A process for the preparation of chiral 4-bromophenylalanine
By reacting L-phenylalanine and D-phenylalanine with N-bromosuccinimide under a mixed catalyst of glacial acetic acid, the problem of preparing chiral bromophenylalanine in the prior art has been solved, and efficient and low-cost industrial production has been achieved.
Patent Information
- Application Number
- CN202311828113.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-28
- Publication Date
- 2026-02-17
- Estimated Expiration
- 2043-12-28
AI Technical Summary
Existing technologies are insufficient for the efficient preparation of chiral bromophenylalanine, and small organic molecule catalysts have poor specificity, making it impossible to effectively synthesize two enantiomers. Domestic research on this topic is also inadequate.
Using L-phenylalanine and D-phenylalanine as raw materials, they were reacted with N-bromosuccinimide in the presence of a mixed catalyst of glacial acetic acid. Through the synergistic effect of the mixed catalyst of glacial acetic acid, S-4-bromophenylalanine and R-4-bromophenylalanine were prepared, respectively, and then purified and separated.
This study establishes an industrial production route that is simple, low-cost, and highly productive, enabling the efficient preparation of chiral 4-bromophenylalanine, which is suitable for industrial production.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of chiral organic compounds, in particular to a preparation method of chiral 4-bromophenylalanine. BACKGROUND
[0002] Chiral compounds refer to molecules with the same molecular weight and molecular structure but opposite arrangements, such as real objects and mirror images, or left and right hands of a person, which are a pair of non-coinciding molecules, and exhibit many identical physical and chemical properties, such as melting point, solubility, etc., but in many biochemical reactions related to biological bodies, chiral compounds exhibit great differences, can interact to generate different products, and because the biochemical reactions of life activities are related to the chirality of organic matter, the chirality of matter, the chiral reaction of matter, and the synthesis and separation of chiral matter are of great significance to humans.
[0003] Phenylalanine is an indispensable amino acid for living beings, and derivatives of phenylalanine often appear in many natural product molecules and drug molecules. The bromophenylalanine can be further derivatized due to its unique aryl bromine structure, and is also helpful for X-ray research on proteins through multi-wavelength characteristic diffraction technology. Therefore, the asymmetric synthesis and chiral separation of bromophenylalanine are of great significance for the synthesis of natural product molecules and drug molecules containing phenylalanine derivative structures.
[0004] At present, the common method is to realize the asymmetric synthesis and chiral separation of bromophenylalanine through organic small molecule catalysts and chiral ligands. However, the organic small molecule catalysts and chiral ligands have strong specificity, and cannot well obtain two chiral bromophenylalanines which are enantiomeric in the synthesis process of bromophenylalanine. Meanwhile, the research in this field is very few in China, and it is necessary to seek a reliable new method to prepare chiral bromophenylalanine.
[0005] In order to solve the above process difficulties, the present application researches a preparation process which is simple, can reduce production cost and has high product productivity, and opens up a process route which is easy to industrialize. SUMMARY
[0006] In order to solve the above process difficulties, the present application researches a preparation process which is simple, can reduce production cost and has high product productivity, and opens up a process route which is easy to industrialize.
