CN117820142A - Preparation method of chiral 4-bromophenylalanine - Google Patents
Preparation method of chiral 4-bromophenylalanine Download PDFInfo
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- CN117820142A CN117820142A CN202311828113.6A CN202311828113A CN117820142A CN 117820142 A CN117820142 A CN 117820142A CN 202311828113 A CN202311828113 A CN 202311828113A CN 117820142 A CN117820142 A CN 117820142A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- PEMUHKUIQHFMTH-QMMMGPOBSA-N (2s)-2-amino-3-(4-bromophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(Br)C=C1 PEMUHKUIQHFMTH-QMMMGPOBSA-N 0.000 title claims abstract description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 178
- 229960000583 acetic acid Drugs 0.000 claims abstract description 89
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 89
- 239000003054 catalyst Substances 0.000 claims abstract description 65
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 36
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims abstract description 35
- PEMUHKUIQHFMTH-MRVPVSSYSA-N (2r)-2-amino-3-(4-bromophenyl)propanoic acid Chemical compound OC(=O)[C@H](N)CC1=CC=C(Br)C=C1 PEMUHKUIQHFMTH-MRVPVSSYSA-N 0.000 claims abstract description 31
- 229960005190 phenylalanine Drugs 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 20
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 claims abstract description 17
- 229930182832 D-phenylalanine Natural products 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims description 85
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 71
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- 239000011259 mixed solution Substances 0.000 claims description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- 239000012071 phase Substances 0.000 claims description 38
- 239000000463 material Substances 0.000 claims description 34
- 238000001816 cooling Methods 0.000 claims description 27
- 230000001105 regulatory effect Effects 0.000 claims description 23
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 15
- 239000012153 distilled water Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 13
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- 230000003472 neutralizing effect Effects 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 11
- 239000008346 aqueous phase Substances 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 238000003760 magnetic stirring Methods 0.000 claims description 2
- 239000012258 stirred mixture Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 3
- 229940024606 amino acid Drugs 0.000 abstract description 2
- 150000001413 amino acids Chemical class 0.000 abstract description 2
- 150000002894 organic compounds Chemical class 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000004904 shortening Methods 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- ULBLZIPFWGIOJF-QMMMGPOBSA-N (2s)-2-(bromoamino)-3-phenylpropanoic acid Chemical compound OC(=O)[C@@H](NBr)CC1=CC=CC=C1 ULBLZIPFWGIOJF-QMMMGPOBSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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Abstract
The invention relates to the technical field of chiral organic compounds, in particular to a preparation method of chiral 4-bromophenylalanine. The method comprises the following steps: preparing a glacial acetic acid mixed catalyst; preparing S-4-bromophenylalanine from the L-phenylalanine; preparation of R-4-bromophenylalanine from D-phenylalanine. The invention takes natural amino acid L-phenylalanine and D-phenylalanine as initial raw materials, respectively puts the initial raw materials into glacial acetic acid to be mixed with N-bromosuccinimide, then adds the prepared glacial acetic acid mixed catalyst, carries out purification and separation after reaction to obtain S-4-bromophenylalanine and R-4-bromophenylalanine, has simple preparation process and low preparation cost, greatly improves the productivity while shortening the production period of chiral 4-bromophenylalanine, and opens up a process route easy for industrial production.
Description
Technical Field
The invention relates to the technical field of chiral organic compounds, in particular to a preparation method of chiral 4-bromophenylalanine.
Background
Chiral compounds refer to molecules with the same molecular weight and molecular structure, but are arranged in opposite directions, such as a physical object and an enantiomer in a mirror, such as the left hand and the right hand of a person, are a pair of molecules which cannot be overlapped, and show a plurality of identical physicochemical properties, such as melting points, solubility and the like, but in a plurality of biochemical reactions closely related to organisms, chiral compounds show great differences and can interact to generate different products, and meanwhile, the chiral correlation of biological activities and organic matters, the chiral reaction of substances, the chiral synthesis and separation of substances and the like have an invisible significance for the human.
