CN117247313A - Preparation method of tetradeuterium glycol - Google Patents
Preparation method of tetradeuterium glycol Download PDFInfo
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- CN117247313A CN117247313A CN202311206314.2A CN202311206314A CN117247313A CN 117247313 A CN117247313 A CN 117247313A CN 202311206314 A CN202311206314 A CN 202311206314A CN 117247313 A CN117247313 A CN 117247313A
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- Prior art keywords
- tetradeuterium
- ethylene glycol
- dripping
- reaction kettle
- tetrahydrofuran
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- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 title claims abstract description 103
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 title claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 50
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 24
- 235000006408 oxalic acid Nutrition 0.000 claims abstract description 16
- -1 oxalic acid diester Chemical class 0.000 claims abstract description 15
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 229910001148 Al-Li alloy Inorganic materials 0.000 claims abstract description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000007864 aqueous solution Substances 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- 230000001105 regulatory effect Effects 0.000 claims description 7
- JKRZOJADNVOXPM-UHFFFAOYSA-N Oxalic acid dibutyl ester Chemical compound CCCCOC(=O)C(=O)OCCCC JKRZOJADNVOXPM-UHFFFAOYSA-N 0.000 claims description 6
- 238000011403 purification operation Methods 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 230000000171 quenching effect Effects 0.000 claims description 6
- 230000001276 controlling effect Effects 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 4
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 claims description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 claims description 3
- HZHMMLIMOUNKCK-UHFFFAOYSA-N dipropyl oxalate Chemical compound CCCOC(=O)C(=O)OCCC HZHMMLIMOUNKCK-UHFFFAOYSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 abstract description 2
- 238000001514 detection method Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 229910052805 deuterium Inorganic materials 0.000 description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 3
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- FCVHBUFELUXTLR-UHFFFAOYSA-N [Li].[AlH3] Chemical group [Li].[AlH3] FCVHBUFELUXTLR-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000005935 nucleophilic addition reaction Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LYCAIKOWRPUZTN-LNLMKGTHSA-N 1,1,2,2-tetradeuterioethane-1,2-diol Chemical compound [2H]C([2H])(O)C([2H])([2H])O LYCAIKOWRPUZTN-LNLMKGTHSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002271 geminal diols Chemical class 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
The invention discloses a preparation method of tetradeuterium ethylene glycol, which is characterized in that the tetradeuterium ethylene glycol with high deuteration degree and high yield is finally realized by oxalic acid diester, tetradeuterium aluminum lithium and tetrahydrofuran and controlling the respective addition amount, the reaction temperature and the reaction time, the deuteration degree of the tetradeuterium ethylene glycol is more than or equal to 95 percent, the yield is more than or equal to 60 percent, the reaction operation is simple, the requirements of green chemistry are met, and the amplified production of the process can be realized.
Description
Technical Field
The invention relates to the technical field of deuterated compound production, in particular to a preparation method of tetradeuterium ethylene glycol.
Background
As knowledge of deuterium containing organics increases, deuterium containing organics become increasingly important. In the field of pharmaceutical chemistry, substitution of deuterium for part of the hydrogen of a drug molecule affects the absorption, distribution, metabolism and excretion of the drug, which was recognized by scientists in the 70 s and 80 s of the 20 th century and was applied to the drug in the beginning of the 21 st century, which is now becoming a popular field for new drug development due to its unique advantages of improving the metabolic and pharmacokinetic characteristics of the drug. Deuterated intermediates are one of the keys in deuterated drug synthesis.
Tetradeuterated ethylene glycol is a deuterated drug intermediate for deuterated drug synthesis, as in the invention patent publication No. WO2009005069A1 (application No. PCT/JP 2008/061924) for deuteration using ruthenium catalyst, in which a method for preparing tetradeuterated ethylene glycol is disclosed, 0.25mmol of ethylene glycol and 5% ru/C20 wt% (15.03 mg) are suspended in 2mL of heavy water, the hydrogen pressure is maintained at 1atm, the mixture is heated and stirred at 80 ℃ for 24 hours, and after displacement, tetradeuterated ethylene glycol is obtained, but the method requires pressurization, the reaction conditions are severe, and process amplification is difficult to achieve.
Disclosure of Invention
The invention aims to provide a preparation method of tetradeuterium ethylene glycol, which has high deuteration degree and high yield.
