Method for preparing deuterated methionine
Deuterated methionine is prepared through a new two-step synthesis route, which solves the problems of unclear contrast and allergic reactions of contrast agents in brain glioma detection, and achieves low-cost and efficient deuterated methionine preparation and tumor detection effects.
Patent Information
- Application Number
- PCT/CN2024/085159
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2024-03-13
- Filing Date
- 2024-04-01
- Publication Date
- 2025-09-18
AI Technical Summary
Existing tumor detection methods, especially those for gliomas, have problems such as unclear contrast of contrast agents, allergic reactions caused by gadolinium-based contrast agents, and renal metabolic burden, which make diagnosis and treatment difficult.
A new two-step synthesis route is adopted, using DL-homocysteine thiolactone hydrochloride as a substrate to prepare deuterated methionine through hydrolysis and deuteration reaction, which simplifies the process and reduces costs. Deuterated iodomethane is used as a deuterium source for the deuteration reaction, avoiding expensive catalysts and complex environmental requirements.
The low-cost and efficient preparation of deuterated methionine has been achieved. As a magnetic resonance imaging contrast agent, it shows the specificity of high uptake by tumor cells and low uptake by normal tissues in the detection of brain gliomas, providing clear contrast and solving the diagnostic difficulties in existing technologies.
Smart Images
Figure CN2024085159_18092025_PF_FP_ABST
Abstract
Description
A preparation method of deuterated methionine Technical Field
[0001] The present application belongs to the field of biotechnology and relates to a method for preparing deuterated methionine, and in particular to the preparation of a novel deuterated amino acid contrast agent for magnetic resonance imaging. Background Art
[0002] In conventional tumor detection methods, tumor tissue often infiltrates with normal tissue, resulting in unclear boundaries of the tumor area, which affects the diagnosis and treatment of the lesions. Therefore, contrast agents are often needed to enhance the signal in the tumor area.
[0003] Positron emission tomography (PET) is currently one of the most popular imaging methods for tumor diagnosis. Its high-resolution imaging of lesions can provide comprehensive information, including tumor staging, diagnosis, and metastasis. It can also provide information on true or false tumor progression and treatment prognosis after surgery. PET relies on the uptake of fluorodeoxyglucose (18F-FDG), a glucose analog, by tumors. Tumor cells have a higher uptake of glucose than normal cells, a phenomenon known as the "Warburg effect." However, since 18F-FDG itself is not metabolized, it is enriched in lesions, resulting in a high signal in the tumor, distinguishing it from normal tissue. However, brain tumors, such as gliomas, do not exhibit such a clear contrast. This is because normal brain tissue also exhibits high glucose uptake, meaning both normal and tumor tissues experience high uptake and accumulation of 18F-FDG, making it difficult to accurately delineate and define glioma boundaries.
[0004] In addition, the gadolinium-based contrast agents commonly used in magnetic resonance imaging introduce exogenous gadolinium-based compounds, which not only cause patients to have allergic reactions of varying severity, but also cannot be used in patients with chronic or severe renal impairment because they increase the metabolic burden on the kidneys. In addition, patients with renal insufficiency also need hemodialysis to clear the gadolinium-based contrast agents from the body.
[0005] In summary, the development of new contrast agents and corresponding preparation methods is of great significance in the field of tumor treatment.
[0006] Summary of the Invention
[0007] The present application provides a method for preparing deuterated methionine, which simplifies the process and reduces the requirements for the synthesis environment, in order to achieve low-cost and efficient preparation of deuterated methionine and further develop magnetic resonance imaging contrast agents.
[0008] In a first aspect, the present application provides a method for preparing deuterated methionine, the preparation method comprising:
[0009] DL-homocysteine thiolactone hydrochloride is used as a substrate for a hydrolysis reaction to obtain DL-homocysteine; the DL-homocysteine is subjected to a deuteration reaction with deuterated iodomethane to obtain the deuterated methionine; the structural formula of the deuterated methionine is shown in Formula I.