Phenylalanine is an indispensable amino acid of living body, and derivatives of phenylalanine are also frequently found in many natural product molecules and drug molecules, wherein bromophenylalanine can be more variously derivatized because of its unique aromatic bromo structure, and further facilitates the X-ray research of proteins by multi-wavelength characteristic diffraction technique, so that research of asymmetric synthesis and chiral resolution of bromophenylalanine has important significance for synthesis of natural product molecules and drug molecules containing phenylalanine derivative structures.
At present, the method is more common to realize asymmetric synthesis and chiral resolution of the bromophenylalanine through an organic small molecular catalyst and a chiral ligand, but the organic small molecular catalyst and the chiral ligand have stronger specificity, two chiral bromophenylalanine which are enantiomers cannot be obtained well in the synthesis process of the bromophenylalanine, meanwhile, the research in the domestic aspect is very little, and a reliable novel method is necessary to be sought for preparing the chiral bromophenylalanine.
In order to solve the technical difficulties, the invention researches a preparation process which is simple, can reduce the production cost and has higher product productivity, and opens up a process route easy for industrial production.
Disclosure of Invention
In order to solve the technical difficulties, the invention researches a preparation process which is simple, can reduce the production cost and has higher product productivity, and opens up a process route easy for industrial production.
The preparation method of chiral 4-bromophenylalanine takes L-phenylalanine and D-phenylalanine as raw materials, and the raw materials react with N-bromosuccinimide under the action of a catalyst to obtain the chiral 4-bromophenylalanine, wherein the reaction equation is as follows:
the preparation method of the chiral 4-bromophenylalanine comprises the following steps:
s1: the preparation of the glacial acetic acid mixed catalyst comprises the following steps:
mixing glacial acetic acid and concentrated sulfuric acid, magnetically stirring to obtain a mixed solution, adding iodobenzene diacetate in the process of heating the mixed solution in a water bath, and stirring to obtain a glacial acetic acid mixed catalyst;
s2: the preparation of S-4-bromophenylalanine from L-phenylalanine comprises:
placing L-phenylalanine and glacial acetic acid into a container, stirring and cooling, then adding N-bromosuccinimide into the container, continuing stirring to obtain a mixed material, slowly adding a glacial acetic acid mixed catalyst into the mixed material, simultaneously carrying out magnetic stirring, regulating the stirring rotation speed to stir when the glacial acetic acid mixed catalyst is completely added to obtain an S-4-bromophenylalanine mixed solution, adding distilled water into the S-4-bromophenylalanine mixed solution, washing with ethyl acetate to obtain an organic phase and a water phase, collecting the water phase, neutralizing the water phase with 2N sodium hydroxide, cooling for crystallization, and filtering to obtain the S-4-bromophenylalanine;
s3: the preparation of R-4-bromophenylalanine from D-phenylalanine comprises:
mixing D-phenylalanine and glacial acetic acid, placing the mixture in a container, stirring and cooling the mixture, adding N-bromosuccinimide into the container, continuously stirring the mixture to obtain a mixed material I, slowly adding a glacial acetic acid mixed catalyst into the mixed material I, simultaneously magnetically stirring the mixed material I, regulating the stirring rotation speed when the glacial acetic acid mixed catalyst is completely added, stirring the mixed material to obtain R-4-bromophenylalanine mixed solution, adding distilled water into the R-4-bromophenylalanine mixed solution, washing the mixed material with ethyl acetate to obtain an organic phase and a water phase, collecting the water phase, neutralizing the water phase with sodium hydroxide solution, cooling and crystallizing the neutralized water phase, and filtering the crystallized product to obtain R-4-bromophenylalanine.
Further, step S1 prepares a glacial acetic acid mixed catalyst, comprising the steps of:
s1.1: placing 20-25 parts by weight of glacial acetic acid in a container, adding 0.3-0.4 part by weight of concentrated sulfuric acid into the container, regulating the rotating speed of a magnetic stirrer to 80-100rpm, and stirring the container for 8-10 minutes to obtain a mixed solution;
s1.2: and (3) placing the mixed solution into a water bath heating pot, heating to 30-35 ℃ in the water bath, adding 0.2-0.5 part by weight of iodobenzene diacetate, and stirring for 10-20 minutes to obtain the glacial acetic acid mixed catalyst.
