the treatment of three wastes simpler, reducing the risk of environmental pollution in the production process, and by optimizing the production process, the generation of by-products can be reduced, and the purity and yield of the obtained target product are higher.
[0031] It is explained that L-Al a-NCA is prepared by reacting N-formylalanine and tetrahydrofuran with thionyl chloride. First, tetrahydrofuran can promote the reaction of N-formylalanine with other compounds. N-formylalanine and tetrahydrofuran are mixed to form a stable solution, i.e., an initial mixed solution. This setting allows N-formylalanine to be fully dissolved in an organic solvent, thereby improving the reaction efficiency. Then, thionyl chloride is added to the initial mixed solution to prepare a secondary mixed solution. The thionyl chloride can replace the formyl group of N-formylalanine with a chlorine atom, thereby generating L-Al a-NCA in an appropriate temperature environment.
[0032] Further, the mixing ratio of N-formylalanine and tetrahydrofuran is in the range of 1:7-1:8.
[0033] Further, in step S1, N-formylalanine and tetrahydrofuran are mixed and stirred, and the temperature is lowered to obtain an initial mixed solution, specifically:
[0034] N-formylalanine and tetrahydrofuran are mixed and stirred according to a mixing ratio, and the temperature is controlled to be in a range of minus 9° C. to minus 10° C. to obtain an initial mixed solution.
[0035] It is explained that the mixing ratio of N-formylalanine and tetrahydrofuran is controlled to achieve the best mixing effect between the two, which is convenient for subsequent experiments; and the reaction temperature of the two is controlled to prevent excessively high or low temperatures from affecting the stability of the mixture.
[0036] Furthermore, the mixing ratio of thionyl chloride to the initial mixed solution is in the range of 1:6-1:7.
[0037] Further, in step S2, thionyl chloride is added to the initial mixed solution, the temperature is slowly raised, and a reflux reaction is performed. After the reaction is completed, TLC detection is performed to obtain a second-generation mixed solution, specifically:
[0038] Add thionyl chloride to the initial mixed solution according to the mixing ratio, slowly raise the temperature to 60-62°C, and perform reflux reaction. After the reaction is completed, perform TLC detection to determine whether the purity meets the standard. If it meets the standard, a second-generation mixed solution is obtained.
[0039] Furthermore, if the purity does not meet the standard, continue to add thionyl chloride to react until the TLC detection meets the standard.
[0040] It is explained that the mixing ratio range of thionyl chloride and the initial mixed solution is strictly controlled to avoid affecting the formation of the final product. Thionyl chloride is added to the initial mixed solution, and the temperature is gradually raised to 60-62°C, followed by a reflux reaction, so that the thionyl chloride and the initial mixed solution are fully in contact, thereby improving the conversion rate of the reaction; then the second-generation mixed solution is tested for purity by thin layer chromatography. If the test result meets the standard, it means that the reaction is successful, so as to obtain the expected second-generation mixed solution; otherwise, if it does not meet the standard, the experimental process is optimized, and thionyl chloride is continued to be added to react until the TLC test meets the standard.
[0041] It can be explained that the reflux reaction mainly utilizes the heat generated by the reaction to convert part of the reactants into products, and the products are cooled into liquids through a cooling device. The liquid products are then reintroduced into the reaction vessel to continue reacting with the remaining reactants, and the reaction process is repeated until the reaction reaches the set conversion rate or termination conditions; it can make the reactants fully contact and react, thereby improving the conversion rate of the reaction, and in the reflux reaction, the continuous circulation of reactants and products increases the reaction rate, which can shorten the reaction cycle. The reflux reaction can achieve full conversion of the reactants, reduce waste generation, and reduce environmental pollution.
[0042] Thin layer chromatography (TLC) is a rapid analytical method that can detect drug components in samples in a short time. It has high sensitivity and can detect trace amounts of drug components, helping to discover and remove potential undesirable impurities and improve drug quality and safety. It also has good repeatability and high consistency of results, which can ensure the reliability of experimental data and the stability of drug quality.