[0010] In this application, a new two-step synthesis route is designed for a specific deuterated methionine. DL-homocysteine thiolactone hydrochloride is first used as a raw material to synthesize DL-homocysteine. Compared with directly using DL-homocysteine as a raw material, this can effectively reduce costs. DL-homocysteine is prepared on-site and then immediately proceeds to the next step of methionine synthesis, avoiding the problem of DL-homocysteine being oxidized during storage. Based on the prepared DL-homocysteine, deuterated iodomethane is used as a deuterium source for the deuteration reaction, greatly simplifying the reaction process steps. Only conventional reagents (such as sodium hydroxide and ethanol) are required as deuterated reaction participants, making the preparation of deuterated methionine more simplified and feasible. Through a completely new design, the present invention can be synthesized under conventional conditions at room temperature (20-30°C), without the need for expensive catalysts, reducing agents, etc., and except for the need to add nitrogen protection during the first step of converting DL-homocysteine, no protective measures are required in the remaining processes. The requirements for the synthesis environment are greatly reduced, which is conducive to improving the production efficiency of deuterated methionine and promoting the application of deuterated methionine.
[0011] Preferably, the hydrolysis reaction specifically includes:
[0012] DL-homocysteine thiolactone hydrochloride, a first alkaline reagent and a first solvent are mixed to carry out a hydrolysis reaction.
[0013] Preferably, the first solvent comprises water.
[0014] Preferably, the first alkaline reagent comprises sodium hydroxide and / or potassium hydroxide.
[0015] Preferably, the molar ratio of DL-homocysteine thiolactone hydrochloride to the base is 1:(3-4).
[0016] Preferably, the temperature of the hydrolysis reaction is 20°C to 30°C, including but not limited to 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C or 29°C.
[0017] Preferably, the deuteration reaction specifically includes:
[0018] The DL-homocysteine, deuterated iodomethane, a second base reagent and a second solvent are mixed to perform a deuteration reaction.
[0019] Preferably, the second alkaline reagent comprises sodium hydroxide and / or potassium hydroxide.
[0020] Preferably, the second solvent includes any one of ethanol, methanol or isopropanol, or a combination of at least two of them.
[0021] Preferably, the molar ratio of DL-homocysteine, deuterated iodomethane and the second alkaline reagent is 1:(1-6), for example, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5 or 1:5.5.
[0022] Preferably, the temperature of the deuteration reaction is 20°C to 30°C, for example, it can be 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C or 29°C, preferably 20°C to 25°C.
[0023] Preferably, the deuteration reaction specifically includes:
[0024] The second alkaline reagent and the second solvent are mixed to obtain an alkaline solution, and the alkaline solution is then mixed with DL-homocysteine and deuterated iodomethane to perform a deuteration reaction.
[0025] Preferably, the concentration of the second alkaline reagent in the alkaline solution in step (3) is 5% to 8% (mass percentage).
[0026] Preferably, the hydrolysis reaction further includes a first purification step.
[0027] Preferably, the first purification comprises: performing chromatography on the product of the hydrolysis reaction using an anion exchange resin chromatography column.
[0028] Preferably, the deuteration reaction further includes a second purification step.
[0029] Preferably, the second purification comprises:
[0030] The product of the deuterated reaction is chromatographed using an anion exchange resin chromatography column, and the chromatographic substance is crystallized and purified.
[0031] As a preferred technical solution, the preparation method of deuterated methionine comprises the following steps:
[0032] (1) mixing DL-homocysteine thiolactone hydrochloride with water, and then adding sodium hydroxide to carry out a hydrolysis reaction;
[0033] (2) washing the anion exchange resin chromatography column with a sodium hydroxide solution, and then washing with water, then adding the product of step (1) to the chromatography column, washing with water, and then eluting with an acetic acid solution, collecting the eluate, and drying it to obtain DL-homocysteine;
[0034] (3) mixing an ethanolic sodium hydroxide solution, deuterated iodomethane, and the DL-homocysteine obtained in step (2) to perform a deuteration reaction;
[0035] (4) washing the anion exchange resin chromatography column with a sodium hydroxide solution, and then washing with water, adding the product of step (3) to the chromatography column, washing with water, and then eluting with an acetic acid solution, collecting the eluate, and drying it to obtain a preliminary product; and
[0036] (5) Mixing the preliminary product of step (4) with water, and then performing crystallization purification using ethanol to obtain deuterated methionine.
