CN118324664A - Serine derivative preparation method - Google Patents
Serine derivative preparation method Download PDFInfo
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- CN118324664A CN118324664A CN202410292116.0A CN202410292116A CN118324664A CN 118324664 A CN118324664 A CN 118324664A CN 202410292116 A CN202410292116 A CN 202410292116A CN 118324664 A CN118324664 A CN 118324664A
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- sodium hydrogen
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- 150000003354 serine derivatives Chemical class 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- FHOAKXBXYSJBGX-YFKPBYRVSA-N (2s)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CO)C(O)=O FHOAKXBXYSJBGX-YFKPBYRVSA-N 0.000 claims abstract description 86
- 238000006243 chemical reaction Methods 0.000 claims abstract description 85
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 50
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims abstract description 45
- 239000011259 mixed solution Substances 0.000 claims abstract description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 37
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims abstract description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000010992 reflux Methods 0.000 claims abstract description 22
- 238000002156 mixing Methods 0.000 claims abstract description 20
- 238000001514 detection method Methods 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 6
- 230000007935 neutral effect Effects 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 abstract description 8
- 230000006340 racemization Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229960001153 serine Drugs 0.000 description 5
- RFGMSGRWQUMJIR-LURJTMIESA-N (2s)-3-methoxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound COC[C@@H](C(O)=O)NC(=O)OC(C)(C)C RFGMSGRWQUMJIR-LURJTMIESA-N 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- -1 t-butoxycarbonyl Chemical group 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- GESQDUURIFFZPE-UHFFFAOYSA-N cyclopenta-1,3-diene-1,2,3,4-tetrol Chemical compound OC1=C(C(=C(C1)O)O)O GESQDUURIFFZPE-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application discloses a preparation method of serine derivatives, which comprises the following steps: mixing and stirring N-tert-butoxycarbonyl-L-serine and tetrahydrofuran, cooling and maintaining to obtain an initial mixed solution; adding sodium hydrogen in batches based on the initial mixed solution, adding methyl iodide for heating after the sodium hydrogen is added, carrying out reflux reaction, and stopping the reaction after the TLC detection reaction is completed to obtain a second-generation mixed solution; adding hydrochloric acid into the second-generation mixed solution to adjust the pH value to be neutral, reacting to obtain a crude Boc-Ser (me), and recrystallizing the crude Boc-Ser (me) to obtain qualified Boc-Ser (me); the Boc-Ser (me) is prepared by adopting tetrahydrofuran to dissolve N-tert-butoxycarbonyl-L-serine, sodium hydrogen and equimolar amount of methyl iodide, the purity is higher, the reaction time of the preparation method is shorter, the racemization degree is lower, the reaction is more thorough, and the generated isomer is below 0.1%, thus being suitable for amplified production.
Description
Technical Field
The invention relates to the field of polypeptide synthesis, in particular to a preparation method of serine derivatives.
Background
In the field of polypeptide synthesis, protected amino acids are structural fragments that constitute the target product, which are key starting materials; most of amino acids constituting polypeptide drugs contain chiral centers, and after enantiomer impurities are introduced into peptide chains, poor-oriented peptide impurities with structures and properties similar to those of target products are formed, so that the purification difficulty is high; wherein, boc-ser (me) -oh is a starting material for synthesizing polypeptide, serine which is a raw material is also an amino acid which is easy to racemize, in the synthesis process of boc-ser (me) -oh, the boc-d-ser (me) -oh isomer is inevitably generated under the material conditions of acid and alkali, etc., the control degree of various synthesis conditions is different, and the content of the generated boc-d-ser (me) -oh isomer is different; in the prior art, boc-ser (me) -oh is synthesized by dissolving Boc-ser in 30% sodium hydroxide solution, adding tetrabutylammonium bromide and dropwise adding dimethyl sulfate, but the process has long reaction time, incomplete reaction, more than 10% isomer, difficult removal, low purity, difficult purification and unfavorable production.
Disclosure of Invention
The application provides a preparation method of serine derivatives, which aims to solve the technical problems that the existing technology for preparing boc-ser (me) -oh is not thorough in reaction, and the purity is low due to high percentage of generated isomer.