Further, the step S2L-phenylalanine for preparing S-4-bromophenylalanine comprises the following steps:
s2.1: mixing 30-35 parts by weight of L-phenylalanine and 300-350 parts by weight of glacial acetic acid, placing the mixture in a container, stirring for 10-15 minutes, cooling to 0-4 ℃, adding 30-50 parts by weight of N-bromosuccinimide into the container, and continuously stirring for 10-15 minutes to obtain a mixed material;
s2.2: slowly adding the glacial acetic acid mixed catalyst into the mixed material, stirring at a rotating speed of 80-100rpm by using a magnetic stirrer, and regulating the stirring rotating speed to 120-150rpm and stirring for 8-10 hours when the glacial acetic acid mixed catalyst is completely added to obtain an S-4-bromophenylalanine mixed solution;
s2.3: concentrating the S-4-bromophenylalanine mixed solution under reduced pressure at 60-70 ℃, adding 180-200 parts by weight of distilled water, washing with 80-100 parts by weight of ethyl acetate for 2-3 times respectively to obtain an organic phase and a water phase, collecting the water phase, neutralizing the water phase with sodium hydroxide solution to pH of 6-7, cooling to 0-4 ℃ for crystallization, and filtering to obtain the S-4-bromophenylalanine.
Further, the step S3D-phenylalanine is used for preparing R-4-bromophenylalanine, and the method comprises the following steps of:
s3.1: mixing 30-35 parts by weight of D-phenylalanine and 300-350 parts by weight of glacial acetic acid, placing in a container, stirring for 10-15 minutes, cooling to 0-4 ℃, adding 30-50 parts by weight of N-bromosuccinimide into the container, and continuing stirring for 10-15 minutes to obtain a mixed material;
s3.2: slowly adding the glacial acetic acid mixed catalyst into the mixed material, stirring at a rotating speed of 80-100rpm by using a magnetic stirrer, and regulating the stirring rotating speed to 120-150rpm and stirring for 8-10 hours when the glacial acetic acid mixed catalyst is completely added to obtain an R-4-bromophenylalanine mixed solution;
s3.3: concentrating the R-4-bromophenylalanine mixed solution under reduced pressure at 60-70 ℃, adding 180-200 parts by weight of distilled water, washing with 80-100 parts by weight of ethyl acetate for 2-3 times respectively to obtain an organic phase and a water phase, collecting the water phase, neutralizing the water phase with sodium hydroxide solution until the pH is 6-7, cooling to 0-4 ℃ for crystallization, and filtering to obtain the R-4-bromophenylalanine.
Further, the step S2.2 is to add the glacial acetic acid mixed catalyst slowly at a speed of completely adding the glacial acetic acid mixed catalyst within 30-35 minutes.
Further, the specific operation of ethyl acetate extraction in step S2.3 is: adding ethyl acetate into the S-4-bromophenylalanine mixed solution, regulating the rotating speed of a stirrer to be 120-150rpm, stirring for 8-10 minutes, standing and layering the stirred mixed solution, and carrying out suction filtration on an upper organic phase and a lower aqueous phase.
The beneficial effects are that: 1. the invention takes natural amino acid L-phenylalanine and D-phenylalanine as initial raw materials, respectively puts the initial raw materials into glacial acetic acid to be mixed with N-bromosuccinimide, then adds the prepared glacial acetic acid mixed catalyst, carries out purification and separation after reaction to obtain S-4-bromophenylalanine and R-4-bromophenylalanine, has simple preparation process and low preparation cost, shortens the production period of chiral 4-bromophenylalanine, has higher production rate, and opens up a process route easy for industrial production.
2. According to the invention, a small amount of concentrated sulfuric acid is added into glacial acetic acid, then iodobenzene diacetate is added in the process of heating in a water bath, and the glacial acetic acid mixed catalyst is obtained by stirring, so that a small amount of concentrated sulfuric acid and iodobenzene diacetate are fully mixed into glacial acetic acid, the synergistic effect of concentrated sulfuric acid and iodobenzene diacetate is enhanced, the reaction system can be catalyzed better in the subsequent reaction process, and the reaction rate is improved.
