A preparation method of hydroxy-deuterated straight-chain alcohol

Abstract

The present invention discloses a method for preparing a hydroxy-deuterated linear alcohol. The method uses a carbonate as a substrate and heavy water as a deuterium source to carry out a deuteration reaction in the presence of a base catalyst to obtain the hydroxy-deuterated linear alcohol. The method achieves a high degree of deuteration, a high yield, and produces only CO2 as a byproduct.

Description

Technical Field

[0001] The present invention relates to the technical field of deuterated compound production, and in particular to a method for preparing hydroxy-deuterated straight-chain alcohol. Background Art

[0002] Deuterated compounds, due to the introduction of the isotope deuterium, have a molecular weight change, thus providing a labeling effect. Furthermore, CD bonds are shorter and more stable than C-H bonds, requiring higher activation energies for their cleavage, resulting in lower kinetic reaction rates. This difference in kinetic reaction rates caused by deuteration is known as the deuterium kinetic isotope effect. With increasing knowledge of deuterated organic compounds, they are becoming increasingly important. Deuterated compounds are widely used in fields such as NMR (Nuclear Magnetic Resonance) analysis, life sciences, food safety, and materials science. In NMR analysis, deuterated compounds can serve as NMR solvents, dissolving and diluting analytes while avoiding the introduction of interfering hydrogen signals and providing a lock field for NMR measurements. In the life sciences, the labeling effect of deuterated compounds, combined with tandem mass spectrometry, enables the study of the absorption, distribution, metabolism, and excretion (ADME) processes of drug molecules in vivo. Furthermore, the deuterium kinetic isotope effect, resulting from the introduction of deuterium, can alter the pharmacokinetics and metabolic pathways of drug molecules, enabling the improvement and development of new drugs. Using deuterated clenbuterol and deuterated Sudan red as internal standards can detect illegal additives in food, thus regulating food safety. Furthermore, due to the stability of CD bonds, optoelectronic materials synthesized using deuterated compounds have a longer luminescence lifetime.

[0003] Deuterium-methanol (CH3OD) and deuterium-ethanol (CH3CH2OD) are deuterated compounds formed by isotope-dextrin substitution of the hydroxyl groups of methanol and ethanol, respectively. They possess unique physical and chemical properties and are widely used in fields such as material synthesis and pharmaceutical research and development, with demand increasing daily.

[0004] For example, the Chinese invention patent "A Method for Preparing Monodeuterated Ethanol" with publication number CN115572211A (application number 202211156086.8) discloses that a compound containing an ethoxy group is mixed with heavy water and then placed in a protective atmosphere for hydrolysis to obtain monodeuterated ethanol. The hydrolysis reaction can also be carried out under base catalysis. The ethoxy group-containing compound is at least one of ethyl formate, ethyl acetate, ethyl silicate, sodium ethoxide, and potassium ethoxide. Although this method can produce monodeuterated ethanol, it has the following shortcomings:

[0005] 1) When ethyl formate, ethyl acetate, and ethyl silicate are used as substrates, in the absence of base catalysis, the reaction product, in addition to monodeuterated ethanol, is produced as a byproduct, including formic acid, acetic acid, and silicic acid, which increases the difficulty of subsequent purification and reduces the reaction yield. When base catalysis is used, such as with sodium deuterium oxide mentioned in the examples, the reaction product, in addition to monodeuterated ethanol, is produced as a byproduct, including sodium formate, sodium acetate, and sodium silicate. These byproducts are solid salts that will encapsulate heavy water, which increases the difficulty of separation and reduces the reaction yield. In addition, the reaction system thickens, reducing the reaction rate.