In order to achieve the above purpose, the technical scheme adopted by the application is as follows: a process for the preparation of serine derivatives comprising the steps of:
obtaining N-tert-butoxycarbonyl-L-serine and tetrahydrofuran, mixing and stirring the N-tert-butoxycarbonyl-L-serine and the tetrahydrofuran, cooling and keeping to obtain an initial mixed solution; sodium hydrogen and methyl iodide are obtained, sodium hydrogen is added in batches based on the initial mixed solution, methyl iodide is added for heating after the sodium hydrogen is added, reflux reaction is carried out, and the reaction is terminated after the reaction is detected to be complete based on TLC, so that a second-generation mixed solution is obtained; and (3) obtaining hydrochloric acid, adding hydrochloric acid based on the second-generation mixed solution to adjust the pH value to be neutral, reacting to obtain a crude Boc-Ser (me), and recrystallizing the crude Boc-Ser (me) to obtain qualified Boc-Ser (me).
As one of the optimized embodiments of the invention, the mixing ratio of the N-t-butoxycarbonyl-L-serine and tetrahydrofuran is in the range of 1:5-1:6.
As one of the optimized embodiments of the invention, N-t-butoxycarbonyl-L-serine and tetrahydrofuran are mixed and stirred, and the temperature is reduced and kept to obtain an initial mixed solution, specifically: mixing and stirring N-tert-butoxycarbonyl-L-serine and tetrahydrofuran according to a mixing ratio, controlling the temperature range to be between 9 ℃ below zero and 10 ℃ below zero, and reacting and maintaining to obtain an initial mixed solution.
As one of the optimized embodiments of the invention, the percentage content of sodium hydrogen is 60%.
As one of the optimized embodiments of the invention, the mixing ratio of the sodium hydrogen and the methyl iodide is in the range of 1:1.5-1:2.
As one of the optimized embodiments of the invention, sodium hydrogen is added in batches based on the initial mixed solution, methyl iodide is added for heating after the sodium hydrogen is added, reflux reaction is carried out, and the reaction is terminated after the reaction is detected to be complete based on TLC, so as to obtain a second-generation mixed solution, which is specifically as follows: 60% sodium hydrogen is added in batches based on the initial mixed solution, methyl iodide is added according to the mixing proportion range, the temperature range is increased to 15-55 ℃, reflux reaction is carried out, whether the reaction is complete or not is judged based on TLC detection reaction, and if the reaction is complete, the second-generation mixed solution is obtained after the reaction is terminated.
As one of the preferred embodiments of the present invention, if the reaction is judged to be incomplete based on TLC detection, the reflux reaction is continued until the TLC detection is complete.
As one of the optimized embodiments of the invention, the concentration of the hydrochloric acid is 3 mol/L.
Compared with the prior art, the invention has the beneficial effects that: the Boc-Ser (me) is prepared by dissolving N-t-butoxycarbonyl-L-serine in tetrahydrofuran, reacting with sodium hydrogen and equimolar amount of methyl iodide, the purity is higher, the reaction time of the preparation method is shorter, the racemization degree is lower, the reaction is more thorough, and the generated isomer is below 0.1%, thus being suitable for amplified production; firstly, dissolving N-tert-butoxycarbonyl-L-serine in tetrahydrofuran, stirring, and controlling the temperature to provide stable reaction conditions for the subsequent steps; adding sodium hydrogen in batches, adding methyl iodide after the addition is finished, heating to perform reflux reaction, judging the completeness of the whole reaction based on TLC detection reaction, and immediately stopping the reaction after the completion of the reaction is detected to obtain second-generation mixed solution; then adjusting the pH value by hydrochloric acid, and reacting to obtain a Boc-Ser (me) crude product; and then purifying and refining the product by recrystallization to obtain high-quality Boc-Ser (me).
Drawings
In order to more clearly illustrate the embodiments of the application or the technical solutions of the prior art, the drawings which are used in the description of the embodiments or the prior art will be briefly described, it being obvious that the drawings in the description below are only some embodiments of the application, and that other drawings can be obtained from these drawings without inventive faculty for a person skilled in the art.
Fig. 1 is a flow chart showing the steps of a method for producing a serine derivative according to the first embodiment of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present application more apparent, the technical solutions of the embodiments of the present application will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present application, and it is apparent that the described embodiments are some embodiments of the present application, but not all embodiments of the present application. The components of the embodiments of the present application generally described and illustrated in the figures herein may be arranged and designed in a wide variety of different configurations.