Drawings
FIG. 1 is a flow chart of a method for preparing chiral 4-bromophenylalanine according to an embodiment of the present invention.
FIG. 2 is a table diagram showing the comparison of the mass sizes of S-4-bromophenylalanine produced in example 1 of the present invention and S-4-bromophenylalanine produced in comparative example 1 at different times.
FIG. 3 is a MS spectrum of S-4-bromophenylalanine produced in example 1 of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1: a preparation method of chiral 4-bromophenylalanine is shown in figure 1, and comprises the following steps:
s1: the preparation of the glacial acetic acid mixed catalyst comprises the following steps:
s1.1: placing 20 parts by weight of glacial acetic acid in a container, adding 0.3 part by weight of 96% concentrated sulfuric acid into the container, regulating the rotating speed of a magnetic stirrer to 80rpm, and stirring the container for 8 minutes to obtain a mixed solution;
s1.2: the mixed solution is placed in a water bath heating pot, then the water bath is heated to 30 ℃, 0.2 weight part of iodobenzene diacetate is added, and stirring is carried out for 15 minutes until the iodobenzene diacetate is completely dissolved, so that the glacial acetic acid mixed catalyst is obtained, a small amount of concentrated sulfuric acid and the iodobenzene diacetate are fully mixed in glacial acetic acid, the catalytic action can be uniformly carried out on a reaction system in the subsequent reaction process, and the reaction rate is better improved.
S2: the preparation of S-4-bromophenylalanine from L-phenylalanine comprises:
s2.1: mixing 30 parts by weight of L-phenylalanine and 300 parts by weight of glacial acetic acid, placing the mixture in a container, stirring for 10 minutes, cooling to 0 ℃, adding 30 parts by weight of N-bromosuccinimide into the container, and continuously stirring for 10 minutes to obtain a mixed material;
s2.2: slowly adding the glacial acetic acid mixed catalyst into the mixed material, completely adding the glacial acetic acid mixed catalyst within 30 minutes, simultaneously stirring the glacial acetic acid mixed catalyst with a magnetic stirrer at a rotating speed of 80rpm, and regulating the stirring rotating speed to 120rpm and stirring the glacial acetic acid mixed catalyst for 8 hours when the glacial acetic acid mixed catalyst is completely added to obtain an S-4-bromophenylalanine mixed solution;
s2.3: concentrating the S-4-bromophenylalanine mixed solution under reduced pressure at 70 ℃ to dryness, adding 180 parts by weight of distilled water, adding 80 parts by weight of ethyl acetate into the S-4-bromophenylalanine mixed solution, regulating the rotating speed of a stirrer to 120rpm for 8 minutes, stirring, standing and layering the stirred mixed solution, separating an upper organic phase and a lower aqueous phase to obtain an organic phase and an aqueous phase, washing for 2 times, collecting the aqueous phase, regulating the pH of the aqueous phase to 6.5 by using a 2N sodium hydroxide aqueous solution, cooling to 4 ℃ for crystallization, and filtering to obtain the S-4-bromophenylalanine. After the product is dried, the melting point is tested: 262-265 ℃; specific rotation: -22.0 °, c=0.5% water; MS 245.0; HPLC purity: 97.2%.
S3: the preparation of R-4-bromophenylalanine from D-phenylalanine comprises:
s3.1: mixing 30 parts by weight of D-phenylalanine and 250 parts by weight of glacial acetic acid, placing the mixture in a container, stirring for 10 minutes, cooling to 0 ℃, adding 40 parts by weight of N-bromosuccinimide into the container, and continuing stirring for 10 minutes to obtain a mixed material I;
s3.2: slowly adding the glacial acetic acid mixed catalyst into the mixed material I, stirring at a rotating speed of 80rpm by using a magnetic stirrer, and regulating the stirring rotating speed to 120rpm and stirring for 8 hours when the glacial acetic acid mixed catalyst is completely added to obtain an R-4-bromophenylalanine mixed solution;
s3.3: concentrating the mixed solution of R-4-bromophenylalanine at 60 ℃ under reduced pressure, adding 180 parts by weight of distilled water, washing with 80 parts by weight of ethyl acetate for 2 times to obtain an organic phase and a water phase, collecting the water phase, adjusting the pH of the water phase to 6.5 by using a 2N sodium hydroxide aqueous solution, cooling to 4 ℃ for crystallization, and filtering to obtain R-4-bromophenylalanine. After the product is dried, the melting point is tested: 261-263 ℃; specific rotation: +21.0°, c=0.5% water; HPLC purity: 98.3%.