[0037] Preferably, the concentration of the ethanol sodium hydroxide solution in step (3) is 5%-8%.
[0038] In a second aspect, the present application provides a composition comprising deuterated methionine prepared by the method for preparing deuterated methionine according to the first aspect.
[0039] In a third aspect, the present application provides use of the composition described in the second aspect in the preparation of a magnetic resonance imaging contrast agent.
[0040] In this application, for the first time, the experimental process and data processing method in in vitro cell experiments and the scanning parameters used in animal models were designed for a specific deuterated methionine, and the deuterated methionine was successfully verified to be capable of being used as a deuterated magnetic resonance imaging amino acid contrast agent, especially for the detection of brain gliomas.
[0041] Compared with the prior art, this application has the following beneficial effects:
[0042] The present application designs a novel two-step synthesis route for a specific deuterated methionine. DL-homocysteine thiolactone hydrochloride is first used as a raw material, which can effectively reduce costs while avoiding the problem of DL-homocysteine being oxidized during storage. Deuterated iodomethane is used as a deuterium source for the deuteration reaction, which greatly simplifies the reaction process steps. The synthesis can be carried out under conventional conditions at room temperature without the need for expensive catalysts, reducing agents, etc., and except for the need to add nitrogen protection during the first step of converting DL-homocysteine, no protective measures are taken in the remaining steps. The requirements for the synthesis environment are greatly reduced, which is conducive to improving the production efficiency of deuterated methionine and promoting the application of deuterated methionine. BRIEF DESCRIPTION OF THE DRAWINGS
[0043] Figure 1 is a comparison of the deuterium spectra of the 0h sample and the 48h sample, where Figure A is the result of C6 cells and Figure B is the result of CTX-TNA2 cells.
[0044] FIG2 shows the results of deuterated methionine consumption in two cell lines over time (**, P=0.005, independent sample t-test).
[0045] FIG3 shows the consumption rate of deuterated methionine in two cells within 48 hours (n=6; **, P=0.008, independent sample t-test).
[0046] FIG4 is a 1H NMR spectrum of deuterated methionine prepared in this application.
[0047] FIG5 is a 2H NMR spectrum of deuterated methionine prepared in this application.
[0048] FIG6 is a mass spectrum of deuterated methionine prepared in this application. DETAILED DESCRIPTION
[0049] To further illustrate the technical means and effects of this application, the following further describes this application in conjunction with examples and drawings. It should be understood that the specific implementation methods described herein are only used to explain this application, rather than to limit this application.
[0050] If no specific techniques or conditions are specified in the examples, the experiments were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.
[0051] Example 1
[0052] This example prepares deuterated methionine.
[0053] The synthetic route is as follows:
[0054] (1) DL-homocysteine thiolactone hydrochloride (10.3 g, 67 mmol) was added to water (200 mL) and fully dissolved. Then, sodium hydroxide (8.04 g, 201 mmol) was added to the aqueous solution. The mixture was fully stirred at 25°C and hydrolyzed under nitrogen protection.
[0055] (2) Subsequently, a 717 anion exchange resin column (350 mL) was first rinsed with 1 L of 5% sodium hydroxide solution to make the resin alkaline, and then rinsed with water to pH = 7. The hydrolyzed DL-homocysteine thiolactone hydrochloride solution was then added to the column that had been rinsed to neutrality, and soluble impurities were washed away with 2 L of water. Then, 2 L of 2 mol / L acetic acid solution was added for elution. The entire solution obtained during the acetic acid solution rinse was collected and subjected to rotary evaporation to obtain a white solid, namely DL-homocysteine.
