A method for preparing tetra-deuterated ethylene glycol

Abstract

The present invention discloses a method for preparing tetra-deuterated ethylene glycol. By using oxalic acid diester, lithium aluminum tetra-deuteride, tetrahydrofuran and controlling their respective addition amounts, as well as controlling the reaction temperature and reaction time, tetra-deuterated ethylene glycol with a high deuterium substitution degree and a high yield is finally achieved. The deuterium substitution degree of tetra-deuterated ethylene glycol is ≥95%, the yield is ≥60%, and the reaction operation is simple, meeting the requirements of green chemistry, and the process can be scaled up for production.

Description

Technical Field

[0001] The present invention relates to the technical field of deuterated compound production, and particularly relates to a method for preparing tetra-deuterated ethylene glycol. Background Art

[0002] With the increasing understanding of deuterated organic compounds, deuterated organic compounds have become increasingly important. In the field of medicinal chemistry, replacing some hydrogen atoms in drug molecules with deuterium can affect the absorption, distribution, metabolism, and excretion of drugs. These were recognized by scientists in the 1970s and 1980s and applied to drugs in the early 21st century. Due to its unique advantage of improving drug metabolism and pharmacokinetic characteristics, it is now becoming a hot field in new drug development. Deuterated intermediates are one of the keys to deuterated drug synthesis.

[0003] Tetra-deuterated ethylene glycol is a deuterated drug intermediate used in deuterated drug synthesis. For example, in the invention patent "A Method for Deuteration Using a Ruthenium Catalyst" with publication number WO2009005069A1 (application number PCT / JP2008 / 061924), a method for preparing tetra-deuterated ethylene glycol is disclosed. 0.25 mmol of ethylene glycol and 5% Ru / C 20 wt% (15.03 mg) were suspended in 2 mL of heavy water, the hydrogen pressure was maintained at 1 atm, the mixture was heated and stirred at 80 °C for 24 hours. After replacement, tetra-deuterated ethylene glycol was obtained. However, this method requires pressurization, the reaction conditions are relatively harsh, and it is difficult to achieve process amplification. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for preparing tetra-deuterated ethylene glycol with high deuteration degree and high yield.

[0005] The technical solution adopted by the present invention to solve its technical problems is:

[0006] A method for preparing tetra-deuterated ethylene glycol, comprising the following preparation steps:

[0007] 1) Under the protection of a nitrogen atmosphere, add lithium aluminum tetra-deuteride to the reaction kettle, and then dropwise add tetrahydrofuran. During the dropping process, the internal temperature of the reaction kettle is controlled at 0 - 5 °C;

[0008] 2) Prepare a mixed solution of oxalic acid diester and tetrahydrofuran, and then dropwise add the mixed solution to the reaction kettle. During the dropping process, the internal temperature of the reaction kettle is controlled at 0 - 5 °C;

[0009] 3) After the dropping is completed, adjust the internal temperature of the reaction kettle to 60 - 70 °C, and stir and reflux for 3 - 5 h;

[0010] 4) Quench the reaction to obtain a product containing tetra-deuterated ethylene glycol;

[0011] The molecular structural formula of the tetra-deuterated ethylene glycol is

[0012]

[0013] The addition amounts of the oxalic acid diester, lithium tetradeuterium aluminum, and tetrahydrofuran satisfy 1 mol: 1-3 mol: 0.5-3 L.

[0014] The present invention involves a nucleophilic addition reaction. The Al-D bond in lithium tetradeuterium aluminum breaks, and the deuterium atom, carrying a pair of electrons, adds to the carbonyl group of the oxalic acid diester. The product acquires a proton to form a deuterated geminal diol. This intermediate state is unstable and, after losing a molecule of water, yields deuterated glyoxal. A similar reduction reaction then generates tetradeuterated ethylene glycol. The present invention achieves selective deuteration.

[0015] In step 1), lithium tetradeuterium aluminum is added to the reactor, and then tetrahydrofuran is added dropwise to form a dispersion of lithium tetradeuterium aluminum, reducing the risk of violent heat release during solid feeding and facilitating process scale-up. A nitrogen atmosphere is used to protect the reaction from external moisture. During the addition process, the internal temperature of the reactor is controlled at 0-5°C. This reaction is exothermic, and high temperatures increase the risk of side reactions, affecting the reaction yield.