Thus, the following detailed description of the embodiments of the application, as presented in the figures, is not intended to limit the scope of the application, as claimed, but is merely representative of selected embodiments of the application. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
It should be noted that: like reference numerals and letters denote like items in the following figures, and thus once an item is defined in one figure, no further definition or explanation thereof is necessary in the following figures.
In the description of the present application, it should be noted that, if the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc. indicate an azimuth or a positional relationship based on that shown in the drawings, or an azimuth or a positional relationship in which a product of the application is conventionally put in use, it is merely for convenience of describing the present application and simplifying the description, and it is not indicated or implied that the referred device or element must have a specific azimuth, be constructed and operated in a specific azimuth, and thus should not be construed as limiting the present application. Furthermore, the terms "first," "second," and the like in the description of the present application, if any, are used for distinguishing between the descriptions and not necessarily for indicating or implying a relative importance.
Furthermore, the terms "horizontal," "vertical," and the like in the description of the present application, if any, do not denote a requirement that the component be absolutely horizontal or overhang, but rather may be slightly inclined. As "horizontal" merely means that its direction is more horizontal than "vertical", and does not mean that the structure must be perfectly horizontal, but may be slightly inclined.
In the description of the present application, it should also be noted that, unless explicitly stated and limited otherwise, the terms "disposed," "mounted," "connected," and "connected" should be construed broadly, and may be, for example, fixedly connected, detachably connected, or integrally connected; can be mechanically or electrically connected; can be directly connected or indirectly connected through an intermediate medium, and can be communication between two elements. The specific meaning of the above terms in the present application will be understood in specific cases by those of ordinary skill in the art.
Referring to fig. 1, a preparation method of a serine derivative according to a first embodiment of the present invention includes the following steps:
Step S1: obtaining N-tert-butoxycarbonyl-L-serine and tetrahydrofuran, mixing and stirring the N-tert-butoxycarbonyl-L-serine and the tetrahydrofuran, cooling and maintaining to obtain an initial mixed solution;
Step S2: sodium hydrogen and methyl iodide are obtained, sodium hydrogen is added in batches based on the initial mixed solution, methyl iodide is added for heating after the sodium hydrogen is added, reflux reaction is carried out, and the reaction is terminated after the reaction is detected to be complete based on TLC, so that a second-generation mixed solution is obtained;
Step S3: and (3) obtaining hydrochloric acid, adding hydrochloric acid based on the second-generation mixed solution to adjust the pH value to be neutral, reacting to obtain a crude Boc-Ser (me), and recrystallizing the crude Boc-Ser (me) to obtain qualified Boc-Ser (me).
Serine derivatives are described as serine converted through a series of chemical reactions, having hydrophilicity and various biological activities, and have a wide range of roles in organisms, which are generally involved in metabolic processes, regulating cell transduction, affecting gene expression, etc.
Further, the mixing ratio of N-t-butoxycarbonyl-L-serine to tetrahydrofuran is in the range of 1:5 to 1:6.
Further, the step S1 specifically includes:
Mixing and stirring N-tert-butoxycarbonyl-L-serine and tetrahydrofuran according to a mixing ratio, controlling the temperature range to be between 9 ℃ below zero and 10 ℃ below zero, and reacting and maintaining to obtain an initial mixed solution.
By way of illustration, N-t-butoxycarbonyl-L-serine is an amino acid derivative consisting of serine and a t-butoxycarbonyl (t-Boc) protecting group, wherein t-butoxycarbonyl is an amino protecting group capable of effectively protecting the amino group from modification in a chemical reaction for ensuring stability and reactivity of serine molecules.
Tetrahydrofuran, namely tetrahydroxycyclopentadiene, is colorless transparent liquid, has good solubility, can dissolve organic compounds, and has high chemical stability; dissolving N-tert-butoxycarbonyl-L-serine in tetrahydrofuran, cooling and maintaining to obtain initial mixed solution, avoiding violent molecular movement of the compound and solvent, and reducing instability in the dissolving process.
Further, the percentage content of sodium hydrogen is 60%, namely the mass ratio of sodium element to hydrogen element, when the percentage content of sodium hydrogen is moderate, the compound can keep stable chemical property, decomposition or explosion is not easy to occur, and the higher the percentage content of sodium hydrogen is, the larger the energy density of the compound is, the more energy can be stored, and the longer the service time is provided for various applications.