[0056] (3) First, sodium hydroxide (34.2 g, 0.855 mol) was added to the reaction flask, and 95% ethanol (1200 mL, 199.5 mmol) was added and stirred until completely dissolved, and then the solution was cooled to 25°C.
[0057] (4) Then, about DL-homocysteine (7.0 g, 40.78 mmol) and deuterated iodomethane (6.0 g, 41.39 mmol) were added to 560 mL of the 95% ethanolic sodium hydroxide solution obtained above, and the mixture was slowly stirred for about 14 h. After refluxing for 1 h, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in 40 mL of water.
[0058] (5) In a 717 anion exchange resin chromatography column (350 mL), the resin was first rinsed with 1 L of 5% sodium hydroxide solution until alkaline, then eluted with water to pH = 7, and then 40 mL of the residual aqueous solution obtained in the previous step was added. The 40 mL residual aqueous solution was added to the chromatography column again, and the soluble impurity salts therein were rinsed with 1 L of water, and then eluted with 2 mol 2 L acetic acid solution. All the solution obtained during the acetic acid solution rinse was collected and rotary evaporated to obtain a white solid, which was the preliminary product.
[0059] (6) The obtained white solid was then dissolved in 40 mL of hot water and then crystallized and purified using 95% ethanol (40 mL). A second batch of crystals, i.e., the final product, was obtained from the final mother liquor residue to obtain deuterated methionine product. The product was confirmed to be deuterated methionine by deuterium nuclear resonance magnetic resonance spectroscopy.
[0060] The target deuterated methionine structure is shown below. 1 The H NMR spectrum is shown in Figure 4. 1 H NMR spectrum scanning, the solvent used is heavy water (D2O). During the scanning process, the carbon atoms 2 and 3 both contain two hydrogen atoms and will not be replaced by deuterium in heavy water, and the one hydrogen atom at the carbon atom 4 will not be replaced by deuterium. However, the hydrogen atoms on the amino and carboxyl groups are chemically more active and will be replaced by deuterium atoms in heavy water during the scanning process and will not appear. 1 On the H NMR spectrum. Therefore, there will be1 The H NMR spectrum showed five hydrogen atoms, and the actual measured 1 The H NMR spectrum is consistent with the theoretical analysis.
[0061] The product obtained 2 The H NMR spectrum is shown in Figure 5. The specific detection process includes: preparing 1 mL of a 500 μM / L methionine aqueous solution, taking 640 μL of the methionine solution and mixing it with 160 μL of 1 mM / L d4-pyrazine. Then, 500 μL was extracted from the 800 μL methionine and pyrazine mixed solution and transferred to a 5 mm NMR tube. The deuterium nuclear resonance spectrum was scanned on a magnetic resonance spectrometer, and the solvent was selected as none. At this time, the pyrazine concentration in 500 μL was 200 μM / L, and the methionine concentration was 400 μM / L. However, because pyrazine contains four deuterium atoms and methionine contains three deuterium atoms, the pyrazine:methionine ratio is 0. 2 The signal ratio in the H NMR spectrum should be 1:1.5, and the actual measured value is 1:1.49, which is consistent with the theoretical value, proving that the prepared product is the target product.
[0062] The mass spectrum of the prepared deuterated methionine is shown in FIG6 .
[0063] Example 2
[0064] This example prepares deuterated methionine.
[0065] (1) DL-homocysteine thiolactone hydrochloride (10.3 g, 67 mmol) was added to water (200 mL) and fully dissolved. Potassium hydroxide (13.16 g, 235 mmol) was then added to the aqueous solution. The mixture was fully stirred at 25°C and hydrolyzed under nitrogen protection.
[0066] (2) Subsequently, a 717 anion exchange resin column (350 mL) was first rinsed with 1 L of 5% sodium hydroxide solution to make the resin alkaline, and then rinsed with water to pH = 7. The hydrolyzed DL-homocysteine thiolactone hydrochloride solution was then added to the column that had been rinsed to neutrality, and soluble impurities were washed away with 2 L of water. Then, 2 L of 2 mol / L acetic acid solution was added for elution. The entire solution obtained during the acetic acid solution rinse was collected and subjected to rotary evaporation to obtain a white solid, namely DL-homocysteine.