[0043] Furthermore, in step S3, vacuum concentration is performed based on the second-generation mixed solution, specifically:
[0044] The second generation mixed solution was passed through a concentration bottle and vacuum concentrated at a temperature range of 60°C-62°C.
[0045] It is explained that vacuum concentration can quickly increase the concentration of the second-generation mixed solution at a lower temperature and control the temperature within the range of 60-62°C, ensuring that the chemical properties of the second-generation mixed solution will not be destroyed due to excessive temperature during the concentration process; as the concentration proceeds, the volume of the mixed solution will gradually decrease and the concentration will gradually increase. When the concentration of the mixed solution reaches the experimental requirements, the concentration process is stopped to prevent excessive concentration from changing the properties of the second-generation mixed solution.
[0046] Specifically, in this embodiment, 117 grams of N-formylalanine is added to a 3L clean and dry three-necked flask, 1L of tetrahydrofuran is added, stirring is started, the temperature is cooled to -10°C and maintained, 150 grams of thionyl chloride is added dropwise, and the temperature is slowly raised to 60°C after the addition is completed, and the reaction is refluxed for 1h. After the TLC detection reaction is completed, it can be transferred to a 2L concentration bottle, 60°C vacuum concentrated to a small volume, 200ml of petroleum ether is added, stirred and crystallized to obtain the target product; then the target product is dried to obtain 85 grams of L-Ala-NCA, the quality of which is above 99%, and the yield is 85.8%.
[0047] It can be shown that the chemical formula for obtaining L-Ala-NCA based on N-formylalanine and tetrahydrofuran is:
[0048]
[0049] Wherein, R is the H element, and may also represent other amino acid groups. In this embodiment, alanine is used as the embodiment itself.
[0050] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims
1. A method for preparing an amino acid derivative, characterized in that: The following steps are involved: Obtaining N-formylalanine and tetrahydrofuran, mixing and stirring the N-formylalanine and tetrahydrofuran, and cooling the mixture to obtain an initial mixed solution; Obtain thionyl chloride, add thionyl chloride to the initial mixed solution, slowly raise the temperature, and perform reflux reaction, and after the reaction is completed, perform TLC detection to obtain a second-generation mixed solution; The second generation mixed solution is vacuum concentrated, petroleum ether is added and stirred for crystallization to obtain the target product, and the target product is dried to obtain an amino acid derivative.
2. The method for preparing an amino acid derivative according to claim 1, wherein: The mixing ratio of N-formylalanine and tetrahydrofuran ranges from 1:7 to 1:
8.
3. The method for preparing an amino acid derivative according to claim 2, characterized in that: N-formylalanine and tetrahydrofuran are mixed and stirred, and the temperature is lowered to obtain an initial mixed solution. Specifically, N-formylalanine and tetrahydrofuran are mixed and stirred according to a mixing ratio, and the temperature is controlled within a range of minus 9 to minus 10° C. to obtain an initial mixed solution.
4. The method for preparing an amino acid derivative according to claim 1, wherein: The mixing ratio of thionyl chloride to the initial mixed solution is in the range of 1:6-1:
7.
5. The method for preparing an amino acid derivative according to claim 4, characterized in that: Add thionyl chloride to the initial mixed solution, slowly raise the temperature, and perform a reflux reaction. After the reaction is completed, perform TLC detection to obtain a second-generation mixed solution. Specifically, add thionyl chloride to the initial mixed solution according to the mixing ratio, slowly raise the temperature to 60-62° C., and perform a reflux reaction. After the reaction is completed, perform TLC detection to determine whether the purity meets the standard. If it meets the standard, a second-generation mixed solution is obtained.
6. The method for preparing an amino acid derivative according to claim 5, characterized in that: If the purity does not meet the standard, continue to add thionyl chloride to react until the TLC detection meets the standard.
7. The method for preparing an amino acid derivative according to claim 1, wherein: The second-generation mixed liquid is vacuum concentrated, specifically, the second-generation mixed liquid is passed through a concentration bottle, and vacuum concentrated based on a temperature range of 60° C.-62° C.