[0007] A preparation method of chiral 4-bromophenylalanine, which takes L-phenylalanine and D-phenylalanine as raw materials, reacts with N-bromosuccinimide under the action of a catalyst to obtain chiral 4-bromophenylalanine, and the reaction equation is as follows:
[0008]
[0009] A method for preparing chiral 4-bromophenylalanine, comprising the steps of:
[0010] S1: preparing glacial acetic acid mixed catalyst comprising:
[0011] After mixing glacial acetic acid and concentrated sulfuric acid, magnetic stirring is performed to obtain a mixed solution, iodobenzene diacetate is added in the process of water bath heating of the mixed solution, and stirring is performed to obtain the glacial acetic acid mixed catalyst;
[0012] S2: preparing S-4-bromophenylalanine from L-phenylalanine comprising:
[0013] L-phenylalanine and glacial acetic acid are placed in a container, stirring is performed and then cooling is performed, N-bromosuccinimide is added into the container, stirring is continuously performed to obtain a mixed material, the glacial acetic acid mixed catalyst is slowly added into the mixed material while magnetic stirring is performed, when the glacial acetic acid mixed catalyst is completely added, the stirring speed is adjusted to perform stirring, a S-4-bromophenylalanine mixed solution is obtained, distilled water is added into the S-4-bromophenylalanine mixed solution, washing is performed with ethyl acetate to obtain an organic phase and an aqueous phase, the aqueous phase is collected, the aqueous phase is neutralized with 2N sodium hydroxide, cooling crystallization is performed, and filtration is performed to obtain S-4-bromophenylalanine;
[0014] S3: preparing R-4-bromophenylalanine from D-phenylalanine comprising:
[0015] D-phenylalanine and glacial acetic acid are mixed and placed in a container, stirring is performed and then cooling is performed, N-bromosuccinimide is added into the container, stirring is continuously performed to obtain a mixed material I, the glacial acetic acid mixed catalyst is slowly added into the mixed material I while magnetic stirring is performed, when the glacial acetic acid mixed catalyst is completely added, the stirring speed is adjusted to perform stirring, an R-4-bromophenylalanine mixed solution is obtained, distilled water is added into the R-4-bromophenylalanine mixed solution, washing is performed with ethyl acetate to obtain an organic phase and an aqueous phase, the aqueous phase is collected, the aqueous phase is neutralized with a sodium hydroxide solution, cooling crystallization is performed, and filtration is performed to obtain R-4-bromophenylalanine.
[0016] Further, step S1 for preparing the glacial acetic acid mixed catalyst comprises the following steps:
[0017] S1.1: 20-25 parts by weight of glacial acetic acid are placed in a container, 0.3-0.4 parts by weight of concentrated sulfuric acid is added into the container, the stirring speed of a magnetic stirrer is adjusted to 80-100 rpm, and stirring is performed on the container for 8-10 minutes to obtain a mixed solution;
[0018] S1.2: the mixed solution is placed in a water bath heating pot, water bath heating is then performed to 30-35℃, and 0.2-0.5 parts by weight of iodobenzene diacetate is added at the same time, and stirring is performed for 10-20 minutes to obtain the glacial acetic acid mixed catalyst.
[0019] Further, the step S2 of preparing S-4-bromophenylalanine from L-phenylalanine comprises the following steps:
[0020] S2.1: Put 30-35 parts by weight of L-phenylalanine and 300-350 parts by weight of glacial acetic acid into a container, stir for 10-15 minutes, and then cool to 0-4°C. Then add 30-50 parts by weight of N-bromosuccinimide to the container, continue to stir for 10-15 minutes, and obtain a mixture;
[0021] S2.2: Slowly add the glacial acetic acid mixed catalyst to the mixture, and at the same time, stir with a magnetic stirrer at a speed of 80-100 rpm. When the glacial acetic acid mixed catalyst is completely added, adjust the stirring speed to 120-150 rpm, and stir for 8-10 hours to obtain an S-4-bromophenylalanine mixture;
[0022] S2.3: Concentrate the S-4-bromophenylalanine mixture under reduced pressure at 60-70°C, then add 180-200 parts by weight of distilled water, wash with 80-100 parts by weight of ethyl acetate for 2-3 times to obtain organic phase and aqueous phase, collect the aqueous phase, neutralize to PH 6-7 with sodium hydroxide solution, cool to 0-4°C, crystallize, and filter to obtain S-4-bromophenylalanine.