[0067] (3) Potassium hydroxide (48.0 g, 0.857 mol) was first added to the reaction flask, and 95% methanol (1200 mL, about 286.8 mmol) was added and stirred until completely dissolved, and then the solution was cooled to 25°C.
[0068] (4) Then, about DL-homocysteine (7.0 g, 40.78 mmol) and deuterated iodomethane (6.0 g, 41.39 mmol) were added to 560 mL of the 95% methanolic potassium hydroxide solution obtained above, and the mixture was slowly stirred for about 14 h. After refluxing for 1 h, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in 40 mL of water.
[0069] (5) In a 717 anion exchange resin chromatography column (350 mL), the resin was first rinsed with 1 L of 5% sodium hydroxide solution until alkaline, then eluted with water to pH = 7, and then 40 mL of the residual aqueous solution obtained in the previous step was added. The 40 mL residual aqueous solution was added to the chromatography column again, and the soluble impurity salts therein were rinsed with 1 L of water, and then eluted with 2 mol 2 L acetic acid solution. All the solution obtained during the acetic acid solution rinse was collected and rotary evaporated to obtain a white solid, which was the preliminary product.
[0070] (6) The obtained white solid was then dissolved in 40 mL of hot water and then crystallized and purified using 95% ethanol (40 mL). A second batch of crystals, i.e., the final product, was obtained from the final mother liquor residue to obtain the deuterated methionine product. 1 H / 2 H magnetic resonance spectroscopy and mass spectrometry confirmed that the product was deuterated methionine.
[0071] Example 3
[0072] This example prepares deuterated methionine.
[0073] (1) DL-homocysteine thiolactone hydrochloride (10.3 g, 67 mmol) was added to water (200 mL) and fully dissolved. Then, sodium hydroxide (8.04 g, 201 mmol) was added to the aqueous solution. The mixture was fully stirred at 25°C and hydrolyzed under nitrogen protection.
[0074] (2) Subsequently, a 717 anion exchange resin column (350 mL) was first rinsed with 1 L of 5% sodium hydroxide solution to make the resin alkaline, and then rinsed with water to pH = 7. The hydrolyzed DL-homocysteine thiolactone hydrochloride solution was then added to the column that had been rinsed to neutrality, and soluble impurities were washed away with 2 L of water. Then, 2 L of 2 mol / L acetic acid solution was added for elution. The entire solution obtained during the acetic acid solution rinse was collected and subjected to rotary evaporation to obtain a white solid, namely DL-homocysteine.
[0075] (3) First, sodium hydroxide (34.2 g, 0.855 mol) was added to the reaction flask, and 95% isopropyl alcohol (1200 mL, about 153 mmol) was added and stirred until completely dissolved, and then the solution was cooled to 25°C.
[0076] (4) Then, about DL-homocysteine (7.0 g, 40.78 mmol) and deuterated iodomethane (36.0 g, 248.34 mmol) were added to 560 mL of the 95% isopropanol sodium hydroxide solution obtained above, and the mixture was slowly stirred for about 14 h. After refluxing for 1 h, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in 40 mL of water.
[0077] (5) In a 717 anion exchange resin chromatography column (350 mL), the resin was first rinsed with 1 L of 5% sodium hydroxide solution until alkaline, then eluted with water to pH = 7, and then 40 mL of the residual aqueous solution obtained in the previous step was added. The 40 mL residual aqueous solution was added to the chromatography column again, and the soluble impurity salts therein were rinsed with 1 L of water, and then eluted with 2 mol 2 L acetic acid solution. All the solution obtained during the acetic acid solution rinse was collected and rotary evaporated to obtain a white solid, which was the preliminary product.
[0078] (6) The obtained white solid was then dissolved in 40 mL of hot water and then crystallized and purified using 95% ethanol (40 mL). A second batch of crystals, i.e., the final product, was obtained from the final mother liquor residue to obtain deuterated methionine product. The product was confirmed to be deuterated methionine by deuterium nuclear resonance magnetic resonance spectroscopy.