[0006] 2) When sodium ethoxide or potassium ethoxide is used as a substrate, the reaction product is monodeuterated ethanol, and the by-products are sodium hydroxide and potassium hydroxide, respectively. The continuously generated sodium hydroxide and potassium hydroxide will act as catalysts, causing the reaction system to accelerate, increase heat release, and thicken the reaction system. The uncontrollable factors of the reaction system increase, and the subsequent purification difficulty is increased, and the reaction yield is reduced. Summary of the Invention

[0007] The object of the present invention is to provide a method for preparing hydroxy-deuterated straight-chain alcohols, which has a high degree of deuteration, a high yield and produces only CO2 as a by-product.

[0008] The technical solution adopted by the present invention to solve its technical problem is:

[0009] A method for preparing a hydroxy-deuterated straight-chain alcohol, comprising: using a carbonate as a substrate and heavy water as a deuterium source, and carrying out a deuteration reaction in the presence of a base catalyst to obtain the hydroxy-deuterated straight-chain alcohol;

[0010] The molecular structural formula of the carbonate is: RO-CO-OR, wherein R=CH3(CH2)n, n=0, 1, 2, 3, 4 or 5; the molecular structural formula of the hydroxydeuterated straight-chain alcohol is: CH3-(CH2)n-OD, n=0, 1, 2, 3, 4 or 5.

[0011] The reaction formula is

[0012] Preferably, the carbonate is dimethyl carbonate, the deuteration reaction temperature is 50-90° C., and the reaction time is 20 h-50 h. In this case, the product is hydroxydeuterated methanol.

[0013] Preferably, the carbonate is diethyl carbonate, the deuteration reaction temperature is 60-100° C., and the reaction time is 12 h to 36 h. In this case, the product is hydroxydeuterated ethanol.

[0014] Preferably, the molar ratio of carbonate ester to heavy water is 1:1-10.

[0015] Preferably, the amount of the base catalyst is 1%-10% of the total weight of the carbonate ester+heavy water.

[0016] Preferably, the base catalyst is selected from potassium carbonate, sodium carbonate and cesium carbonate.

[0017] The beneficial effects of the present invention are as follows: carbonate is used as a substrate and heavy water is used as a deuterium source. Under the action of an alkali catalyst, in addition to obtaining a hydroxydeuterated straight-chain alcohol, only carbon dioxide byproduct is generated. The byproduct leaves the reaction system as soon as it is generated, thereby ensuring that, in addition to the raw materials (carbonate, heavy water, alkali catalyst) and the deuterated product, no other byproducts are present in the crude reaction product, greatly reducing the difficulty of subsequent purification, that is, ensuring the deuteration degree of the product and improving the yield. The deuteration degree is above 99.0%, and the yield is above 95.0%. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 This is the nuclear magnetic resonance detection spectrum of the deuterium substitution degree of hydroxydeuterated methanol in Example 1 of the present invention.

[0019] Figure 2 This is the NMR detection spectrum of the deuterium substitution degree of hydroxydeuterated ethanol in Example 6 of the present invention. DETAILED DESCRIPTION

[0020] The technical solution of the present invention is further described in detail below through specific embodiments.

[0021] 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 examples, unless otherwise specified, are all conventional methods in the art.

[0022] The present invention provides 10 embodiments, wherein embodiments 1-5 are methods for preparing hydroxydeuterated methanol, and embodiments 6-10 are methods for preparing hydroxydeuterated ethanol. Specific key preparation parameters are shown in Table 1.

[0023] Examples 1-5 are methods for preparing hydroxydeuterated methanol. Specifically, the reaction system comprises a carbonate, heavy water, and an alkaline catalyst. The alkaline catalyst and heavy water are first mixed, and then the carbonate is added dropwise to the heavy water. The carbonate is dimethyl carbonate. The reaction temperature is 50-90°C, the reaction time is 20-50 hours, the molar ratio of carbonate to heavy water is 1:1-10, and the amount of catalyst added is 1%-10% of the total mass of the carbonate and heavy water. Key process parameters are shown in Table 1.