Further, the mixing ratio of sodium hydrogen to methyl iodide is in the range of 1:1.5-1:2.
Further, the step S2 specifically includes:
60% sodium hydrogen is added in batches based on the initial mixed solution, methyl iodide is added according to the mixing proportion range, the temperature range is increased to 15-55 ℃, reflux reaction is carried out, whether the reaction is complete or not is judged based on TLC detection reaction, and if the reaction is complete, the second-generation mixed solution is obtained after the reaction is terminated.
Further, if the reaction is judged to be incomplete based on the TLC detection reaction, the reflux reaction is continued until the TLC detection reaction is complete.
Sodium hydrogen is an active hydride, has high reaction activity, and can effectively control the reaction rate by adding sodium hydrogen in batches, so that the impurity of a product or the runaway of the reaction caused by too severe reaction is avoided, and the sodium hydrogen can be uniformly distributed and fully contacted with other components in an initial mixed solution; methyl iodide is a methylation reagent, which is mainly used for substitution reaction, addition reaction and the like; after methyl iodide is added, the temperature is raised to accelerate the reaction rate, and simultaneously, the reflux reaction is carried out, namely, the utilization rate of reactants and the purity of products can be improved by introducing the gas generated by the reaction into a reaction system again; and the reaction progress is monitored in real time by TLC detection reaction, so that the reaction can be stopped in time when the reaction is complete.
Further, the concentration of hydrochloric acid was 3 mol/L.
By way of illustration, the concentration of the hydrochloric acid solution determines the strength of the acidity, and the higher the concentration, the higher the ionization degree of the HCl molecules, the higher the concentration of H + ions generated in the solution, and the stronger the acidity of the solution.
And adding hydrochloric acid to the second-generation mixed solution to adjust the pH value to be neutral, so that the second-generation mixed solution reaches an optimal acid-base balance state, and reacting to obtain a Boc-Ser (Me) crude product containing a small amount of Boc-N-Me-Ser, wherein the Boc-Ser (Me), namely N-t-butoxycarbonyl-O-methyl-L-serine, is an amino protecting group which can protect amino from being influenced in a chemical reaction, ser represents serine and provides an amino acid residue, and (Me) refers to O-methyl, namely hydroxyl in N-t-butoxycarbonyl-L-serine is converted into methyl ether. This means that the hydroxyl group in N-t-butoxycarbonyl-L-serine is up-converted to a methyl ether; and Boc-N-Me-Ser, N-methyl-N-t-butoxycarbonyl-L-serine, affects the purity of Boc-Ser (Me).
As an alternative implementation mode, the method for preparing the Boc-Ser (me) crude product comprises the steps of adding hydrochloric acid to adjust the pH value to be neutral based on the second-generation mixed solution, concentrating tetrahydrofuran in vacuum, adding ethyl acetate, continuously adding hydrochloric acid to control the pH value of the solution to be 2-3, washing the pH value of the target product to be 6-7 by adopting semi-saturated salt water on an ethyl acetate layer, adding anhydrous sodium sulfate to dry for 2-3 hours, carrying out suction filtration, concentrating filtrate to be dry, adding petroleum ether to pulp after induced crystallization, and carrying out suction filtration to obtain the Boc-Ser (me) crude product.
It can be understood that Boc-Ser (me) is prepared by dissolving N-t-butoxycarbonyl-L-serine with tetrahydrofuran, reacting with sodium hydrogen and equimolar amount of methyl iodide, the purity is higher, the reaction time of the preparation method is shorter, the racemization degree is lower, the reaction is more thorough, and the generated isomer is below 0.1%, thus being suitable for amplified production; firstly, dissolving N-tert-butoxycarbonyl-L-serine in tetrahydrofuran, stirring, and controlling the temperature to provide stable reaction conditions for the subsequent steps; adding sodium hydrogen in batches, adding methyl iodide after the addition is finished, heating to perform reflux reaction, judging the completeness of the whole reaction based on TLC detection reaction, and immediately stopping the reaction after the completion of the reaction is detected to obtain second-generation mixed solution; then adjusting the pH value by hydrochloric acid, and reacting to obtain a Boc-Ser (me) crude product; and then purifying and refining the product by recrystallization to obtain high-quality Boc-Ser (me).