[0079] The deuterated methionine prepared in the above example was collected and weighed, and the yield was calculated. The yield was about 79% to 88% (calculated based on deuterated iodomethane).
[0080] Example 4
[0081] This example tests the effect of deuterated methionine as a magnetic resonance imaging contrast agent.
[0082] Methionine-free DMEM was prepared using DMEM (Gibco 21013024, minus glutamine, cysteine, and methionine). L-cystine dihydrochloride, 200 mM liquid l-glutamine, and sodium pyruvate were then added to DMEM to obtain methionine-free DMEM (DMEM Met-free).
[0083] Rat brain glioma cells (C6) and rat normal brain glial cells (CTX-TNA2) were used as comparisons. When C6 and CTX-TNA2 cells reached 80% growth density in the cell culture flask, they were transferred to five groups of 6-well cell culture dishes (n=6). The number of cells was counted before inoculation to ensure that there were 10 cells in each well. 6cells. Once the cells have completely adhered to the 6-well culture dish, wash them twice with phosphate-buffered saline (PBS). The cells were incubated in a mixture of methionine-free DMEM (1900 μL) and 10 mM deuterated methionine (100 μL) solution (dissolved in PBS). Samples were extracted at 0, 6, 24, and 48 hours. At the same time, all cells were digested and counted. The extracted sample was mixed with d4-pyrazine. The mixed solution contained 640 μL of extract and 160 μL of 1 mM d4-pyrazine. Then, 500 μL of the composition was extracted from 800 μL of the mixed solution, transferred to a 5 mm nuclear magnetic resonance tube, and deuterium nuclear resonance spectroscopy was scanned on a magnetic resonance spectrometer. All cell cultures were maintained in a humid environment at 37°C and 5% CO2.
[0084] The deuterium magnetic resonance spectrum was scanned on a Bruker 600MHz nuclear magnetic resonance instrument. The scanning parameters were: TR = 3s, average value = 1024, scan spectrum width SW = 1013.51Hz, sampling point = 1024. The obtained deuterium spectrum was processed in Mestrenova software with line broadening = 0.3Hz and phase correction. The spectrum was then fitted to the mixed Lorentz model. Based on the signal intensity of pyrazine-normalized hemi-heavy water (HDO) and methionine, the content (μmol) of HDO and methionine in each sample was determined. The content of HDO and methionine in each sample was then determined by unit time (hour) and unit cell number (10 6 ) to assess the methionine consumption rate.
[0085] Figure 1 shows the deuterium spectra of the two cells 48 hours after the addition of deuterated methionine. The methionine peak in C6 cells was significantly reduced, indicating that the uptake of methionine by tumor cells is higher than that of normal glial cells. Figure 2 compares the methionine consumption of C6 cells and CTX-TNA2 cells over time. It can be observed that the consumption of deuterated methionine by tumor cells increases over time. After 48 hours of methionine addition, there was a significant difference in consumption between tumor cells and normal cells (P=0.005). In contrast, normal glial cells had almost no uptake throughout the experiment. After normalization to cell number, the methionine consumption rate of C6 tumor cells was also higher than that of glial cells, as shown in Figure 3.
[0086] In summary, the present application designs a new two-step synthesis route for a specific deuterated methionine, which can effectively reduce costs and avoid the problem of oxidation during the storage of DL-homocysteine; using deuterated iodomethane as a deuterium source for the deuteration reaction greatly simplifies the reaction process steps, and can be synthesized under normal conditions at room temperature without the need for expensive catalysts, reducing agents, etc., and the requirements for the synthesis environment are greatly reduced, which is conducive to improving the production efficiency of deuterated methionine and promoting the application of deuterated methionine. The high specific uptake of deuterated methionine in tumor cells in the brain area and the low uptake in normal tissues are used to distinguish, reflecting the vigorous metabolism of tumor tissue areas and tumors. The excellent contrast of the different deuterated methionine uptake in different tissue areas of the brain is demonstrated, proving that it can be used as a magnetic resonance imaging contrast agent for diagnosing brain gliomas.