Example 2: a preparation method of chiral 4-bromophenylalanine is shown in figure 1, and comprises the following steps:
s1: the preparation of the glacial acetic acid mixed catalyst comprises the following steps:
s1.1: placing 25 parts by weight of glacial acetic acid in a container, adding 0.4 part by weight of concentrated sulfuric acid with the concentration of 98% into the container, regulating the rotating speed of a magnetic stirrer to 80rpm, and stirring the container for 8 minutes to obtain a mixed solution;
s1.2: the mixed solution is placed in a water bath heating pot, then the water bath is heated to 35 ℃, 0.3 part by weight of iodobenzene diacetate is added, and stirring is carried out for 15 minutes until the iodobenzene diacetate is completely dissolved, so that the glacial acetic acid mixed catalyst is obtained, a small amount of concentrated sulfuric acid and the iodobenzene diacetate are fully mixed in glacial acetic acid, the catalytic action can be uniformly carried out on a reaction system in the subsequent reaction process, and the reaction rate is better improved.
S2: the preparation of S-4-bromophenylalanine from L-phenylalanine comprises:
s2.1: mixing 35 parts by weight of L-phenylalanine and 350 parts by weight of glacial acetic acid, placing the mixture in a container, stirring for 10 minutes, cooling to 0 ℃, adding 50 parts by weight of N-bromosuccinimide into the container, and continuously stirring for 10 minutes to obtain a mixed material;
s2.2: slowly adding the glacial acetic acid mixed catalyst into the mixed material, completely adding the glacial acetic acid mixed catalyst within 30 minutes, simultaneously stirring the glacial acetic acid mixed catalyst with a magnetic stirrer at a rotating speed of 80rpm, and regulating the stirring rotating speed to 120rpm and stirring the glacial acetic acid mixed catalyst for 8 hours when the glacial acetic acid mixed catalyst is completely added to obtain an S-4-bromophenylalanine mixed solution;
s2.3: concentrating the S-4-bromophenylalanine mixed solution under reduced pressure at 65 ℃ and adding 200 parts by weight of distilled water, adding 100 parts by weight of ethyl acetate into the S-4-bromophenylalanine mixed solution, regulating the rotating speed of a stirrer to 120rpm for 8 minutes, stirring, standing and layering the stirred mixed solution, carrying out suction filtration on an upper organic phase and a lower aqueous phase to obtain an organic phase and an aqueous phase, washing for 2 times, collecting the aqueous phase, neutralizing the aqueous phase with a 2N sodium hydroxide solution to pH of 6, cooling to 0 ℃ for crystallization, and filtering to obtain the S-4-bromophenylalanine. After baking the product at 80 ℃ for 4 hours, the melting point is tested: 263-265 ℃; specific rotation: -22.5 °, c=0.5% water; HPLC purity: 97.6%.
S3: the preparation of R-4-bromophenylalanine from D-phenylalanine comprises:
s3.1: mixing 35 parts by weight of D-phenylalanine and 300 parts by weight of glacial acetic acid, placing the mixture in a container, stirring for 10 minutes, cooling to 0 ℃, adding 45 parts by weight of N-bromosuccinimide into the container, and continuing stirring for 10 minutes to obtain a mixed material I;
s3.2: slowly adding the glacial acetic acid mixed catalyst into the mixed material I, stirring at a rotating speed of 80rpm by using a magnetic stirrer, and regulating the stirring rotating speed to 120rpm and stirring for 8 hours when the glacial acetic acid mixed catalyst is completely added to obtain an R-4-bromophenylalanine mixed solution;
s3.3: concentrating the R-4-bromophenylalanine mixed solution at 60 ℃ under reduced pressure, adding 200 parts by weight of distilled water, washing with 100 parts by weight of ethyl acetate for 2 times to obtain an organic phase and a water phase, collecting the water phase, neutralizing the water phase with 2N sodium hydroxide solution until the pH is 7.0, cooling to 4 ℃ for crystallization, and filtering to obtain the R-4-bromophenylalanine. After baking the product at 80 ℃ for 4 hours, the melting point is tested: 261-262 ℃; specific rotation: +23.0°, c=0.5% water; HPLC purity: 97.3%.
