A method for synthesizing deuterated butyric acid

Abstract

The application discloses a synthesis method of deuterated butyric acid and belongs to the technical field of chemical synthesis. The deuterated butyric acid is prepared from deuterated redox active ester and acrylic ester compound as starting materials, and after reaction, a deuterated butyric acid ester compound is obtained, and the deuterated butyric acid is obtained by hydrolysis; the structure of the deuterated redox active ester is as follows: the structure of the deuterated butyric acid ester compound is as follows: and the structure of the deuterated butyric acid is as follows: the deuterated butyric acid is obtained from cheap and easily obtained deuterated products, the deuterium site is inert and is not prone to hydrogen-deuterium exchange, the selectivity is good, the yield is high, the reaction condition is mild, and the operation is simple and easy to implement, and therefore the application has important significance for the synthesis of deuterated alkyl carboxylic acid and derivatives thereof, scientific research and research and development of deuterated drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of deutero-butyric acid. BACKGROUND

[0002] The information disclosed in this Background section is only for the purpose of increasing the understanding of the general background of the application and does not necessarily constitute an admission or a recognition that the information forms part of the prior art already known to a person of ordinary skill in the art.

[0003] Deuteration is widely used as a labeling technique in various fields, such as reaction mechanism exploration, isotope tracing, drug research and development, nuclear magnetic resonance spectroscopy, and mass spectrometry. In particular, researchers in the biological field often need to conduct in vitro enzyme reactions and isotope feeding to study the biosynthesis pathways of natural products. The development of these research fields has led to an increasing demand for synthesis methods of deutero-alkyl carboxylic acids. In addition, carboxylic acid compounds and their derivatives are very important for the construction of some drug molecules and polymer materials. Therefore, the synthesis of deutero-alkyl carboxylic acids and their derivatives is of great significance for scientific research and the development of deutero-drugs.

[0004] Existing synthesis methods of deutero-alkyl carboxylic acids either perform deuteration at the ortho position of the carbonyl group which is prone to hydrogen-deuterium exchange, but such deutero-products are easily converted into non-deutero-products, or indiscriminately perform full deuteration modification on alkyl carboxylic acids, which still has the possibility of converting the more active sites into partially non-deutero-products, thereby causing great difficulty for mass spectrometry analysis. Moreover, most of the existing synthesis methods of deutero-alkyl carboxylic acids are carried out in deuterated solvents, resulting in low yield of deutero-alkyl carboxylic acids. SUMMARY

[0005] In order to solve the problems of the prior art, the present application aims to provide a synthesis method of deutero-butyric acid. The synthesis method provided by the present application has the advantages of inexpensive reagents and raw materials, mild reaction conditions, and simple and easy operation.

[0006] In order to achieve the above-mentioned purpose, the technical scheme of the present application is as follows:

[0007] In a first aspect, the present application provides a synthesis method of deutero-butyric acid, comprising:

[0008] The deutero-oxidation-reduction active ester is reacted with an acrylic ester compound to obtain a deutero-butyric acid ester compound, which is hydrolyzed to obtain deutero-butyric acid.

[0009] The structure of the deutero-oxidation-reduction active ester is as follows:

[0010]

[0011] The structure of the deuterated butyric acid ester compound is as follows:

[0012]

[0013] The structure of the deuterated butyric acid ester compound is as follows:

[0014]

[0015] In some embodiments of the present application, R in the deuterated butyric acid ester compound is selected from one of methyl, ethyl, tert-butyl, phenyl or benzyl.

[0016] In some embodiments of the present application, the method for preparing the deuterated redox active ester comprises the following steps:

[0017] The deuterated redox active ester is obtained by reacting tetra-deuterated acetic acid with N-hydroxyphthalimide;

[0018] Alternatively, the deuterated redox active ester is obtained by reacting tetra-deuterated acetic acid with oxalyl chloride to obtain tri-deuterated acetyl chloride, and then reacting the tri-deuterated acetyl chloride with N-hydroxyphthalimide.

[0019] In some embodiments of the present application, the synthesis method comprises: under the protection of nitrogen, the deuterated redox active ester reacts with an acrylic ester compound under the action of light, a catalyst and a reducing agent to obtain the deuterated butyric acid ester compound.

[0020] The deuterated butyric acid is obtained by mixing a base solution with the deuterated butyric acid ester compound for hydrolysis at room temperature.