[0087] The applicant declares that while the above-mentioned embodiments are used to illustrate the detailed methods of the present application, the present application is not limited to the above-mentioned detailed methods, which does not mean that the present application must rely on the above-mentioned detailed methods in order to be implemented. Those skilled in the art should understand that any improvements to the present application, equivalent replacements for the raw materials of the present application's products, addition of auxiliary ingredients, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present application.
Claims
1. A method for preparing deuterated methionine, comprising: DL-homocysteine thiolactone hydrochloride is used as a substrate for hydrolysis reaction to obtain DL-homocysteine; Performing a deuteration reaction using the DL-homocysteine and deuterated iodomethane to obtain the deuterated methionine; The structural formula of the deuterated methionine is shown in Formula I:
2. The method for preparing deuterated methionine according to claim 1, wherein The hydrolysis reaction specifically comprises: DL-homocysteine thiolactone hydrochloride, a first alkaline reagent and a first solvent are mixed to carry out a hydrolysis reaction.
3. The method for preparing deuterated methionine according to claim 2, wherein The first solvent includes water; Preferably, the first alkaline reagent comprises sodium hydroxide and / or potassium hydroxide; Preferably, the molar ratio of DL-homocysteine thiolactone hydrochloride to the base is 1:(3-4); Preferably, the temperature of the hydrolysis reaction is 20-30°C.
4. The method for preparing deuterated methionine according to any one of claims 1 to 3, wherein The deuteration reaction specifically includes: The DL-homocysteine, deuterated iodomethane, a second alkaline reagent and a second solvent are mixed to perform a deuteration reaction.
5. The method for preparing deuterated methionine according to any one of claims 1 to 4, wherein: The second alkaline reagent includes sodium hydroxide and / or potassium hydroxide; Preferably, the second solvent comprises any one of ethanol, methanol or isopropanol or a combination of at least two thereof; Preferably, the molar ratio of DL-homocysteine to deuterated iodomethane is 1:(1-6); Preferably, the temperature of the deuteration reaction is 20-30°C, preferably 20-25°C.
6. The method for preparing deuterated methionine according to any one of claims 1 to 5, wherein: The hydrolysis reaction also includes a first purification step; Preferably, the first purification comprises: performing chromatography on the product of the hydrolysis reaction using an anion exchange resin chromatography column.
7. The method for preparing deuterated methionine according to any one of claims 1 to 6, wherein: The deuteration reaction further includes a second purification step; Preferably, the second purification comprises: The product of the deuterated reaction is chromatographed using an anion exchange resin chromatography column, and the chromatographic substance is crystallized and purified.
8. The method for preparing deuterated methionine according to any one of claims 1 to 7, wherein: The preparation method comprises the following steps: (1) mixing DL-homocysteine thiolactone hydrochloride with water, and then adding sodium hydroxide to carry out a hydrolysis reaction; (2) washing the anion exchange resin chromatography column with a sodium hydroxide solution, and then washing with water, then adding the product of step (1) to the chromatography column, washing with water, and then eluting with an acetic acid solution, collecting the eluate, and drying it to obtain DL-homocysteine; (3) mixing an ethanolic sodium hydroxide solution, deuterated iodomethane, and the DL-homocysteine obtained in step (2) to perform a deuteration reaction; (4) washing the anion exchange resin chromatography column with a sodium hydroxide solution, and then washing with water, adding the product of step (3) to the chromatography column, washing with water, and then eluting with an acetic acid solution, collecting the eluate, and drying it to obtain a preliminary product; and (5) Mixing the preliminary product of step (4) with water, and then performing crystallization purification using ethanol to obtain deuterated methionine.
9. A composition comprising deuterated methionine prepared by the method for preparing deuterated methionine according to any one of claims 1 to 8.
10. Use of the composition according to claim 9 in the preparation of a magnetic resonance imaging contrast agent.