[0016] In step 2), the oxalic acid diester is mixed with tetrahydrofuran to reduce the concentration of the reaction system and mitigate the risk of violent exotherm. The temperature inside the reactor is controlled at 0-5°C. High temperature increases the risk of side reactions and affects the reaction yield.

[0017] In step 3), the internal temperature of the reactor is adjusted to 60-70° C., and the tetrahydrofuran is refluxed to fully allow the nucleophilic addition reaction to increase the reaction yield.

[0018] The addition amount of oxalic acid diester and lithium tetradeuterium aluminum satisfies 1 mol:1-3 mol. Within this range, a balance between yield and cost is achieved.

[0019] The addition amount of oxalic acid diester and tetrahydrofuran satisfies 1 mol: 0.5~3 L. Within this range, it is possible to avoid severe heat release during the reaction and ensure the overall reaction yield.

[0020] Preferably, the amount of tetrahydrofuran used in step 1) accounts for 10-30% of the total volume content of tetrahydrofuran.

[0021] The oxalic acid diester is selected from one of dimethyl oxalate, diethyl oxalate, dipropyl oxalate and dibutyl oxalate.

[0022] In step 1), the dropping rate of tetrahydrofuran is controlled at 0.2 to 0.5 h / L.

[0023] In step 2), the dropping speed of the mixed solution is controlled at 0.2 to 0.5 h / L.

[0024] The operation of the quenching reaction is as follows: adjusting the internal temperature of the reactor to 0-5°C, first adding water dropwise, then adding sodium hydroxide aqueous solution dropwise, and finally adding water dropwise for a second time, wherein the addition amounts of lithium tetradeuterium aluminum, primary water, sodium hydroxide aqueous solution, and secondary water satisfy 1 mol: 0.01-0.1 L: 0.01-0.1 L: 0.1-0.5 L.

[0025] The dropping speed of the primary water is 0.5 to 2 h / L, the dropping speed of the sodium hydroxide aqueous solution is 5 to 20 min / L, and the dropping speed of the secondary water is 2 to 10 min / L.

[0026] The mass concentration of the sodium hydroxide aqueous solution is 10-20%.

[0027] The deuterium substitution degree of tetradeuterium ethylene glycol is ≥95%, and the yield is ≥60%.

[0028] It also includes purification operations, which are specifically:

[0029] Step 4) The obtained product containing tetradeuterium ethylene glycol is filtered to obtain a filtrate, the filtrate is decompressed and concentrated at 40-50° C. until no liquid drips, and the concentrated liquid is added to a distillation kettle for distillation with a vacuum degree of not more than 100 mmbar and an internal temperature of 120-140° C., and tetradeuterium ethylene glycol is collected.

[0030] The obtained product contains tetrahydrofuran, tetradeuterium glycol, water and metaaluminate. The metaaluminate is removed after filtration, and the filtrate is reduced in pressure and concentrated at 40-50° C. until no liquid is dripped. In this process, tetrahydrofuran is removed, and then water and tetradeuterium glycol are separated in a distillation process.

[0031] After the purification operation, the purity of the obtained tetradeuterated ethylene glycol is above 98 wt%.

[0032] The beneficial effects of the present invention are as follows: by controlling the addition amounts of oxalic acid diester, lithium tetradeuterium aluminum, and tetrahydrofuran, as well as the reaction temperature and reaction time, tetradeuterium ethylene glycol with a high deuterium substitution degree and a high yield is finally achieved; the deuterium substitution degree of the tetradeuterium ethylene glycol is ≥95% and the yield is ≥60%, and the reaction operation is simple, meeting the requirements of green chemistry, and enabling process scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The synthetic route of tetradeuterated ethylene glycol of the present invention is as follows;

[0034] Figure 2 This is the GC test data of tetradeuterated ethylene glycol in Example 1 of the present invention;

[0035] Figure 3 This is the nuclear magnetic resonance detection spectrum of the deuterium substitution degree of tetradeuterium ethylene glycol in Example 1 of the present invention. DETAILED DESCRIPTION

[0036] The technical solution of the present invention will be further specifically described below through specific embodiments.

