Deuterium selectively-labeled methyl zinc acetate hydrate as well as synthesis method and application of deuterium selectively-labeled methyl zinc acetate hydrate

Abstract

The invention provides deuterium selectively labeled methyl zinc acetate hydrate as well as a synthesis method and application thereof, belongs to isotope reagent preparation, and is characterized in that a zinc acetate hydrate crystal with a fully labeled signal is prepared from deuterium fully labeled acetic acid, water and zinc oxide. The deuterium selectively labeled methyl zinc acetate hydrate crystal is further prepared from the zinc acetate hydrate crystal with a full-labeled signal and water. Compared with the prior art, the invention designs a simple and feasible synthetic route of deuterium selectively-labeled methyl zinc acetate hydrate, and the route can realize preparation of deuterium selectively-labeled methyl zinc acetate hydrate and fully-labeled zinc acetate hydrate (the fully-labeled zinc acetate hydrate is an intermediate product).

Description

Technical Field

[0001] The present invention relates to the technical field of isotope reagents, and particularly relates to a deuterium-selectively labeled zinc acetate hydrate with a methyl position, a synthesis method thereof, and an application thereof. Background Art

[0002] Deuterated compounds have important applications in aspects such as mechanism research in metabolomics, proteomics, and synthetic chemistry. Since the C-D bond is more stable than the C-H bond, it can significantly improve the in vivo metabolic stability and biological half-life of deuterated drugs. Selective D-labeling reagents are often difficult in the field of isotope reagent synthesis due to the limited availability of raw materials.

[0003] The synthesis of zinc acetate hydrate with natural abundance (natural abundance refers to the abundances of the three isotopes of hydrogen, protium, deuterium, and tritium in nature, where the abundance of protium is approximately 99.98%, the abundance of deuterium is approximately 0.016%, and the abundance of tritium is equivalent to the concentration of 1 tritium atom in 10 18 hydrogen atoms) mostly uses glacial acetic acid (acetic acid), water, and zinc salt as raw materials, reacts under normal temperature and pressure, and is obtained after drying to remove water. For example, CN113620800B proposes a method for preparing zinc acetate hydrate by reacting a diethylzinc n-hexane solution with glacial acetic acid.

[0004] In the synthesis of natural zinc acetate hydrate, water (water with natural abundance) is used as a solvent, and glacial acetic acid reacts with a zinc salt. This reaction releases heat and causes the solution temperature to rise. After the reaction has proceeded for a period of time to form a saturated solution of zinc acetate (zinc acetate), the temperature of the solution is lowered, so that the zinc acetate solution changes from a saturated solution to a supersaturated solution and crystallizes zinc acetate hydrate. Subsequently, if the precipitated crystals of zinc acetate hydrate are dehydrated, anhydrous zinc acetate crystals can be obtained.

[0005] However, when the raw material glacial acetic acid is replaced with deuterium fully labeled acetic acid (deuterated acetic acid), the original process cannot obtain a deuterium-selectively labeled zinc acetate hydrate product with a methyl position. The combined water in the obtained zinc acetate hydrate product also has a D abundance of 40 - 50 atom%, and a single-labeled zinc acetate hydrate with a methyl position cannot be obtained. The above-mentioned preparation process of natural abundance water and zinc acetate is not applicable to the preparation of zinc acetate hydrate with a deuterated methyl position. Summary of the Invention

[0006] The object of the present invention is to solve the above problems by providing a zinc acetate hydrate with deuterium selectively labeled at the methyl position, its synthesis method and application. Based on the problem of the lack of methods in the synthesis process of zinc acetate hydrate with deuterium selectively labeled at the methyl position, a synthesis method of zinc acetate hydrate with deuterium selectively labeled at the methyl position is provided. Zinc acetate hydrate crystals with fully labeled signals are prepared by using deuterium fully labeled acetic acid, water and zinc oxide, and the zinc acetate hydrate crystals with deuterium selectively labeled at the methyl position are further prepared by using the zinc acetate hydrate crystals with fully labeled signals and water.

[0007] The object of the present invention is achieved by the following technical solutions:

[0008] The first object of the present invention is to provide a synthesis method of zinc acetate hydrate with deuterium selectively labeled at the methyl position, and the synthesis method includes the following steps:

[0009] (1) Zinc acetate hydrate with fully labeled signals is prepared by using deuterium fully labeled acetic acid, water and zinc oxide;

[0010] (2) The zinc acetate hydrate with deuterium selectively labeled at the methyl position is prepared by using the zinc acetate hydrate with fully labeled signals obtained in step (1) and water.