[0021] Preferably, the light is one of red light, orange light, yellow light, green light, blue light or purple light.

[0022] Preferably, the catalyst is one of sodium iodide, potassium iodide, lithium iodide, tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium fluoride.

[0023] Preferably, the reducing agent is one of sodium borohydride, lithium aluminum hydride, trimethylsilane, tris(trimethylsilyl)silane or 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid diethyl ester.

[0024] Preferably, the molar ratio of the deuterated redox active ester, the acrylic ester compound, the reducing agent and the catalyst is 1:(1-1.5):(1-2):(0.01-0.2).

[0025] Preferably, the reaction solvent is one of methanol, ethanol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylacetamide or N,N-dimethylformamide, the reaction temperature is 0-30°C, and stirring is performed during the reaction.

[0026] Preferably, the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or triethylamine.

[0027] Preferably, the base solution is an aqueous solution of the base, with a concentration of 5-25wt%.

[0028] Preferably, the hydrolysis temperature is 20-70℃.

[0029] In some embodiments of the present application, the synthesis method comprises: under the protection of nitrogen, the deuterated redox active ester reacts with the acrylic ester compound under the action of a reducing agent to obtain a deuterated butyric ester compound;

[0030] The base solution is mixed with the deuterated butyric ester compound at room temperature to perform hydrolysis, to obtain the deuterated butyric acid.

[0031] Preferably, the deuterated redox active ester reacts with the acrylic ester compound under heating to 60-120℃.

[0032] Preferably, the reducing agent is one of sodium borohydride, lithium aluminum hydride, trimethylsilane, tris(trimethylsilyl)silane or diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate.

[0033] Preferably, the molar ratio of the deuterated redox active ester, the acrylic ester compound and the reducing agent is 1:(1-1.5):(1-2).

[0034] Preferably, the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or triethylamine.

[0035] Preferably, the base solution is an aqueous solution of the base, with a concentration of 5-25wt%.

[0036] Preferably, the hydrolysis temperature is 20-70℃.

[0037] The present application has the following beneficial effects:

[0038] The present application provides a synthesis method of deuterated butyric acid, which takes deuterated redox active ester and acrylic ester compound as starting materials, and performs free radical addition reaction in a solvent, and then performs ester hydrolysis to obtain the target product. Compared with the existing process, the synthesis method of deuterated butyric acid provided by the present application uses cheap deuterated iodide as raw material, efficiently synthesizes long-chain deuterated alkyl carboxylic acid with higher value, does not need high-temperature and high-pressure environment, and has mild reaction conditions; at the same time, strong reducing agents and strong oxidizing agents are not used, and the reaction is safer; the deuterium substitution site of the obtained deuterated butyric acid is inert, and is not easy to undergo hydrogen-deuterium exchange, has good selectivity, high yield, and the purity can be up to 98%, and the yield can be up to 87%, and has good application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0039] The accompanying drawings, which form a part of this specification, are included to provide a further understanding of the application, and are incorporated herein by reference. The embodiments illustrated in the drawings are provided merely as examples of the application, and therefore are not to be considered as limiting the scope of the application.

[0040] Figure 1 NMR hydrogen spectrum of deuterated butyric acid prepared for example 1 of the present application;

[0041] Figure 2 NMR carbon spectrum of deuterated butyric acid prepared for example 1 of the present application;

[0042] Figure 3 Stability test hydrogen spectrum of deuterated butyric acid prepared for example 1 of the present application under chloroform dissolution condition. DETAILED DESCRIPTION

[0043] The technical solutions of the present application will be described clearly and completely below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0044] The first typical embodiment of the present application provides a synthesis method of deuterated butyric acid, comprising:

[0045] The deuterated redox active ester is reacted with an acrylic ester compound to obtain a deuterated butyric ester compound, and the deuterated butyric ester compound is hydrolyzed to obtain the deuterated butyric acid;

[0046] The structure of the deuterated redox active ester is as follows:

[0047]

[0048] The structure of the deuterated butyric ester compound is as follows:

[0049]

[0050] The structure of the deuterated butyric acid is as follows:

[0051]

[0052] The synthesis route of the deuterated butyric acid provided by the present application is as follows:

[0053]

[0054] The synthetic deuterated butyric acid is deuterated butyric acid with inert site, which is not prone to hydrogen-deuterium exchange, has good selectivity and high yield. The synthetic deuterated butyric acid can be used in the fields of instrument analysis, isotope labeling, mechanism research, drug research and development, and material science.