[0037] In the present invention, unless otherwise specified, the raw materials and equipment used can be purchased from the market or are commonly used in the art. The methods in the following embodiments are all conventional methods in the art unless otherwise specified.

[0038] Embodiment:

[0039] The present invention provides 15 embodiments for preparing tetradeuterated ethylene glycol, and the preparation steps are as follows ( Figure 1 ):

[0040] 1) Under the protection of a nitrogen atmosphere, add lithium aluminum tetradeuteride to the reaction kettle, and then dropwise add tetrahydrofuran. During the dropping process, the internal temperature of the reaction kettle is controlled at 0 - 5°C; the dropping rate of tetrahydrofuran is controlled at 0.2 - 0.5 h / L; in each embodiment of the present invention, the amount of tetrahydrofuran used in step 1) accounts for 20% of the total volume of tetrahydrofuran;

[0041] 2) Prepare a mixed solution of oxalic acid diester and the tetrahydrofuran, and then dropwise add the mixed solution to the reaction kettle. During the dropping process, the internal temperature of the reaction kettle is controlled at 0 - 5°C; the dropping rate of the mixed solution is controlled at 0.2 - 0.5 h / L;

[0042] 3) After the dropping is completed, adjust the internal temperature of the reaction kettle to 60 - 70°C, and stir and reflux for 3 - 5 h;

[0043] 4) Quench to obtain a product containing tetradeuterated ethylene glycol; the quenching process is to adjust the internal temperature of the reaction kettle to 0 - 5°C, first dropwise add water once, then dropwise add a sodium hydroxide aqueous solution with a mass content of 10 - 20%, and finally dropwise add water twice. The addition amounts of lithium aluminum tetradeuteride, water once, sodium hydroxide aqueous solution, and water twice satisfy 1 mol: 0.01 - 0.1 L: 0.01 - 0.1 L: 0.05 - 0.5 L. The dropping rate of water once is 0.5 - 2 h / L, the dropping rate of the sodium hydroxide aqueous solution is 5 - 20 min / L, and the dropping rate of water twice is 2 - 10 min / L.

[0044] The oxalic acid diester is selected from one of dimethyl oxalate, diethyl oxalate, dipropyl oxalate, and dibutyl oxalate;

[0045] The addition amounts of the oxalic acid diester, lithium aluminum tetradeuteride, and tetrahydrofuran satisfy 1 mol: 0.5 - 3 mol: 0.5 - 3 L, and the key process parameters are shown in Tables 1 and 2.

[0046] Let the addition amounts of the oxalic acid diester, lithium aluminum tetradeuteride, and tetrahydrofuran satisfy X;

[0047] It is noted that the addition amounts of lithium aluminum deuteride, primary water, aqueous sodium hydroxide solution, and secondary water satisfy Y;

[0048] The obtained products containing ethylene glycol-d4 from 15 examples were purified. The purification method was to filter the obtained products to obtain a filtrate, reduce the pressure of the filtrate and concentrate it at 40 - 50 °C until no more dripping occurred, add the concentrated liquid to a distillation kettle for distillation, with a vacuum degree not higher than 100 mmbar and an internal temperature of 120 - 140 °C, and collect ethylene glycol-d4. The key process parameters are shown in Table 2.

[0049] The obtained examples were subjected to the following tests:

[0050] 1) Deuteration degree:

[0051] The deuteration degree of the obtained examples and comparative examples was detected by nuclear magnetic resonance hydrogen spectroscopy and calculated using the following formula:

[0052]

[0053] Among them, A is the hydrogen peak area of the deuterated sample, D is the deuteration degree, m1 is the added mass of the deuterated sample, in 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, in g, m2 is the added mass of the internal standard, in g, n2 is the number of H atoms in the deuterated sample, and M2 is the relative molecular mass of the internal standard.