Example 3: a preparation method of chiral 4-bromophenylalanine is shown in figure 1, and comprises the following steps:
s1: the preparation of the glacial acetic acid mixed catalyst comprises the following steps:
s1.1: placing 20 parts by weight of glacial acetic acid in a container, adding 0.4 part by weight of 96% concentrated sulfuric acid into the container, regulating the rotating speed of a magnetic stirrer to 100rpm, and stirring the container for 10 minutes to obtain a mixed solution;
s1.2: the mixed solution is placed in a water bath heating pot, then the water bath is heated to 35 ℃, 0.2 weight part of iodobenzene diacetate is added, and stirring is carried out for 20 minutes until the iodobenzene diacetate is completely dissolved, so that the glacial acetic acid mixed catalyst is obtained, a small amount of concentrated sulfuric acid and the iodobenzene diacetate are fully mixed in glacial acetic acid, the catalytic action can be uniformly carried out on a reaction system in the subsequent reaction process, and the reaction rate is better improved.
S2: the preparation of S-4-bromophenylalanine from L-phenylalanine comprises:
s2.1: mixing 30 parts by weight of L-phenylalanine and 300 parts by weight of glacial acetic acid, placing the mixture in a container, stirring for 15 minutes, cooling to 4 ℃, adding 30 parts by weight of N-bromosuccinimide into the container, and continuously stirring for 15 minutes to obtain a mixed material;
s2.2: slowly adding the glacial acetic acid mixed catalyst into the mixed material, completely adding the glacial acetic acid mixed catalyst within 30 minutes, simultaneously stirring the glacial acetic acid mixed catalyst with a magnetic stirrer at a rotating speed of 100rpm, and regulating the stirring rotating speed to 150rpm and stirring the glacial acetic acid mixed catalyst for 10 hours when the glacial acetic acid mixed catalyst is completely added to obtain an S-4-bromophenylalanine mixed solution;
s2.3: concentrating the S-4-bromophenylalanine mixed solution at 65 ℃ under reduced pressure, adding 180 parts by weight of distilled water, washing with 80 parts by weight of ethyl acetate for 2 times to obtain an organic phase and a water phase, collecting the water phase, neutralizing the water phase with 2N sodium hydroxide solution to pH 6.5, cooling to 2 ℃ for crystallization, and filtering to obtain the S-4-bromophenylalanine. After baking the product at 80 ℃ for 4 hours, the melting point is tested: 263-264 ℃; specific rotation: -23.0 °, c=0.5% water; HPLC purity: 98.6%.
S3: the preparation of R-4-bromophenylalanine from D-phenylalanine comprises:
s3.1: 50 parts by weight of D-phenylalanine and 350 parts by weight of glacial acetic acid are mixed and placed in a container, the mixture is stirred for 15 minutes and then cooled to 4 ℃, 50 parts by weight of N-bromosuccinimide is added into the container, and the mixture is continuously stirred for 15 minutes to obtain a mixed material I;
s3.2: slowly adding the glacial acetic acid mixed catalyst into the mixed material I, stirring at a rotating speed of 100rpm by using a magnetic stirrer, and regulating the stirring rotating speed to 150rpm and stirring for 10 hours when the glacial acetic acid mixed catalyst is completely added to obtain an R-4-bromophenylalanine mixed solution;
s3.3: concentrating the R-4-bromophenylalanine mixed solution at a temperature below 70 ℃ under reduced pressure, adding 200 parts by weight of distilled water, washing with 100 parts by weight of ethyl acetate for 2 times to obtain an organic phase and a water phase, collecting the water phase, neutralizing the water phase with 2N sodium hydroxide solution to pH 6.0, cooling to 4 ℃ for crystallization, and filtering to obtain R-4-bromophenylalanine. After baking the product at 80 ℃ for 4 hours, the melting point is tested: 262-265 ℃; specific rotation: +22.5°, c=0.5% water; HPLC purity: 97.5%.