The technical scheme adopted for solving the technical problems is as follows:
the preparation method of the tetradeuterium glycol comprises the following preparation steps:
1) Adding lithium tetradeuterium aluminum into a reaction kettle under the protection of nitrogen atmosphere, then dropwise adding tetrahydrofuran, and controlling the internal temperature of the reaction kettle to be 0-5 ℃ in the dropwise adding process;
2) Preparing a mixed solution of oxalic acid diester and tetrahydrofuran, and then dripping the mixed solution into a reaction kettle, wherein the internal temperature of the reaction kettle is controlled to be 0-5 ℃ in the dripping process;
3) After the dripping is finished, regulating the internal temperature of the reaction kettle to be 60-70 ℃, stirring and refluxing, and reacting for 3-5 h;
4) Quenching reaction to obtain a tetradeuterium ethylene glycol-containing product;
the molecular structural formula of the tetradeuterium ethylene glycol is
The addition amount of the oxalic acid diester, the lithium aluminum tetradeuterium and the tetrahydrofuran is 1mol: 1-3 mol: 0.5-3L.
The invention is nucleophilic addition reaction, al-D bond in tetradeuterium aluminum lithium is broken, at the same time, deuterium atom carries a pair of electron pair oxalic acid diester carbonyl addition, product gets a proton to generate deuterated gem-diol, the intermediate state is unstable, deuterium glyoxal is obtained after losing a molecule of water, and then tetradeuterium glycol is generated by a round of similar reduction reaction. By the reaction of the present invention, selective deuteration is achieved.
In the step 1), the tetradeuterium aluminum lithium is added into a reaction kettle, and then tetrahydrofuran is added dropwise, so that the tetradeuterium aluminum lithium forms a dispersion, the risk of violent heat release of solid feeding is reduced, and the process amplification is facilitated. The nitrogen atmosphere is protected from the interference of external moisture on the reaction. The internal temperature of the reaction kettle is controlled to be 0-5 ℃ in the dropping process, the reaction is exothermic, the temperature is high, the risk of side reaction is increased, and the reaction yield is affected.
In the step 2), oxalic acid diester is mixed with tetrahydrofuran, so that the concentration of a reaction system is reduced, and the risk of violent heat release of the reaction is slowed down. The internal temperature of the reaction kettle is controlled to be 0-5 ℃, and the high temperature has the risk of increasing side reactions and affecting the reaction yield.
In the step 3), the internal temperature of the reaction kettle is regulated to be 60-70 ℃, and the nucleophilic addition reaction is fully performed while the tetrahydrofuran is refluxed, so that the reaction yield is improved.
The addition amount of the oxalic acid diester and the tetradeuterium aluminum lithium satisfies 1mol:1 to 3mol, and in this range, the yield and the cost are balanced.
The addition amount of oxalic acid diester and tetrahydrofuran satisfies 1mol: within this range, 0.5 to 3L can prevent the intense heat release during the reaction and ensure the overall reaction yield.
Preferably, the tetrahydrofuran in the step 1) accounts for 10 to 30 percent of the total volume content of the tetrahydrofuran.
The oxalic acid diester is selected from one of dimethyl oxalate, diethyl oxalate, dipropyl oxalate and dibutyl oxalate.
In the step 1), the dropping speed of tetrahydrofuran is controlled to be 0.2-0.5 h/L.
In the step 2), the dropping speed of the mixed solution is controlled to be 0.2-0.5 h/L.
The quenching reaction is operated as follows: the internal temperature of the reaction kettle is regulated to be 0-5 ℃, primary water is firstly dripped, then sodium hydroxide aqueous solution is dripped, and finally secondary water is dripped, wherein the addition amounts of tetradeuterium aluminum lithium, primary water, sodium hydroxide aqueous solution and secondary water satisfy 1mol:0.01 to 0.1L:0.01 to 0.1L: 0.1-0.5L.
The dripping speed of the primary water is 0.5-2 h/L, the dripping speed of the sodium hydroxide aqueous solution is 5-20 min/L, and the dripping speed of the secondary water is 2-10 min/L.
The mass concentration of the sodium hydroxide aqueous solution is 10-20%.
The deuteration degree of tetradeuterium glycol is more than or equal to 95%, and the yield is more than or equal to 60%.
The method also comprises a purification operation, wherein the purification operation is specifically as follows:
filtering the obtained product containing tetradeuterium ethylene glycol obtained in the step 4) to obtain filtrate, decompressing the filtrate, concentrating the filtrate at 40-50 ℃ until no dripping is caused, adding the concentrated liquid into a rectifying still for rectifying, wherein the vacuum degree is not higher than 100mmbar, the internal temperature is 120-140 ℃, and collecting the tetradeuterium ethylene glycol.
The obtained product contains tetrahydrofuran, tetradeuterium glycol, water and meta-aluminate, the meta-aluminate is removed after filtration, the filtrate is decompressed and concentrated at 40-50 ℃ until no dropping liquid is produced, the tetrahydrofuran is removed in the process, and then the water and the tetradeuterium glycol are separated in the rectification process.