[0055] In some embodiments of the embodiment, R in the deuterated butyric acid ester compound includes but is not limited to one of alkyl, alkoxy and aryl, for example, one of methyl, ethyl, tert-butyl, phenyl or benzyl; preferably aryl, and further preferably one of phenyl or benzyl.

[0056] It should be noted that when R is one of alkyl, alkoxy or aryl, the reaction of the deuterated redox active ester with the acrylic ester compound can be carried out. When R is aryl, especially phenyl or benzyl, the reaction effect is good, and the yield of the deuterated butyric acid ester compound is high.

[0057] In some embodiments of the embodiment, the preparation method of the deuterated redox active ester includes the following steps:

[0058] The deuterated redox active ester is obtained by reacting tetra-deuterated acetic acid with N-hydroxy phthalimide.

[0059] The synthetic route is as follows:

[0060]

[0061] In some embodiments of the embodiment, the preparation method of the deuterated redox active ester includes the following steps:

[0062] The deuterated redox active ester is obtained by reacting tetra-deuterated acetic acid with oxalyl chloride, and then reacting the obtained tritium-deuterated acetyl chloride with N-hydroxy phthalimide.

[0063] The synthetic route is as follows:

[0064]

[0065] In some embodiments of the embodiment, the deuterated butyric acid can be synthesized by a photocatalytic method. Specifically, the synthesis method includes: under the action of light, a catalyst and a reducing agent, the deuterated redox active ester is reacted with the acrylic ester compound to obtain the deuterated butyric acid ester compound under the protection of nitrogen.

[0066] The deuterated butyric acid is obtained by mixing the base solution with the deuterated butyric acid ester compound at room temperature and hydrolyzing.

[0067] The photocatalytic synthetic route is as follows:

[0068]

[0069] Specifically, under the action of light, a catalyst and a reducing agent, a radical addition reaction occurs between the deuterated redox active ester and the acrylic ester compound under the protection of nitrogen, and after the reaction is completed, separation is performed to obtain the deuterated butyric ester compound.

[0070] At room temperature, a base solution is added to the deuterated butyric ester compound for hydrolysis to obtain the deuterated butyric acid.

[0071] It should be noted that the separation can be performed by column chromatography.

[0072] The light is one of red light, orange light, yellow light, green light, blue light or purple light, and is preferably blue light.

[0073] It should be noted that under the light, the deuterated redox active ester and the acrylic ester compound undergo a radical addition reaction, and the light irradiation time is the same as the reaction time. For example, if the reaction time is 5 min to 24 h, the light irradiation time is also 5 min to 24 h.

[0074] The catalyst is one of sodium iodide, potassium iodide, lithium iodide, tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium fluoride.

[0075] The reducing agent is one of sodium borohydride, lithium aluminum hydride, trimethylsilane, tris(trimethylsilyl)silane or 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid diethyl ester, and is preferably 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid diethyl ester.

[0076] The molar ratio of the deuterated redox active ester, the acrylic ester compound, the reducing agent and the catalyst is 1:(1-1.5):(1-2):(0.01-0.2).

[0077] The reaction solvent is one of methanol, ethanol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylacetamide or N,N-dimethylformamide, and is preferably one of methanol, dimethyl sulfoxide or N,N-dimethylacetamide; the reaction temperature is 0-30°C, and stirring is performed during the reaction.

[0078] It should be noted that the stirring is performed at a stirring speed of 800 r / min.

[0079] The base includes but is not limited to one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or triethylamine, and is preferably sodium hydroxide.

[0080] The base solution is an aqueous solution of the base, and the concentration of the base is 5-25 wt%.

[0081] The hydrolysis temperature is 20-70°C.

[0082] It should be noted that, in order to accelerate the hydrolysis rate, stirring can be performed during the hydrolysis, such as stirring at 20-70°C for 20-30 min, to ensure that the deuterated butyric acid ester compound is rapidly and completely hydrolyzed.

[0083] The synthesis method further comprises the step of separating and purifying the deuterated butyric acid after the hydrolysis is completed.

[0084] The separation and purification comprises the steps of adjusting the pH of the reaction solution to be acidic after the hydrolysis is completed, extracting, and removing the solvent to obtain the deuterated butyric acid.