[0011] Furthermore, the zinc acetate hydrate with fully labeled signals in step (1) is zinc acetate hydrate crystals with fully labeled signals, and the zinc acetate hydrate with deuterium selectively labeled at the methyl position in step (2) is zinc acetate hydrate crystals with deuterium selectively labeled at the methyl position.

[0012] Furthermore, the synthesis method specifically includes the following steps:

[0013] (1) Synthesis of zinc acetate hydrate with deuterium selectively labeled at the methyl position

[0014] Mix deuterium fully labeled acetic acid and water, stir and heat to obtain a uniformly mixed solution, then add zinc oxide to the uniformly mixed solution, react at the first reaction temperature to obtain a first solution, and then perform first crystallization to obtain zinc acetate hydrate crystals with fully labeled signals;

[0015] (2) Dilution of the crystal water abundance of zinc acetate hydrate with deuterium selectively labeled at the methyl position

[0016] Heat and stir the zinc acetate hydrate crystals with fully labeled signals obtained in step (1) and water with natural abundance at the second reaction temperature to dissolve the zinc acetate hydrate crystals with fully labeled signals to obtain a second solution, and then perform second crystallization to obtain zinc acetate hydrate crystals with deuterium selectively labeled at the methyl position.

[0017] Furthermore, in step (1), the first reaction temperature is 50 - 90 °C.

[0018] Further, in step (1), the first reaction temperature is preferably 70 °C.

[0019] Further, in step (2), the second reaction temperature is 50 - 90 °C.

[0020] Further, in step (2), the second reaction temperature is preferably 70 °C.

[0021] Further, in step (1), the first crystallization is rotary evaporation to remove solvent crystallization or evaporation to dryness for precipitation crystallization.

[0022] Further, in step (2), the second crystallization is rotary evaporation to remove solvent crystallization or evaporation to dryness for precipitation crystallization.

[0023] Further, the temperature for evaporation to dryness for precipitation crystallization is 70 - 90 °C.

[0024] Further, there are no special requirements for the conditions of the rotary evaporation, and it is only necessary to remove the water (solvent) in the first solution or the second solution.

[0025] Further, in step (1), the molar ratio of zinc oxide (ZnO) to deuterium fully labeled acetic acid (CD3COOD) is 1:(2.0 - 2.5).

[0026] Further, in step (1), the molar ratio of zinc oxide to deuterium fully labeled acetic acid is preferably 1:(2.0 - 2.2).

[0027] Further, in step (1), the molar ratio of deuterium fully labeled acetic acid (CD3COOD) to water (H2O) is 1:(10 - 25).

[0028] Further, in step (1), the molar ratio of deuterium fully labeled acetic acid (CD3COOD) to water (H2O) is preferably 1:(15 - 20).

[0029] Further, in step (2), the molar ratio of fully labeled signal zinc acetate dihydrate (fully labeled signal zinc acetate dihydrate crystal) (Zn(CD3COO)2·2D2O) to water (H2O) is 1:(50 - 100).

[0030] Further, in step (2), the molar ratio of fully labeled signal zinc acetate dihydrate crystal (Zn(CD3COO)2·2D2O) to water (H2O) is preferably 1:(50 - 80).

[0031] Further, the methyl site abundance of deuterium selectively labeled methyl site zinc acetate dihydrate is greater than 98 atom% D, and the coordinated water abundance is less than 10 atom% D.

[0032] Further preferably, the abundance of the water of crystallization of the deuterium selectively labeled zinc acetate monohydrate at the methyl position is less than 6 atom% D.

[0033] Further preferably, the abundance of the water of crystallization of the deuterium selectively labeled zinc acetate monohydrate at the methyl position can reach the natural abundance.

[0034] Furthermore, the abundance of the methyl position of the deuterium selectively labeled zinc acetate monohydrate refers to the abundance of the hydrogen in the methyl group of the deuterium selectively labeled zinc acetate monohydrate, and the abundance of the water of crystallization of the deuterium selectively labeled zinc acetate monohydrate refers to the abundance of the hydrogen in the water of crystallization of the deuterium selectively labeled zinc acetate monohydrate.

[0035] Furthermore, in step (1), the water is water with natural abundance (deionized water).

[0036] Furthermore, in step (2), the water is water with natural abundance (deionized water).

[0037] Furthermore, the yield of the deuterium selectively labeled zinc acetate monohydrate can reach more than 80%.