[0023] Further, the step S3 of preparing R-4-bromophenylalanine from D-phenylalanine comprises the following steps:
[0024] S3.1: Put 30-35 parts by weight of D-phenylalanine and 300-350 parts by weight of glacial acetic acid into a container, stir for 10-15 minutes, and then cool to 0-4°C. Then add 30-50 parts by weight of N-bromosuccinimide to the container, continue to stir for 10-15 minutes, and obtain a mixture;
[0025] S3.2: Slowly add the glacial acetic acid mixed catalyst to the mixture, and at the same time, stir with a magnetic stirrer at a speed of 80-100 rpm. When the glacial acetic acid mixed catalyst is completely added, adjust the stirring speed to 120-150 rpm, and stir for 8-10 hours to obtain an R-4-bromophenylalanine mixture;
[0026] S3.3: Concentrate the R-4-bromophenylalanine mixture under reduced pressure at 60-70°C, then add 180-200 parts by weight of distilled water, wash with 80-100 parts by weight of ethyl acetate for 2-3 times to obtain organic phase and aqueous phase, collect the aqueous phase, neutralize to PH 6-7 with sodium hydroxide solution, cool to 0-4°C, crystallize, and filter to obtain R-4-bromophenylalanine.
[0027] Further, the speed of slowly adding the glacial acetic acid mixed catalyst in step S2.2 is to completely add the glacial acetic acid mixed catalyst within 30-35 minutes.
[0028] Further, the specific operation of the ethyl acetate extraction in step S2.3 is to add ethyl acetate into the S-4-bromophenylalanine mixed solution, adjust the stirring speed of the stirrer to 120-150 rpm for 8-10 minutes of stirring, and after the stirring of the mixed solution is completed and the mixed solution is stratified, the upper organic phase and the lower aqueous phase are separated by filtration.
[0029] Beneficial effects are: 1. The natural amino acids L-phenylalanine and D-phenylalanine are used as starting materials, which are mixed with N-bromosuccinimide in glacial acetic acid, and then the prepared glacial acetic acid mixed catalyst is added, and after reaction and purification, S-4-bromophenylalanine and R-4-bromophenylalanine are obtained, which has the advantages of simple preparation process, low preparation cost, short production cycle of chiral 4-bromophenylalanine, and high production rate, and opens up an easy industrial production process.
[0030] 2. A small amount of concentrated sulfuric acid is first added to glacial acetic acid, and then iodobenzene diacetate is added during water bath heating, and the mixture is stirred to obtain a glacial acetic acid mixed catalyst, which can enhance the synergistic effect of concentrated sulfuric acid and iodobenzene diacetate in glacial acetic acid, and can better catalyze the reaction system in the subsequent reaction process, thereby improving the reaction rate. BRIEF DESCRIPTION OF DRAWINGS
[0031] Figure 1 A flow chart of a chiral 4-bromophenylalanine preparation method used in the embodiments of the present application.
[0032] Figure 2 A comparison table of the mass of S-4-bromophenylalanine generated in Example 1 of the present application and S-4-bromophenylalanine generated in Comparative Example 1 at different times.
[0033] Figure 3 An MS spectrum of S-4-bromophenylalanine generated in Example 1 of the present application. DETAILED DESCRIPTION
[0034] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.
[0035] Example 1: A chiral 4-bromophenylalanine preparation method, as shown inFigure 1 as shown, comprising the following steps:
[0036] S1: Preparation of glacial acetic acid mixed catalyst comprising:
[0037] S1.1: Take 20 parts by weight of glacial acetic acid into a container, add 0.3 parts by weight of concentrated sulfuric acid with a concentration of 96% into the container, adjust the speed of the magnetic stirrer to 80 rpm, and stir the container for 8 minutes to obtain a mixed solution;
[0038] S1.2: Place the mixed solution in a water bath heating pot, then heat the water bath to 30°C, while adding 0.2 parts by weight of iodobenzene diacetate, stir for 15 minutes until the iodobenzene diacetate is completely dissolved, to obtain the glacial acetic acid mixed catalyst, which can uniformly catalyze the reaction system during the subsequent reaction process, and better improve the reaction rate.