[0085] Preferably, vacuum concentration or reduced pressure distillation can be used to remove the solvent.

[0086] In some embodiments of the embodiment, the deuterated butyric acid can be synthesized by a thermal catalytic method. Specifically, the synthesis method comprises: under the protection of nitrogen, the deuterated redox active ester reacts with the acrylic ester compound under the action of heating and a reducing agent to obtain the deuterated butyric acid ester compound.

[0087] The base solution is mixed with the deuterated butyric acid ester compound at room temperature to perform hydrolysis, and the deuterated butyric acid is obtained.

[0088] The photocatalytic synthesis route is as follows:

[0089]

[0090] Specifically, under the protection of nitrogen, the deuterated redox active ester undergoes free radical homolysis and free radical addition reaction with the acrylic ester compound under the action of heating and a reducing agent. After the reaction is completed, separation is performed to obtain the deuterated butyric acid ester compound.

[0091] The base solution is mixed with the deuterated butyric acid ester compound at room temperature to perform hydrolysis, and the deuterated butyric acid is obtained.

[0092] It should be noted that the separation can be performed by column chromatography.

[0093] The deuterated redox active ester reacts with the acrylic ester compound by heating to 60-120°C.

[0094] The reducing agent is one of sodium borohydride, lithium aluminum hydride, trimethylsilane, tris(trimethylsilyl)silane, or 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid diethyl ester, and is preferably 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid diethyl ester.

[0095] The molar ratio of the deuterated redox active ester, the acrylate compound and the reducing agent is 1:(1-1.5):(1-2).

[0096] The reaction solution is selected from one of methanol, ethanol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylacetamide or N,N-dimethylformamide, preferably one of tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylacetamide.

[0097] The base includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or triethylamine, preferably sodium hydroxide.

[0098] The base solution is an aqueous solution of the base with a concentration of 5-25wt%.

[0099] The hydrolysis temperature is 20-70℃.

[0100] The synthesis method further includes a step of separating and purifying the deuterated butyric acid after the hydrolysis is completed.

[0101] The separating and purifying includes a step of adjusting the pH of the solution after the reaction to be acidic, extracting, removing the solvent, and obtaining the deuterated butyric acid.

[0102] Preferably, the solvent can be removed by vacuum concentration or reduced pressure distillation.

[0103] In order to enable those skilled in the art to more clearly understand the technical solutions of the present application, the technical solutions of the present application will be described in detail below in combination with specific examples.

[0104] Unless otherwise specified in the examples, the techniques or conditions are carried out according to the techniques or conditions described in the literature in the art or according to the product instructions. Unless otherwise specified, the reagents or instruments used are conventional products that can be purchased on the market. All raw materials of the present application are not particularly limited in purity, and the present application preferably uses analytical pure.

[0105] The synthesis route and method of the deuterated redox active ester used in the following examples are as follows:

[0106]

[0107] 640mg of deuterated acetic acid, 2.0g of N-hydroxyphthalimide (1.2eq) and 122mg of DMAP (10mol%) were dissolved in about 20mL of DCM, and then 2.47g of DCC (1.2eq) was added. After stirring the mixture for 18 hours, column chromatography was used to separate 400mg of the corresponding redox ester, with a yield of 19%.

[0108]

[0109] 640 mg of deuterated alkyl carboxylic acid was dissolved in DCM, a drop of DMF was added, the solution was cooled to 0 °C, and 1.89 g of oxalyl chloride was added. It was stirred at room temperature for 0.5 h. After 3.26 g of N-hydroxyphthalimide and 4.04 g of triethylamine were added, the mixture was stirred for 8 h, and column chromatography was used to isolate 1.4 g of the corresponding redox ester, with a yield of 67%.

[0110] Example 1

[0111] A method for synthesizing deuterated butyric acid, the synthetic route is as follows:

[0112]

[0113] including the following steps:

[0114] To the 20 mL methanol solution, deuterated redox active ester (2.50 g, 12.0 mmol), tetrabutylammonium iodide (369 mg, 1 mmol), 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid diethyl ester (5.08 g, 20 mmol), benzyl acrylate (1.62 g, 10 mmol) were added, and under the condition of nitrogen protection, continuous light irradiation was carried out with a 40 W blue light lamp, and stirring was carried out at 800 r / min for 12 h. After the reaction was completed, column chromatography was used to isolate 0.80 g of deuterated benzyl butyrate, with a yield of 87%.