[0038] Furthermore, the natural abundance refers to the abundances of the three isotopes of hydrogen, protium, deuterium, and tritium, in nature, where the abundance of protium is approximately 99.98%, the abundance of deuterium is approximately 0.016%, and the abundance of tritium is equivalent to 10 18 the concentration of 1 tritium atom in a hydrogen atom. And water with natural abundance refers to water in which the hydrogen is of natural abundance.

[0039] Furthermore, the reaction process is as follows:

[0040]

[0041] Further preferably, the chemical formula of the deuterium selectively labeled zinc acetate monohydrate prepared in step (2) is Zn(CD3COO)2·2H2O.

[0042] The second object of the present invention is to provide a deuterium selectively labeled zinc acetate monohydrate, which is prepared by the above synthesis method.

[0043] Further preferably, the chemical formula of the deuterium selectively labeled zinc acetate monohydrate is Zn(CD3COO)2·2H2O.

[0044] The third object of the present invention is to provide an application of deuterium selectively labeled zinc acetate monohydrate with methyl position, using the deuterium selectively labeled zinc acetate monohydrate as an isotope labeling reagent or a tracer in organic synthesis reactions to trace the paths of zinc ions or acetate ions in chemical reactions; in drug development, deuterium-labeled zinc acetate can be used to trace its absorption, distribution, metabolism and excretion (ADME) paths in organisms through mass spectrometry, especially for studying the metabolic pathways of zinc supplements or the interactions with other metals; or when determining the zinc content in environmental or biological samples, the original concentration of zinc can be calculated through the isotope ratio of deuterium-labeled zinc acetate to reduce matrix interference, etc.

[0045] Compared with the prior art, the present invention has the following characteristics:

[0046] 1) The present invention provides a synthesis method of deuterium selectively labeled zinc acetate monohydrate with methyl position, and designs a simple and feasible synthesis route of deuterium selectively labeled zinc acetate monohydrate with methyl position, which can realize the preparation of deuterium selectively labeled zinc acetate monohydrate with methyl position and fully labeled zinc acetate monohydrate (fully labeled zinc acetate monohydrate is an intermediate product).

[0047] 2) The present invention provides a synthesis method of deuterium selectively labeled zinc acetate monohydrate with methyl position, the reaction conditions are mild, the post-treatment process is simple, and the isotope abundance will not be diluted during the reaction process.

[0048] 3) The present invention provides a synthesis method of deuterium selectively labeled zinc acetate monohydrate with methyl position, the test method is simple and feasible, the reaction process is easy to control, and the yield is relatively high (basically can reach more than 80%, and even can reach more than 85%).

[0049] 4) The present invention provides a synthesis method of deuterium selectively labeled zinc acetate monohydrate with methyl position, the deuterium abundance at the methyl position of the synthesized deuterium selectively labeled zinc acetate monohydrate with methyl position is greater than 98 atom% D, and the coordinated water abundance is less than 10 atom% (even can reach the natural abundance). Specific embodiments

[0050] The present invention will be described in detail below in conjunction with specific embodiments, but it is by no means a limitation to the present invention. Features such as preparation means, materials, structures or composition ratios not clearly described in the technical solution of the present invention are regarded as common technical features disclosed in the prior art. The present invention will be described in detail below in conjunction with specific embodiments. This embodiment is implemented on the premise of the technical solution of the present invention, and gives detailed implementation manners and specific operation processes, but the protection scope of the present invention is not limited to the following embodiments.

[0051] It should be noted that in the present invention, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "comprising", "including" or any other variant thereof are intended to cover non-exclusive inclusion, such that a process, method, article or device comprising a series of elements not only includes those elements but also includes other elements not expressly listed, or also includes elements inherent to such process, method, article or device. Without further limitation, an element defined by the statement "comprising an..." does not exclude the presence of additional identical elements in the process, method, article or device comprising the element.

[0052] Unless otherwise specified, the reagents, methods, instruments and equipment used in the present invention are conventional reagents, methods, instruments and equipment in the art. Unless otherwise specified, the reagents and materials used in the following examples are all commercially available. In the following examples, unless otherwise specified for raw materials or treatment techniques, it indicates that they are all conventional commercially available raw material products or conventional treatment techniques in the art.

[0053] In the following examples, deuterium fully labeled acetic acid is commercially available deuterated acetic acid with a CAS registry number of 1186 - 52 - 3.