[0039] S2: Preparation of S-4-bromophenylalanine from L-phenylalanine comprising:
[0040] S2.1: Take 30 parts by weight of L-phenylalanine and 300 parts by weight of glacial acetic acid and mix them in a container, cool to 0°C after stirring for 10 minutes, then add 30 parts by weight of N-bromosuccinimide to the container, continue to stir for 10 minutes to obtain a mixture;
[0041] S2.2: Slowly add the glacial acetic acid mixed catalyst to the mixture, completely add it within 30 minutes, while stirring with a magnetic stirrer at a speed of 80 rpm, when the glacial acetic acid mixed catalyst is completely added, adjust the stirring speed to 120 rpm, and stir for 8 hours to obtain a mixed solution of S-4-bromophenylalanine;
[0042] S2.3: Concentrate the mixed solution of S-4-bromophenylalanine at 70°C under reduced pressure, then add 180 parts by weight of distilled water, add 80 parts by weight of ethyl acetate to the mixed solution of S-4-bromophenylalanine, adjust the stirring speed of the stirrer to 120 rpm for 8 minutes of stirring, after the stirring of the mixed solution, stand and separate the upper organic phase and the lower aqueous phase to obtain the organic phase and the aqueous phase, wash twice, collect the aqueous phase, adjust the pH to 6.5 with 2N sodium hydroxide aqueous solution, cool to 4°C to crystallize, then filter to obtain S-4-bromophenylalanine. After drying the product, test the melting point: 262-265°C; specific optical rotation: -22.0°, C=0.5% water; MS: 245.0; HPLC purity: 97.2%.
[0043] S3: Preparation of R-4-bromophenylalanine from D-phenylalanine comprising:
[0044] S3.1: 30 parts by weight of D-phenylalanine and 250 parts by weight of glacial acetic acid were mixed in a container, stirred for 10 minutes, and then cooled to 0°C. Then 40 parts by weight of N-bromosuccinimide was added to the container, and stirring was continued for 10 minutes to obtain a mixture I;
[0045] S3.2: The mixture I was slowly added with the catalyst of glacial acetic acid mixture while stirring at a speed of 80 rpm with a magnetic stirrer. When the catalyst of glacial acetic acid mixture was completely added, the stirring speed was adjusted to 120 rpm, and stirring was continued for 8 hours to obtain an R-4-bromophenylalanine mixture.
[0046] S3.3: The R-4-bromophenylalanine mixture was concentrated under reduced pressure at 60°C, and then 180 parts by weight of distilled water was added. The mixture was washed with 80 parts by weight of ethyl acetate twice to obtain an organic phase and an aqueous phase. The aqueous phase was collected, and the pH was adjusted to 6.5 with 2N sodium hydroxide aqueous solution. The mixture was cooled to 4°C to crystallize, and then filtered to obtain R-4-bromophenylalanine. After drying, the product was tested for melting point: 261-263°C; specific optical rotation: +21.0°, C=0.5% water; HPLC purity: 98.3%.
[0047] Example 2: A method for preparing a chiral 4-bromophenylalanine, as shown in Figure 1 , comprising the following steps:
[0048] S1: Preparation of a catalyst of glacial acetic acid mixture comprises:
[0049] S1.1: 25 parts by weight of glacial acetic acid was placed in a container, and 0.4 parts by weight of concentrated sulfuric acid with a concentration of 98% was added to the container. The stirring speed of the magnetic stirrer was adjusted to 80 rpm, and the container was stirred for 8 minutes to obtain a mixed solution.
[0050] S1.2: The mixed solution was placed in a water bath heating pot, and then heated to 35°C in a water bath. While stirring for 15 minutes until the iodoacetic acid was completely dissolved, 0.3 parts by weight of iodoacetic acid was added to obtain a catalyst of glacial acetic acid mixture. A small amount of concentrated sulfuric acid and iodoacetic acid was mixed in the glacial acetic acid to uniformly catalyze the reaction system in the subsequent reaction process, which better improved the reaction rate.
[0051] S2: Preparation of S-4-bromophenylalanine from L-phenylalanine comprises:
[0052] S2.1: 35 parts by weight of L-phenylalanine and 350 parts by weight of glacial acetic acid were mixed in a container, stirred for 10 minutes, and then cooled to 0°C. Then 50 parts by weight of N-bromosuccinimide was added to the container, and stirring was continued for 10 minutes to obtain a mixture.