Comparative example 1: comparative example 1 was different from example 1 in that comparative example 1 was conducted in the removal of step S1, concentrated sulfuric acid and iodobenzene diacetate were directly added to the reaction system, and the other steps were the same as in example 1.
Setting 1 part by weight to be 1g, preparing S-4-bromophenylalanine by using the example 1 and the comparative example 1 respectively, taking 20ml of reaction solution at 2 hours, 5 hours and 8 hours after completely adding the glacial acetic acid mixed catalyst and completely adding the concentrated sulfuric acid and the iodobenzene diacetate respectively, preparing the S-4-bromophenylalanine by adopting the process of the step S2.3 and adjusting the raw material dosage, weighing the mass of the S-4-bromophenylalanine, recording the obtained data and preparing a table, and analyzing that the mass of the S-4-bromophenylalanine produced at 2 hours, 5 hours and 8 hours of the example 1, the example 2 and the example 3 is larger than the mass of the S-4-bromophenylalanine produced at 2 hours, 5 hours and 8 hours of the comparative example 1 respectively, so that the preparation of the glacial acetic acid mixed catalyst can be proved to be capable of improving the reaction rate.
The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and are not intended to limit the invention. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is intended that all equivalent modifications and variations of the invention be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.
Claims (7)
1. The preparation method of chiral 4-bromophenylalanine is characterized in that L-phenylalanine and D-phenylalanine are used as raw materials, and react with N-bromosuccinimide under the action of a catalyst to obtain chiral 4-bromophenylalanine, wherein the reaction equation is as follows:
2. the preparation method of the chiral 4-bromophenylalanine is characterized by comprising the following steps of:
s1: the preparation of the glacial acetic acid mixed catalyst comprises the following steps:
mixing glacial acetic acid and concentrated sulfuric acid, magnetically stirring to obtain a mixed solution, adding iodobenzene diacetate in the process of heating the mixed solution in a water bath, and stirring to obtain a glacial acetic acid mixed catalyst;
s2: the preparation of S-4-bromophenylalanine from L-phenylalanine comprises:
placing L-phenylalanine and glacial acetic acid into a container, stirring and cooling, then adding N-bromosuccinimide into the container, continuing stirring to obtain a mixed material, slowly adding a glacial acetic acid mixed catalyst into the mixed material, simultaneously carrying out magnetic stirring, regulating the stirring rotation speed to stir when the glacial acetic acid mixed catalyst is completely added to obtain an S-4-bromophenylalanine mixed solution, adding distilled water into the S-4-bromophenylalanine mixed solution, washing with ethyl acetate to obtain an organic phase and a water phase, collecting the water phase, neutralizing the water phase with 2N sodium hydroxide, cooling for crystallization, and filtering to obtain the S-4-bromophenylalanine;
s3: the preparation of R-4-bromophenylalanine from D-phenylalanine comprises:
mixing D-phenylalanine and glacial acetic acid, placing the mixture in a container, stirring and cooling the mixture, adding N-bromosuccinimide into the container, continuously stirring the mixture to obtain a mixed material I, slowly adding a glacial acetic acid mixed catalyst into the mixed material I, simultaneously magnetically stirring the mixed material I, regulating the stirring rotation speed when the glacial acetic acid mixed catalyst is completely added, stirring the mixed material to obtain R-4-bromophenylalanine mixed solution, adding distilled water into the R-4-bromophenylalanine mixed solution, washing the mixed material with ethyl acetate to obtain an organic phase and a water phase, collecting the water phase, neutralizing the water phase with sodium hydroxide solution, cooling and crystallizing the neutralized water phase, and filtering the crystallized product to obtain R-4-bromophenylalanine.