[0054] Example 1:

[0055] A method for synthesizing deuterium selectively labeled zinc acetate monohydrate at the methyl position is provided in this example, which includes the following steps:

[0056] (1) Add 8.0 g of deuterium fully labeled acetic acid and 45 g of natural abundance deionized water to a 250 mL round-bottom flask, stir and heat (heating temperature is 70 °C) to obtain a uniformly mixed solution. Then weigh 5.0 g of zinc oxide and add it to the above uniformly mixed solution, and react at 70 °C until the zinc oxide is completely dissolved; remove the solvent by rotary evaporation to obtain 12.54 g of zinc acetate monohydrate crystals with a full labeling signal. (2) Add the obtained zinc acetate monohydrate crystals with a full labeling signal (deuterium-labeled zinc acetate monohydrate crystals) to a 250 mL round-bottom flask, add 50 mL of natural abundance deionized water, heat and stir at 70 °C until the zinc acetate monohydrate crystals with a full labeling signal are completely dissolved, remove the solvent by rotary evaporation or evaporate the water to dryness and crystallize at 70 - 90 °C (in this example, the solvent is removed by rotary evaporation at 55 °C and -0.1 MPa) to obtain 12.0 g of deuterium selectively labeled zinc acetate monohydrate (as the dihydrate) crystals. After isotope mass spectrometry detection, the deuterium abundance at the methyl position of deuterium selectively labeled zinc acetate monohydrate is 98.89 atom% D, the abundance of the coordinated water is the natural abundance, and the yield is 87%.

[0057] Example 2:

[0058] In this example, a method for synthesizing deuterium-selectively labeled zinc acetate monohydrate at the methyl position is provided. Compared with Example 1, most of them are the same, except that the reaction temperature in step (2) is 50 °C, and 11.78 g of deuterium-selectively labeled zinc acetate monohydrate crystals are prepared. After detection by isotope mass spectrometry, the deuterium abundance at the methyl position of deuterium-selectively labeled zinc acetate monohydrate is 98.5 atom% D, the abundance of bound water is the natural abundance, and the yield is 85%.

[0059] Example 3:

[0060] In this example, a method for synthesizing deuterium-selectively labeled zinc acetate monohydrate at the methyl position is provided. Compared with Example 1, most of them are the same, except that the reaction temperature in step (2) is 90 °C, and 11.2 g of deuterium-selectively labeled zinc acetate monohydrate crystals are prepared. After detection by isotope mass spectrometry, the deuterium abundance at the methyl position of deuterium-selectively labeled zinc acetate monohydrate is 98.2 atom% D, the abundance of bound water is the natural abundance, and the yield is 81%.

[0061] Example 4:

[0062] In this example, a method for synthesizing deuterium-selectively labeled zinc acetate monohydrate at the methyl position is provided. Compared with Example 1, most of them are the same, except that the reaction temperature in step (1) is 50 °C, and 11.99 g of deuterium-selectively labeled zinc acetate monohydrate crystals are prepared. After detection by isotope mass spectrometry, the deuterium abundance at the methyl position of deuterium-selectively labeled zinc acetate monohydrate is 98.5 atom% D, the abundance of bound water is the natural abundance, and the yield is 87%.

[0063] Example 5:

[0064] In this example, a method for synthesizing deuterium-selectively labeled zinc acetate monohydrate at the methyl position is provided. Compared with Example 1, most of them are the same, except that the molar ratio of fully deuterated acetic acid (CD3COOD) to deionized water (H2O) with natural abundance in step (1) is 1:15 (adjust the addition amount of deionized water), and 11.2 g of deuterium-selectively labeled zinc acetate monohydrate crystals are prepared. After detection by isotope mass spectrometry, the deuterium abundance at the methyl position of deuterium-selectively labeled zinc acetate monohydrate is 98.3 atom% D, the abundance of bound water is 5.2 atom% D, and the yield is 81%.

[0065] Example 6:

[0066] Compared with Example 1, most of them are the same, except that 10 g of fully deuterated acetic acid is added. After detection by isotope mass spectrometry, the deuterium abundance at the methyl position of the prepared deuterium-selectively labeled zinc acetate monohydrate is 98.7 atom% D, the abundance of bound water is 8.7 atom% D, and the yield is 88%.

[0067] Comparative Example 1:

[0068] Compared with Example 1, most of them are the same, except that the deionized water added in step (1) is 12 g. After the deuterium-selectively labeled zinc acetate monohydrate at the methyl position is detected by isotope mass spectrometry, the abundance at the methyl position is 98.5 atom% D, the abundance of the coordinated water is 45 atom% D, and the yield is 78%.