[0054] Taking ethylene glycol-d4 of Example 1 as a typical example, the NMR detection spectrum of its deuteration degree is shown in Figure 3 .

[0055] 2) Purity detection: It was detected using a gas chromatograph. Taking ethylene glycol-d4 of Example 1 as a typical example, its GC detection data is shown in Figure 2 .

[0056] 3) Yield detection: The calculation formula is actual obtained weight / theoretically obtained weight * %.

[0057] The analytical data of the ethylene glycol-d4 compound are as follows: 1H NMR (399 MHz, Chloroform-d) δ 5.45 (s, 2H), δ 3.65 (s, 0.02H) MS (EI) 62.04.

[0058] The specific detection results are shown in Table 3.

[0059] Table 1 Key parameter control of the examples for preparing ethylene glycol-d4 in the present invention

[0060]

[0061]

[0062] Table 2 Key parameter control for the preparation and purification of tetradeuterated ethylene glycol in the examples of the present invention

[0063]

[0064] Table 3 Test results of the examples of the present invention

[0065]

[0066]

[0067] The above-described embodiments are only a preferred solution of the present invention and do not impose any form of limitation on the present invention. There are other variations and modifications without exceeding the technical solutions recited in the claims.

Claims

1. A method for preparing tetra-deuterated ethylene glycol, characterized in that: It includes the following preparation steps: 1) Under the protection of a nitrogen atmosphere, add lithium aluminum tetradeuteride to a reaction kettle, and then dropwise add tetrahydrofuran. During the dropping process, the internal temperature of the reaction kettle is controlled at 0 - 5°C; 2) Prepare a mixed solution of oxalic acid diester and tetrahydrofuran, and then dropwise add the mixed solution to the reaction kettle. During the dropping process, the internal temperature of the reaction kettle is controlled at 0 - 5°C; 3) After the dropping is completed, adjust the internal temperature of the reaction kettle to 60 - 70°C, and stir and reflux for 3 - 5 h; 4) Quench the reaction to obtain a product containing tetradeuteroethylene glycol; The molecular structural formula of the tetradeuteroethylene glycol is The addition amounts of the oxalic acid diester, lithium aluminum tetradeuteride, and tetrahydrofuran satisfy 1 mol: 1 - 3 mol: 0.5 - 3 L; The operation of quenching the reaction is: adjust the internal temperature of the reaction kettle to 0 - 5°C, first dropwise add water once, then dropwise add an aqueous sodium hydroxide solution, and finally dropwise add water twice. The addition amounts of lithium aluminum tetradeuteride, water once, the aqueous sodium hydroxide solution, and water twice satisfy 1 mol: 0.01 - 0.1 L: 0.01 - 0.1 L: 0.1 - 0.5 L.

2. The preparation method 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 preparation method according to claim 1, characterized in that: In step 1), the dropping rate of tetrahydrofuran is controlled at 0.2 - 0.5 h / L.

4. The preparation method according to claim 1, characterized in that: In step 2), the dropping rate of the mixed solution is controlled at 0.2 - 0.5 h / L.

5. The preparation method according to claim 1, characterized in that: The dropping rate of the water once is 0.5 - 2 h / L, the dropping rate of the aqueous sodium hydroxide solution is 5 - 20 min / L, and the dropping rate of the water twice is 2 - 10 min / L.

6. The preparation method according to claim 1, characterized in that: The mass concentration of the aqueous sodium hydroxide solution is 10 - 20%.

7. The preparation method according to any one of claims 1-6, characterized in that: It also includes a purification operation, and the purification operation is specifically as follows: The product containing tetradeuteroethylene glycol obtained in step 4) is filtered to obtain a filtrate. The filtrate is decompressed and concentrated at 40 - 50°C until no more drops fall. The concentrated liquid is added to a distillation kettle for distillation. The vacuum degree is not higher than 100 mmbar, and the internal temperature is 120 - 140°C. Collect tetradeuteroethylene glycol.

8. The preparation method according to claim 7, characterized in that: After the purification operation, the purity of the obtained tetradeuteroethylene glycol is above 98 wt%.

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