3. The method for preparing chiral 4-bromophenylalanine according to claim 2, wherein the step S1 of preparing a glacial acetic acid mixed catalyst comprises the steps of:
s1.1: placing 20-25 parts by weight of glacial acetic acid in a container, adding 0.3-0.4 part by weight of concentrated sulfuric acid into the container, regulating the rotating speed of a magnetic stirrer to 80-100rpm, and stirring the container for 8-10 minutes to obtain a mixed solution;
s1.2: and (3) placing the mixed solution into a water bath heating pot, heating to 30-35 ℃ in the water bath, adding 0.2-0.5 part by weight of iodobenzene diacetate, and stirring for 10-20 minutes to obtain the glacial acetic acid mixed catalyst.
4. A method for preparing chiral 4-bromophenylalanine according to claim 3, wherein the step of preparing S-4-bromophenylalanine from S2L-phenylalanine comprises the steps of:
s2.1: mixing 30-35 parts by weight of L-phenylalanine and 300-350 parts by weight of glacial acetic acid, placing the mixture in a container, stirring for 10-15 minutes, cooling to 0-4 ℃, adding 30-50 parts by weight of N-bromosuccinimide into the container, and continuously stirring for 10-15 minutes to obtain a mixed material;
s2.2: slowly adding the glacial acetic acid mixed catalyst into the mixed material, stirring at a rotating speed of 80-100rpm by using a magnetic stirrer, and regulating the stirring rotating speed to 120-150rpm and stirring for 8-10 hours when the glacial acetic acid mixed catalyst is completely added to obtain an S-4-bromophenylalanine mixed solution;
s2.3: concentrating the S-4-bromophenylalanine mixed solution under reduced pressure at 60-70 ℃, adding 180-200 parts by weight of distilled water, washing with 80-100 parts by weight of ethyl acetate for 2-3 times respectively to obtain an organic phase and a water phase, collecting the water phase, neutralizing the water phase with sodium hydroxide solution to pH of 6-7, cooling to 0-4 ℃ for crystallization, and filtering to obtain the S-4-bromophenylalanine.
5. The method for preparing chiral 4-bromophenylalanine according to claim 4, wherein the preparation of R-4-bromophenylalanine from S3D-phenylalanine comprises the steps of:
s3.1: mixing 30-35 parts by weight of D-phenylalanine and 300-350 parts by weight of glacial acetic acid, placing in a container, stirring for 10-15 minutes, cooling to 0-4 ℃, adding 30-50 parts by weight of N-bromosuccinimide into the container, and continuing stirring for 10-15 minutes to obtain a mixed material;
s3.2: slowly adding the glacial acetic acid mixed catalyst into the mixed material, stirring at a rotating speed of 80-100rpm by using a magnetic stirrer, and regulating the stirring rotating speed to 120-150rpm and stirring for 8-10 hours when the glacial acetic acid mixed catalyst is completely added to obtain an R-4-bromophenylalanine mixed solution;
s3.3: concentrating the R-4-bromophenylalanine mixed solution under reduced pressure at 60-70 ℃, adding 180-200 parts by weight of distilled water, washing with 80-100 parts by weight of ethyl acetate for 2-3 times respectively to obtain an organic phase and a water phase, collecting the water phase, neutralizing the water phase with sodium hydroxide solution until the pH is 6-7, cooling to 0-4 ℃ for crystallization, and filtering to obtain the R-4-bromophenylalanine.
6. The method for preparing chiral 4-bromophenylalanine according to claim 4, wherein the step S2.2 of adding the glacial acetic acid mixed catalyst slowly is performed at a rate of adding the glacial acetic acid mixed catalyst completely within 30 to 35 minutes.
7. The method for preparing chiral 4-bromophenylalanine according to claim 4, wherein the specific operation of washing ethyl acetate in step S2.3 is to add ethyl acetate into the S-4-bromophenylalanine mixture, stir the mixture for 8-10 minutes by adjusting the rotation speed of a stirrer to 120-150rpm, and suction-filter and separate an upper organic phase from a lower aqueous phase after the stirred mixture is allowed to stand and delaminate.
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