[0069] Comparative Example 2:

[0070] Compared with Example 1, most of them are the same, except that the reaction temperature in step (1) is room temperature. After the deuterium-selectively labeled zinc acetate monohydrate at the methyl position is detected by isotope mass spectrometry, the abundance at the methyl position is 98.8 atom% D, the abundance of the coordinated water is 3.7 atom% D, and the yield is 79%.

[0071] Comparative Example 3:

[0072] Compared with Example 1, most of them are the same, except that the reaction temperature in step (2) is room temperature. After the deuterium-selectively labeled zinc acetate monohydrate at the methyl position is detected by isotope mass spectrometry, the abundance at the methyl position is 98.3 atom% D, the abundance of the coordinated water is 21 atom% D, and the yield is 79%.

[0073] The above description of the embodiments is for the convenience of those of ordinary skill in the art to understand and use the invention. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative efforts. Therefore, the present invention is not limited to the above embodiments, and the improvements and modifications made by those skilled in the art without departing from the scope of the present invention according to the disclosure of the present invention should be within the protection scope of the present invention.

Claims

1. A method for synthesizing deuterium-selectively labeled zinc acetate monohydrate with deuterium at the methyl position, characterized in that, The synthesis method includes the following steps: (1) Prepare zinc acetate dihydrate with fully labeled signals by using deuterium fully labeled acetic acid, water, and zinc oxide; (2) Prepare the deuterium selectively labeled methyl-position zinc acetate dihydrate by using the zinc acetate dihydrate with fully labeled signals obtained in step (1) and water.

2. The synthesis method of zinc acetate monohydrate with deuterium selectively labeled at the methyl position according to claim 1, wherein The synthesis method specifically includes the following steps: (1) Mix deuterium fully labeled acetic acid and water, stir and heat to obtain a uniformly mixed solution, then add zinc oxide to the uniformly mixed solution, react at the first reaction temperature, and then perform the first crystallization to obtain zinc acetate dihydrate crystals with fully labeled signals; (2) Heat and stir the zinc acetate dihydrate crystals with fully labeled signals obtained in step (1) and natural abundance water at the second reaction temperature to dissolve the zinc acetate dihydrate crystals with fully labeled signals, and then perform the second crystallization to obtain deuterium selectively labeled methyl-position zinc acetate dihydrate crystals.

3. The synthesis method of zinc acetate monohydrate with deuterium selectively labeled at the methyl position according to claim 2, characterized in that, In step (1), the first reaction temperature is 50 - 90 °C; In step (2), the second reaction temperature is 50 - 90 °C.

4. The synthesis method of zinc acetate monohydrate with deuterium selectively labeled at the methyl position according to claim 2, wherein, In step (1), the first crystallization is rotary evaporation to remove solvent crystallization or evaporation to dryness for precipitation crystallization; In step (2), the second crystallization is rotary evaporation to remove solvent crystallization or evaporation to dryness for precipitation crystallization; The temperature for evaporation to dryness for precipitation crystallization is 70 - 90 °C.

5. The synthesis method of zinc acetate monohydrate with deuterium selectively labeled at the methyl position according to claim 1, characterized in that, In step (1), the molar ratio of zinc oxide to deuterium fully labeled acetic acid is 1:(2.0 - 2.5); In step (1), the molar ratio of deuterium fully labeled acetic acid to water is 1:(10 - 25).

6. The synthesis method of zinc acetate hydrate with deuterium selectively labeled at the methyl position according to claim 1, wherein In step (2), the molar ratio of zinc acetate dihydrate with fully labeled signals to water is 1:(50 - 100).

7. The synthesis method of zinc acetate monohydrate with deuterium selectively labeled at the methyl position according to claim 1, characterized in that, The methyl-position abundance of the deuterium selectively labeled methyl-position zinc acetate dihydrate is greater than 98 atom% D, and the coordinated water abundance is less than 10 atom% D.

8. The synthesis method of zinc acetate monohydrate with deuterium selectively labeled at the methyl position according to claim 1, characterized in that, In step (1), the water is natural abundance water; In step (2), the water is natural abundance water.

9. A zinc acetate hydrate with deuterium selectively labeled at the methyl position, characterized in that, The deuterium selectively labeled methyl-position zinc acetate dihydrate is prepared by using the synthesis method described in any one of claims 1 - 8.

10. Use of zinc acetate monohydrate with deuterium selectively labeled at the methyl position as described in claim 9, characterized in that, Use the deuterium selectively labeled methyl-position zinc acetate dihydrate as an isotope labeling reagent or a tracer in organic synthesis reactions.

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