[0053] S2.2: Slowly add glacial acetic acid mixed catalyst to the mixture while stirring with a magnetic stirrer at 80 rpm. When the glacial acetic acid mixed catalyst is completely added, adjust the stirring speed to 120 rpm and stir for 8 hours to obtain a S-4-bromophenylalanine mixture;
[0054] S2.3: Concentrate the S-4-bromophenylalanine mixture under reduced pressure at 65°C and add 200 parts by weight of distilled water. Add 100 parts by weight of ethyl acetate to the S-4-bromophenylalanine mixture, adjust the stirring speed of the stirrer to 120 rpm and stir for 8 minutes. After the stirred mixture is allowed to stand and separate into layers, separate the upper organic phase and the lower aqueous phase by suction filtration to obtain an organic phase and an aqueous phase. Wash the organic phase twice and collect the aqueous phase to neutralize it to a pH of 6 with 2N sodium hydroxide solution. Cool to 0°C to crystallize and filter to obtain S-4-bromophenylalanine. After the product is dried at 80°C for 4 hours, test the melting point: 263-265°C; specific optical rotation: -22.5°, C = 0.5% water; HPLC purity: 97.6%.
[0055] S3: Preparation of R-4-bromophenylalanine from D-phenylalanine includes:
[0056] S3.1: Place 35 parts by weight of D-phenylalanine and 300 parts by weight of glacial acetic acid in a container, cool to 0°C after stirring for 10 minutes, and add 45 parts by weight of N-bromosuccinimide to the container. Continue stirring for 10 minutes to obtain a mixture I;
[0057] S3.2: Slowly add glacial acetic acid mixed catalyst to the mixture I while stirring with a magnetic stirrer at 80 rpm. When the glacial acetic acid mixed catalyst is completely added, adjust the stirring speed to 120 rpm and stir for 8 hours to obtain an R-4-bromophenylalanine mixture;
[0058] S3.3: Concentrate the R-4-bromophenylalanine mixture under reduced pressure at 60°C and then add 200 parts by weight of distilled water. Wash the mixture twice with 100 parts by weight of ethyl acetate to obtain an organic phase and an aqueous phase. Collect the aqueous phase to neutralize it to a pH of 7.0 with 2N sodium hydroxide solution. Cool to 4°C to crystallize and filter to obtain R-4-bromophenylalanine. After the product is dried at 80°C for 4 hours, test the melting point: 261-262°C; specific optical rotation: +23.0°, C = 0.5% water; HPLC purity: 97.3%.
[0059] Example 3: A method of preparing a chiral 4-bromophenylalanine, as shown in Figure 1 , includes the following steps:
[0060] S1: Preparation of a glacial acetic acid mixed catalyst includes:
[0061] S1.1: Take 20 parts by weight of glacial acetic acid into a container, add 0.4 parts by weight of concentrated sulfuric acid with a concentration of 96% into the container, adjust the rotation speed of the magnetic stirrer to 100 rpm, and stir the container for 10 minutes to obtain a mixed solution;
[0062] S1.2: Place the mixed solution in a water bath heating pot, then heat the water bath to 35°C, while adding 0.2 parts by weight of iodobenzene diacetate, and stirring for 20 minutes until the iodobenzene diacetate is completely dissolved to obtain a glacial acetic acid mixed catalyst. A small amount of concentrated sulfuric acid and iodobenzene diacetate are first mixed in the glacial acetic acid, which can uniformly catalyze the reaction system during the subsequent reaction process, and better improve the reaction rate.
[0063] S2: Preparation of S-4-bromophenylalanine from L-phenylalanine includes:
[0064] S2.1: Take 30 parts by weight of L-phenylalanine and 300 parts by weight of glacial acetic acid and mix them in a container, cool to 4°C after stirring for 15 minutes, then add 30 parts by weight of N-bromosuccinimide to the container, and continue to stir for 15 minutes to obtain a mixture;
[0065] S2.2: Slowly add the glacial acetic acid mixed catalyst to the mixture, completely add it within 30 minutes, and stir with a magnetic stirrer at a rotation speed of 100 rpm at the same time. When the glacial acetic acid mixed catalyst is completely added, adjust the stirring speed to 150 rpm, and stir for 10 hours to obtain an S-4-bromophenylalanine mixture;
[0066] S2.3: Concentrate the S-4-bromophenylalanine mixture under reduced pressure at 65°C until dry, then add 180 parts by weight of distilled water, wash twice with 80 parts by weight of ethyl acetate to obtain an organic phase and an aqueous phase, collect the aqueous phase, neutralize it to a pH of 6.5 with 2N sodium hydroxide solution, cool it to 2°C to crystallize, and filter to obtain S-4-bromophenylalanine. After the product is baked at 80°C for 4 hours, the melting point is tested: 263-264°C; specific optical rotation: -23.0°, C=0.5% water; HPLC purity: 98.6%.