Specifically, in this example, 205 g of N-t-butoxycarbonyl-L-serine was added to a 5L clean and dry three-necked flask, tetrahydrofuran 2L was added, stirring was started, the internal temperature was lowered to-10℃and maintained, 80 g of 60% sodium hydrogen was added in portions, 142 g of methyl iodide was added after the sodium hydrogen addition was completed, the temperature was slowly raised to 45℃after the addition was completed, the reaction was weakly refluxed for 1 hour, and the reaction was terminated immediately after the completion of TLC detection. Dropwise adding 3N hydrochloric acid to adjust pH to neutrality, vacuum concentrating to obtain tetrahydrofuran, adding ethyl acetate 1L, dropwise adding 3N hydrochloric acid to adjust pH to 2-3, and washing the product solution with half saturated saline solution 200 ml/time to pH 6-7. And adding anhydrous sodium sulfate into the product solution to dry for 2-3h, carrying out suction filtration, concentrating the filtrate to dryness, adding petroleum ether to pulp after induced crystallization, carrying out suction filtration to obtain a crude product of Boc-Ser (Me), containing a small amount of Boc-N-Me-Ser, and recrystallizing with ethyl acetate and petroleum ether to obtain qualified Boc-Ser (Me), wherein 180 g of Boc-Ser (Me) is obtained, the purity is 98.2%, the isomer is 0.09%, and the yield is 82.19%.
It can be stated that the chemical equation for Boc-Ser (me) prepared based on sodium hydrogen and methyl iodide is:
to make an explanation, in order to obtain the best experimental data, the corresponding experimental data is obtained based on the control variable method.
Firstly, 60g, 80g and 100g of 60% sodium hydrogen are added in batches to react respectively, the experimental data finally obtained are 60g sodium hydrogen, 95.5 g Boc-Ser (me) is obtained, the purity is 96.5%, the isomer is 0.12%, and the yield is 43.56%; 80g of sodium hydrogen, 180 g of Boc-Ser (me) is obtained, the purity is 98.2%, the isomer is 0.09%, and the yield is 82.19%; 100g of sodium hydrogen, 83 g of Boc-Ser (me) is obtained, the purity is 94.5%, the isomer is 0.25%, and the yield is 38.2%; it can be known that the addition of sodium hydrogen has a larger influence on the yield and purity of the final Boc-Ser (me), and sodium hydrogen with less than twice molar amount causes incomplete reaction and reduces the product yield; more than twice the molar amount of sodium hydrogen is preferable because it causes more side reactions, more isomers are produced, and purification is not facilitated.
Secondly, the addition amount of methyl iodide is 120g, 142g and 160g respectively for reaction, the obtained experimental data is 120g of methyl iodide, 120g of Boc-Ser (me) is obtained, the purity is 97.1%, the isomer is 0.12%, and the yield is 55.3%; 142g of methyl iodide, 180 g of Boc-Ser (me) is obtained, the purity is 98.2%, the isomer is 0.09%, and the yield is 82.19%; 160g of methyl iodide, 141 g of Boc-Ser (me) is obtained, the purity is 97.4%, the isomer is 0.09%, and the yield is 64.9%; it is found that the addition of methyl iodide in an amount of less than or more than 1 time by mole affects the yield, and the amount of methyl iodide added in an amount of 1 time by mole is optimal because the amount of impurities generated is large and the loss of the product by recrystallization is large.
Thirdly, raising the temperature after the addition of methyl iodide to 25 ℃, 45 ℃ and 55 ℃ respectively, observing the corresponding reaction, and obtaining experimental data that the temperature is raised to 25 ℃ to obtain 100 g of Boc-Ser (me), wherein the purity is 96.3%, the isomer is 0.09%, and the yield is 46%; the temperature is increased to 45 ℃, 180 g of Boc-Ser (me) is obtained, the purity is 98.2%, the isomer is 0.09%, and the yield is 82.19%; raising the temperature to 55 ℃ to obtain 110 g of Boc-Ser (me), wherein the purity is 96.3%, the isomer is 0.21%, and the yield is 50.7%; it is found that 45℃is optimal because of lower temperature or higher temperature yields and purities.