After the purification operation, the purity of the obtained tetradeuterium ethylene glycol is more than 98 wt%.
The beneficial effects of the invention are as follows: the high-deuteration and high-yield tetradeuterated ethylene glycol is finally realized by controlling the respective addition amount of oxalic acid diester, tetradeuterated aluminum lithium and tetrahydrofuran and controlling the reaction temperature and the reaction time, the deuteration degree of the tetradeuterated ethylene glycol is more than or equal to 95 percent, the yield is more than or equal to 60 percent, the reaction operation is simple, the requirements of green chemistry are met, and the amplified production of the process can be realized.
Drawings
FIG. 1 is a synthetic route diagram of tetradeuterium ethylene glycol of the present invention;
FIG. 2 is GC detection data of tetradeuterium ethylene glycol of example 1 of the present invention;
FIG. 3 is a nuclear magnetic resonance spectrum of deuteration degree of tetra-deuterated ethylene glycol according to example 1 of the present invention.
Detailed Description
The technical scheme of the invention is further specifically described by the following specific examples.
In the present invention, the materials and equipment used are commercially available or commonly used in the art, unless otherwise specified. The methods in the following examples are conventional in the art unless otherwise specified.
Examples:
the present invention provides 15 examples of the preparation of tetradeuterium ethylene glycol, the preparation steps are as follows (fig. 1):
1) Adding lithium tetradeuterium aluminum into a reaction kettle under the protection of nitrogen atmosphere, then dropwise adding tetrahydrofuran, and controlling the internal temperature of the reaction kettle to be 0-5 ℃ in the dropwise adding process; the dropping speed of tetrahydrofuran is controlled to be 0.2-0.5 h/L; in the embodiments of the invention, the tetrahydrofuran in the step 1) accounts for 20% of the total volume of the tetrahydrofuran;
2) Preparing a mixed solution of oxalic acid diester and tetrahydrofuran, and then dripping the mixed solution into a reaction kettle, wherein the internal temperature of the reaction kettle is controlled to be 0-5 ℃ in the dripping process; the dropping speed of the mixed solution is controlled to be 0.2-0.5 h/L;
3) After the dripping is finished, regulating the internal temperature of the reaction kettle to be 60-70 ℃, stirring and refluxing, and reacting for 3-5 hours;
4) Quenching to obtain a tetradeuterium ethylene glycol-containing product; the quenching process comprises the steps of regulating the internal temperature of a reaction kettle to be 0-5 ℃, firstly dropwise adding primary water, then dropwise adding sodium hydroxide aqueous solution with the mass content of 10-20%, and finally dropwise adding secondary water, wherein the addition amount of the lithium aluminum tetradeuterium, the primary water, the sodium hydroxide aqueous solution and the secondary water satisfies 1mol:0.01 to 0.1L:0.01 to 0.1L: 0.05-0.5L. The dripping speed of the primary water is 0.5-2 h/L, the dripping speed of the sodium hydroxide aqueous solution is 5-20 min/L, and the dripping speed of the secondary water is 2-10 min/L.
The oxalic acid diester is selected from one of dimethyl oxalate, diethyl oxalate, dipropyl oxalate and dibutyl oxalate;
the addition amount of the oxalic acid diester, the tetradeuterium aluminum lithium and the tetrahydrofuran is 1mol:0.5 to 3mol: 0.5-3L, and key technological parameters are shown in tables 1 and 2.
Recording the addition amount of oxalic acid diester, tetradeuterium aluminum lithium and tetrahydrofuran to meet X;
recording the addition amount of lithium aluminum tetradeuterium, primary water, sodium hydroxide aqueous solution and secondary water to meet Y;
purifying the obtained product containing the tetradeuterium ethylene glycol obtained in 15 examples, wherein the purification method is to filter the obtained product to obtain filtrate, decompress the filtrate and concentrate the filtrate to be free from dripping at the temperature of 40-50 ℃, adding the concentrated liquid into a rectifying kettle for rectifying, wherein the vacuum degree is not higher than 100mmbar, the internal temperature is 120-140 ℃, and collecting the tetradeuterium ethylene glycol. The key process parameters are shown in Table 2.