[0024] The H NMR spectrum of the hydroxydeuterated methanol prepared in Example 1 is characterized as follows: 1 H NMR (399MHz, CD3OD) δ = 4.91–4.86 (m, 1H), 3.31 (s, 299H).

[0025] Examples 6-10 provide methods for preparing hydroxydeuterated ethanol. Specifically, the reaction system comprises a carbonate, heavy water, and an alkaline catalyst. The alkaline catalyst and heavy water are first mixed and reacted under a nitrogen atmosphere. The carbonate is diethyl carbonate. The reaction temperature is 60-100°C, the reaction time is 12-36 hours, the molar ratio of carbonate to heavy water is 1:1-10, and the amount of catalyst added is 1%-10% of the total mass of the carbonate and heavy water. Key process parameters are shown in Table 1.

[0026] The H NMR spectrum of the hydroxydeuterated ethanol prepared in Example 6 is characterized as follows: 1 H NMR (399MHz, DMSO) δ4.39 (s, 1H), 3.43 (d, J = 7.0Hz, 199H), 1.05 (t, J = 7.0Hz, 300H).

[0027] The difference between Comparative Example 1 and Example 6 is that ethyl formate is used instead of diethyl carbonate (Example 6 uses diethyl carbonate), so hydroxydeuterated ethanol is obtained and formic acid is the by-product.

[0028] The difference between Comparative Example 2 and Example 6 is that sodium ethoxide is used instead of diethyl carbonate (Example 6 uses diethyl carbonate), so hydroxydeuterated ethanol is obtained and the by-product is sodium salt.

[0029] The following tests were performed on the obtained embodiments:

[0030] 1) The deuterium substitution degree was detected by hydrogen nuclear magnetic resonance spectroscopy and calculated using the following formula:

[0031]

[0032] Wherein, A is the hydrogen peak area of ​​the deuterated sample, D is the degree of deuteration, 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.

[0033] 2) Yield detection: The calculation formula is theoretical weight / actual weight*%.

[0034] The specific test results are shown in Table 2.

[0035] Table 1 Key process parameter control of the embodiment of the present invention

[0036]

[0037]

[0038] Table 2 Detection performance of the embodiment of the present invention

[0039] serial number Deuterium substitution degree / % Yield / % Example 1 99.8 97.3 Example 2 99.5 96.8 Example 3 99.2 95.8 Example 4 99.8 96.3 Example 5 99.5 97.2 Example 6 99.3 98.2 Example 7 99.4 98.6 Example 8 99.6 98.8 Example 9 99.5 97.3 Example 10 99.5 96.8 Comparative Example 1 99.2 89.2 Comparative Example 2 99.3 93.4 .

[0040] The embodiment described above is only a preferred solution of the present invention and does not limit the present invention in any form. Other variations and modifications are possible without exceeding the technical solution described in the claims.

Claims

1. A method for preparing a hydroxydeuterated straight-chain alcohol, characterized in that: Using carbonate as substrate and heavy water as deuterium source, deuteration reaction is carried out in the presence of base catalyst to obtain hydroxy-deuterated straight-chain alcohol; The molecular formula of the carbonate is: RO-CO-OR, wherein R=CH3(CH2)n, n=0, 1, 2, 3, 4 or 5; the molecular formula of the hydroxydeuterated linear alcohol is: CH3-(CH2)n-OD, n=0, 1, 2, 3, 4 or 5; The molar ratio of the carbonate ester to heavy water is 1:1-10; The amount of the base catalyst is 1%-10% of the total weight of carbonate + heavy water; The base catalyst is selected from one of potassium carbonate, sodium carbonate and cesium carbonate.

2. The preparation method according to claim 1, wherein: The carbonate is dimethyl carbonate, the deuteration reaction temperature is 50-90° C., and the reaction time is 20 h to 50 h.

3. The preparation method according to claim 1, wherein: The carbonate is diethyl carbonate, the deuteration reaction temperature is 60-100° C., and the reaction time is 12 h to 36 h.

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