Fourthly, after 142g of methyl iodide is added, the temperature is raised to 45 ℃, the time of reflux reaction is controlled, and after 0.5h, 1h and 2h of reaction are respectively carried out, the obtained experimental data are that the reflux reaction is carried out for 0.5h, 52 g of Boc-Ser (me) is obtained, the purity is 96.3%, the isomer is 0.08%, and the yield is 23.9%; reflux reaction is carried out for 1h, 180 g of Boc-Ser (me) is obtained, the purity is 98.2%, the isomer is 0.09%, and the yield is 82.19%; reflux reaction is carried out for 2 hours, 182 g of Boc-Ser (me) is obtained, the purity is 98.2%, the isomer is 0.32%, and the yield is 83.9%; it is found that when the reflux reaction time is short, the yield is low, the purity is low, and after the reaction time reaches 1h, the formation of the target product is not significantly improved, but the isomer index becomes large, which is unfavorable for purification, so that the reflux reaction time is preferably controlled to 1 h.
Based on the experimental data, it can be known that, in order to prepare sodium hydrogen with high purity and lower isomer under the reaction condition of twice molar quantity, methyl iodide with 1 time molar quantity is added, the reaction temperature is 45 ℃, and the reflux reaction time is 1h, so that the obtained target product has the best quality and the optimal yield.
The above description is only of the preferred embodiments of the present application and is not intended to limit the present application, but various modifications and variations can be made to the present application by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (8)
1. A process for the preparation of serine derivatives characterized in that: the method comprises the following steps:
Obtaining N-tert-butoxycarbonyl-L-serine and tetrahydrofuran, mixing and stirring the N-tert-butoxycarbonyl-L-serine and the tetrahydrofuran, cooling and keeping to obtain an initial mixed solution;
Sodium hydrogen and methyl iodide are obtained, sodium hydrogen is added in batches based on the initial mixed solution, methyl iodide is added for heating after the sodium hydrogen is added, reflux reaction is carried out, and the reaction is terminated after the reaction is detected to be complete based on TLC, so that a second-generation mixed solution is obtained;
And (3) obtaining hydrochloric acid, adding hydrochloric acid based on the second-generation mixed solution to adjust the pH value to be neutral, reacting to obtain a crude Boc-Ser (me), and recrystallizing the crude Boc-Ser (me) to obtain qualified Boc-Ser (me).
2. The method for producing serine derivatives according to claim 1, wherein: the mixing ratio of the N-tert-butoxycarbonyl-L-serine to the tetrahydrofuran is in the range of 1:5-1:6.
3. The method for producing serine derivatives according to claim 2, wherein: mixing and stirring N-tert-butoxycarbonyl-L-serine and tetrahydrofuran, cooling and maintaining to obtain an initial mixed solution, wherein the specific steps are as follows: mixing and stirring N-tert-butoxycarbonyl-L-serine and tetrahydrofuran according to a mixing ratio, controlling the temperature range to be between 9 ℃ below zero and 10 ℃ below zero, and reacting and maintaining to obtain an initial mixed solution.
4. The method for producing serine derivatives according to claim 1, wherein: the percentage content of sodium hydrogen is 60%.
5. The method for producing serine derivatives according to claim 4, wherein: the mixing ratio of the sodium hydrogen to the methyl iodide is 1:1.5-1:2.
6. The method for producing serine derivatives according to claim 5, wherein: adding sodium hydrogen in batches based on the initial mixed solution, adding methyl iodide for heating after the sodium hydrogen is added, carrying out reflux reaction, and stopping reaction after the completion of the reaction based on TLC detection to obtain a second-generation mixed solution, wherein the method specifically comprises the following steps of: 60% sodium hydrogen is added in batches based on the initial mixed solution, methyl iodide is added according to the mixing proportion range, the temperature range is increased to 15-55 ℃, reflux reaction is carried out, whether the reaction is complete or not is judged based on TLC detection reaction, and if the reaction is complete, the second-generation mixed solution is obtained after the reaction is terminated.
7. The method for producing serine derivatives according to claim 6, wherein: if the reaction is judged to be incomplete based on TLC detection, the reflux reaction is continued until the TLC detection is complete.
8. The method for producing serine derivatives according to claim 1, wherein: the concentration of the hydrochloric acid is 3mol/L.
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