[0067] S3: Preparation of R-4-bromophenylalanine from D-phenylalanine includes:
[0068] S3.1: Mix 50 parts by weight of D-phenylalanine and 350 parts by weight of glacial acetic acid in a container, cool to 4°C after stirring for 15 minutes, and add 50 parts by weight of N-bromosuccinimide to the container, and continue to stir for 15 minutes to obtain a mixture I;
[0069] S3.2: Slowly add glacial acetic acid mixed catalyst to the mixture I while stirring with a magnetic stirrer at a speed of 100 rpm. When the glacial acetic acid mixed catalyst is completely added, adjust the stirring speed to 150 rpm and stir for 10 hours to obtain a mixed solution of R-4-bromophenylalanine;
[0070] S3.3: Concentrate the mixed solution of R-4-bromophenylalanine under reduced pressure at a temperature below 70°C, then add 200 parts by weight of distilled water, wash twice with 100 parts by weight of ethyl acetate to obtain an organic phase and an aqueous phase, collect the aqueous phase, neutralize to a pH of 6.0 with 2N sodium hydroxide solution, cool to 4°C to crystallize, and filter to obtain R-4-bromophenylalanine. After the product is baked at 80°C for 4 hours, test the melting point: 262-265°C; specific optical rotation: +22.5°, C=0.5% water; HPLC purity: 97.5%.
[0071] Comparative Example 1: Compared with Example 1, the difference between Comparative Example 1 and Example 1 is that Comparative Example 1 removes step S1, and directly adds concentrated sulfuric acid and iodine benzene diacetate to the reaction system, and the remaining steps are the same as those of Example 1.
[0072] Set 1 part by weight as 1 g, and prepare S-4-bromophenylalanine by using Example 1 and Comparative Example 1 respectively. After completely adding the glacial acetic acid mixed catalyst and completely adding the concentrated sulfuric acid and iodine benzene diacetate, respectively take 20 ml of reaction solution at 2 hours, 5 hours and 8 hours, prepare S-4-bromophenylalanine by using the process of step S2.3 and adjusting the amount of raw materials, weigh the mass of S-4-bromophenylalanine, record the obtained data and make a table as shown in Table 1. Figure 2 As shown in Table 1, analysis shows that the mass of S-4-bromophenylalanine generated by Example 1, Example 2 and Example 3 at 2 hours, 5 hours and 8 hours is greater than that of S-4-bromophenylalanine generated by Comparative Example 1, which can prove that the preparation of glacial acetic acid mixed catalyst can improve the reaction rate.
[0073] The above examples are only illustrative of the principles and effects of the present application, and are not intended to limit the present application. Any person skilled in the art can modify or change the above examples without departing from the spirit and scope of the present application. Therefore, all equivalent modifications or changes made by those skilled in the art without departing from the spirit and technical thought disclosed by the present application should be covered by the claims of the present application.