[0115] At room temperature, deuterated benzyl butyrate obtained in the previous step was added to 20 mL of 1M sodium hydroxide solution, and the temperature was raised to 60 °C, and stirring was carried out at 800 r / min for 30 min, and then the aqueous phase was extracted and reserved, and the pH was adjusted to be acidic with 3M hydrochloric acid, and then extraction and vacuum concentration were carried out to obtain deuterated butyric acid, with a yield of 100%.

[0116] 1 H NMR (500 MHz, Chloroform-d) δ 2.36 (t, J = 7.4 Hz, 2H), 1.68 (t, J = 7.4 Hz, 2H).

[0117] 13 C NMR (126 MHz, CDCl3) δ 179.0, 35.7, 17.9.

[0118] Stability test:

[0119] The deuterated butyric acid obtained in Example 1 was stored in chloroform solution at room temperature for 7 days, and then nuclear magnetic detection was carried out again, and no deterioration occurred. The obtained nuclear magnetic hydrogen spectrum is shown in Figure 3 , and the nuclear magnetic resonance hydrogen spectrum data is as follows:

[0120] 1H NMR (500 MHz, Chloroform-d) δ 2.36 (t, J = 7.4 Hz, 2H), 1.68 (t, J = 7.4 Hz, 2H).

[0121] By Figure 1 and Figure 3 It can be seen that the deuterated butyric acid obtained in Example 1 is inert site deuterium substitution, stable in nature, and not prone to hydrogen-deuterium exchange.

[0122] Example 2

[0123] A synthesis method of deuterated butyric acid, the synthesis route is as follows:

[0124]

[0125] The method comprises the following steps:

[0126] Into 20 mL DMSO solution, add deuterated redox active ester (2.50 g, 12.0 mmol), tetrabutylammonium iodide (369 mg, 1 mmol), 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid diethyl ester (5.08 g, 20 mmol), benzyl acrylate (1.62 g, 10 mmol), under the condition of nitrogen protection, use 40W blue light lamp for continuous irradiation, 800r / min stirring for 12 hours. After the reaction is completed, deuterated butyric acid benzyl ester 0.72 g is obtained by column chromatography separation, the yield is 79%.

[0127] At room temperature, add deuterated butyric acid benzyl ester obtained in the above step into 20 mL of 1M sodium hydroxide solution, heat to 60°C, 800r / min stirring for 30 min, then extract the water phase, adjust the pH to acidic with 3M hydrochloric acid, then extract, and distill under reduced pressure to obtain deuterated butyric acid, the yield is 100%.

[0128] The nuclear magnetic hydrogen spectrum of the deuterated butyric acid obtained in Example 2 is consistent with that of Example 1.

[0129] Example 3

[0130] A synthesis method of deuterated butyric acid, the synthesis route is as follows:

[0131]

[0132] The method comprises the following steps:

[0133] To a 20 mL solution of DMSO, add deuterated redox active ester (2.50 g, 12.0 mmol), tetrabutylammonium iodide (369 mg, 1 mmol), diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (5.08 g, 20 mmol), benzyl acrylate (1.62 g, 10 mmol), under nitrogen protection, irradiate continuously with a 40 W blue light lamp, stir at 800 r / min for 12 h. After the reaction is complete, separate benzyl deuterated butyrate 0.77 g by column chromatography, with a yield of 85%.

[0134] At room temperature, add the benzyl deuterated butyrate from the previous step to a 20 mL solution of 1 M sodium hydroxide, heat to 60 °C, stir at 800 r / min for 30 min, then extract and retain the aqueous phase, adjust the pH to be acidic with 3 M hydrochloric acid, then extract, and concentrate under vacuum to obtain deuterated butyric acid, with a yield of 100%.

[0135] The nuclear magnetic hydrogen spectrum of the deuterated butyric acid obtained in this Example 3 is consistent with that of Example 1.

[0136] Example 4

[0137] A method for synthesizing deuterated butyric acid, with a synthesis route as follows:

[0138]

[0139] Comprising the following steps:

[0140] To a 20 mL solution of tetrahydrofuran, add deuterated redox active ester (2.50 g, 12.0 mmol), diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (5.08 g, 20 mmol), benzyl acrylate (1.62 g, 10 mmol), under nitrogen protection, stir at 800 r / min for 12 h at 60 °C. After the reaction is complete, separate benzyl deuterated butyrate 1.28 g by column chromatography, with a yield of 73%.