The following tests were carried out on the examples obtained:
1) Degree of deuteration:
deuteration degree detection is carried out on the obtained examples and comparative examples by adopting a nuclear magnetic resonance hydrogen spectrum method, and the deuteration degree detection is calculated by adopting the following formula:
wherein A is the hydrogen peak area of the deuterated sample, D is the deuteration degree, M1 is the added mass of the deuterated sample, the unit is g, n1 is the number of H atoms to be deuterated in the deuterated sample, M1 is the relative molecular mass of the sample before deuteration, the unit is g, M2 is the added mass of the internal standard, the unit is g, n2 is the number of H atoms in the deuterated sample, and M2 is the relative molecular mass of the internal standard.
Example 1 tetradeuterium ethylene glycol is used as a typical example, and the nuclear magnetic detection pattern of deuteration degree is shown in fig. 3.
2) And (3) purity detection: and detecting by adopting a gas chromatograph. Example 1 tetradeuterium ethylene glycol is used as a typical example, and the GC detection data thereof is shown in fig. 2.
3) And (3) yield detection: the calculation formula is the actual weight/theoretical weight.
The tetradeuterium ethylene glycol (ethylene glycol-d 4) compound analysis data is as follows: 1H NMR (399 MHz, chloro form-d) δ5.45 (s, 2H), δ3.65 (s, 0.02H) MS (EI) 62.04.
The specific detection results are shown in Table 3.
TABLE 1 critical parameter control for the inventive examples of preparation of tetradeuterium ethylene glycol
TABLE 2 critical parameter control for the preparation and purification of the tetradeuterium ethylene glycol examples of the present invention
TABLE 3 detection results of the examples of the present invention
The above-described embodiment is only a preferred embodiment of the present invention, and is not limited in any way, and other variations and modifications may be made without departing from the technical aspects set forth in the claims.
Claims (9)
1. A preparation method of tetradeuterium glycol is characterized in that: the preparation method comprises the following preparation steps:
1) Adding lithium tetradeuterium aluminum into a reaction kettle under the protection of nitrogen atmosphere, then dropwise adding tetrahydrofuran, and controlling the internal temperature of the reaction kettle to be 0-5 ℃ in the dropwise adding process;
2) Preparing a mixed solution of oxalic acid diester and tetrahydrofuran, and then dripping the mixed solution into a reaction kettle, wherein the internal temperature of the reaction kettle is controlled to be 0-5 ℃ in the dripping process;
3) After the dripping is finished, regulating the internal temperature of the reaction kettle to be 60-70 ℃, stirring and refluxing, and reacting for 3-5 h;
4) Quenching reaction to obtain a tetradeuterium ethylene glycol-containing product;
the molecular structural formula of the tetradeuterium ethylene glycol is
The addition amount of the oxalic acid diester, the lithium aluminum tetradeuterium and the tetrahydrofuran is 1mol: 1-3 mol: 0.5-3L.
2. The method of manufacturing according to claim 1, characterized in that: the oxalic acid diester is selected from one of dimethyl oxalate, diethyl oxalate, dipropyl oxalate and dibutyl oxalate.
3. The method of manufacturing according to claim 1, characterized in that: in the step 1), the dropping speed of tetrahydrofuran is controlled to be 0.2-0.5 h/L.
4. The method of manufacturing according to claim 1, characterized in that: in the step 2), the dropping speed of the mixed solution is controlled to be 0.2-0.5 h/L.
5. The method of manufacturing according to claim 1, characterized in that: the quenching reaction is operated as follows: the internal temperature of the reaction kettle is regulated to be 0-5 ℃, primary water is firstly dripped, then sodium hydroxide aqueous solution is dripped, and finally secondary water is dripped, wherein the addition amounts of tetradeuterium aluminum lithium, primary water, sodium hydroxide aqueous solution and secondary water satisfy 1mol:0.01 to 0.1L:0.01 to 0.1L: 0.1-0.5L.
6. The method of manufacturing according to claim 5, wherein: the dripping speed of the primary water is 0.5-2 h/L, the dripping speed of the sodium hydroxide aqueous solution is 5-20 min/L, and the dripping speed of the secondary water is 2-10 min/L.
7. The method of manufacturing according to claim 5, wherein: the mass concentration of the sodium hydroxide aqueous solution is 10-20%.
8. The method of any one of claims 1-7, wherein: the method also comprises a purification operation, wherein the purification operation is specifically as follows:
filtering the obtained product containing tetradeuterium ethylene glycol obtained in the step 4) to obtain filtrate, decompressing the filtrate, concentrating the filtrate at 40-50 ℃ until no dripping is caused, adding the concentrated liquid into a rectifying still for rectifying, wherein the vacuum degree is not higher than 100mmbar, the internal temperature is 120-140 ℃, and collecting the tetradeuterium ethylene glycol.
9. The method according to any one of claims 8, wherein: after the purification operation, the purity of the obtained tetradeuterium ethylene glycol is more than 98 wt%.
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