Claims
1. A process for the preparation of chiral 4-bromophenylalanine, characterized in that, The chiral 4-bromophenylalanine is prepared by reacting L-phenylalanine and D-phenylalanine with N-bromosuccinimide under the action of a catalyst, and the reaction equation is as follows: The preparation method of the chiral 4-bromophenylalanine comprises the following steps: S1: preparing the glacial acetic acid mixed catalyst comprises: After mixing the glacial acetic acid and concentrated sulfuric acid, magnetic stirring is performed to obtain a mixed solution, and iodobenzene diacetate is added in the process of water bath heating of the mixed solution, and after stirring, the glacial acetic acid mixed catalyst is obtained; S2: L-phenylalanine is used to prepare S-4-bromophenylalanine, which comprises: S2.1: 30-35 parts by weight of L-phenylalanine and 300-350 parts by weight of glacial acetic acid are mixed in a container, stirred for 10-15 minutes, and then cooled to 0-4 DEG C, then 30-50 parts by weight of N-bromosuccinimide is added to the container, and stirring is continued for 10-15 minutes to obtain a mixture; S2.2: slowly add the glacial acetic acid mixed catalyst to the mixture, and stir at a speed of 80-100 rpm with a magnetic stirrer at the same time, when the glacial acetic acid mixed catalyst is completely added, adjust the stirring speed to 120-150 rpm, and stir for 8-10 hours to obtain an S-4-bromophenylalanine mixture; S2.3: the S-4-bromophenylalanine mixture is concentrated under reduced pressure at 60-70 DEG C, then 180-200 parts by weight of distilled water is added, and then washed with 80-100 parts by weight of ethyl acetate for 2-3 times to obtain an organic phase and an aqueous phase, the aqueous phase is collected and neutralized to PH 6-7 with sodium hydroxide solution, cooled to 0-4 DEG C to crystallize, and filtered to obtain S-4-bromophenylalanine; S3: D-phenylalanine is used to prepare R-4-bromophenylalanine, which comprises: S3.1: 30-35 parts by weight of D-phenylalanine and 300-350 parts by weight of glacial acetic acid are mixed in a container, stirred for 10-15 minutes, and then cooled to 0-4 DEG C, then 30-50 parts by weight of N-bromosuccinimide is added to the container, and stirring is continued for 10-15 minutes to obtain a mixture; S3.2: slowly add the glacial acetic acid mixed catalyst to the mixture, and stir at a speed of 80-100 rpm with a magnetic stirrer at the same time, when the glacial acetic acid mixed catalyst is completely added, adjust the stirring speed to 120-150 rpm, and stir for 8-10 hours to obtain an R-4-bromophenylalanine mixture; S3.3: the R-4-bromophenylalanine mixture is concentrated under reduced pressure at 60-70 DEG C, then 180-200 parts by weight of distilled water is added, and then washed with 80-100 parts by weight of ethyl acetate for 2-3 times to obtain an organic phase and an aqueous phase, the aqueous phase is collected and neutralized to PH 6-7 with sodium hydroxide solution, cooled to 0-4 DEG C to crystallize, and filtered to obtain R-4-bromophenylalanine.
2. The process for the preparation of chiral 4-bromophenylalanine according to claim 1, characterized in that, Step S1 for preparing the glacial acetic acid mixed catalyst comprises the following steps: S1.1: Take 20-25 parts by weight of glacial acetic acid into a container, add 0.3-0.4 parts by weight of concentrated sulfuric acid into the container, adjust the speed of the magnetic stirrer to 80-100 rpm, and stir the contents in the container for 8-10 minutes to obtain a mixed solution; S1.2: Place the mixed solution in a water bath heating pot, then heat the water bath to 30-35°C, while adding 0.2-0.5 parts by weight of iodobenzene diacetate, and stir for 10-20 minutes to obtain a glacial acetic acid mixed catalyst.
3. The process for the preparation of chiral 4-bromophenylalanine according to claim 1, characterized in that, The speed of slowly adding the glacial acetic acid mixed catalyst in step S2.2 is to completely add the glacial acetic acid mixed catalyst within 30-35 minutes.
4. The process for the preparation of chiral 4-bromophenylalanine according to claim 1, characterized in that, The specific operation of the ethyl acetate washing in step S2.3 is to add ethyl acetate into the S-4-bromophenylalanine mixed solution, adjust the speed of the stirrer to 120-150 rpm, and stir for 8-10 minutes, then let the stirred mixed solution stand and separate into layers, and then separate and filter the upper organic phase and the lower aqueous phase.
Citation Information
Patent Citations
Method for selectively synthesizing halogenated aryl amine through copper catalysis
CN112047879A