[0141] At room temperature, add the benzyl deuterated butyrate from the previous step to a 20 mL solution of 1 M sodium hydroxide, heat to 60 °C, stir at 800 r / min for 30 min, then extract and retain the aqueous phase, adjust the pH to be acidic with 3 M hydrochloric acid, then extract, and concentrate under vacuum to obtain deuterated butyric acid, with a yield of 100%.

[0142] The nuclear magnetic hydrogen spectrum of the deuterated butyric acid obtained in this Example 4 is consistent with that of Example 1.

[0143] Example 5

[0144] A method for synthesizing deuterated butyric acid, with a synthesis route as follows:

[0145]

[0146] comprising the steps of:

[0147] To 20 mL of DMSO solution, add deuterated redox active ester (2.50 g, 12.0 mmol), 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (5.08 g, 20 mmol), benzyl acrylate (1.62 g, 10 mmol), and stir at 800 r / min under nitrogen protection at 60 °C for 12 hours. After the reaction is complete, separate the deuterated benzyl butyrate by column chromatography to obtain 1.02 g of deuterated benzyl butyrate with a yield of 57%.

[0148] At room temperature, add the deuterated benzyl butyrate from the previous step to 20 mL of 1M sodium hydroxide solution, and stir at 800 r / min at 60 °C for 30 min, then extract the water phase, adjust the pH to be acidic with 3M hydrochloric acid, and then extract and distill under reduced pressure to obtain deuterated butyric acid with a yield of 100%.

[0149] The nuclear magnetic resonance hydrogen spectrum of the deuterated butyric acid obtained in this example 5 is consistent with that of example 1.

[0150] Example 6

[0151] A method for synthesizing deuterated butyric acid, and the synthetic route is as follows:

[0152]

[0153] comprising the steps of:

[0154] To 20 mL of DMA solution, add deuterated redox active ester (2.50 g, 12.0 mmol), 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (5.08 g, 20 mmol), benzyl acrylate (1.62 g, 10 mmol), and stir at 800 r / min under nitrogen protection at 60 °C for 12 hours. After the reaction is complete, separate the deuterated benzyl butyrate by column chromatography to obtain 0.77 g of deuterated benzyl butyrate with a yield of 43%.

[0155] At room temperature, add the deuterated benzyl butyrate from the previous step to 20 mL of 1M sodium hydroxide solution, and stir at 800 r / min at 60 °C for 30 min, then extract the water phase, adjust the pH to be acidic with 3M hydrochloric acid, and then extract and distill under reduced pressure to obtain deuterated butyric acid with a yield of 100%.

[0156] The nuclear magnetic resonance hydrogen spectrum of the deuterated butyric acid obtained in this example 6 is consistent with that of example 1.

[0157] The above merely provides the preferred embodiments of the present application, and is not used to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the principles and technical scope of the present application shall fall into the scope of the present application.

Claims

1. A method for synthesizing deuterated butyric acid, characterized by, include: Under nitrogen protection and in the presence of light, a catalyst, and a reducing agent, deuterated redox reactive esters react with acrylate compounds to yield deuterated butyrate compounds; hydrolysis yields deuterated butyric acid. The structure of the deuterated redox-active ester is: , The structure of the acrylate compound is: R is selected from one of methyl, ethyl, tert-butyl, phenyl, benzyl, The structure of the deuterated butyric acid ester compound is: R is selected from one of methyl, ethyl, tert-butyl, phenyl, benzyl, The structure of the deuterated butyric acid is: , The catalyst is one of tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, and tetrabutylammonium fluoride; The reducing agent is diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate; The reaction solvent is one of methanol, ethanol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylacetamide, and N,N-dimethylformamide; The molar ratio of the deuterated redox active ester, acrylate compound, reducing agent and catalyst is 1:(1~1.5):(1~2):(0.01~0.2).

2. The method of synthesis of claim 1, wherein, The synthesis method further includes: The reaction of tetradeuterated acetic acid with N-hydroxyphthalimide yields a deuterated redox active ester; Alternatively, tetradeuterated acetic acid reacts with oxalyl chloride to yield trideuterated acetyl chloride, which then reacts with N-hydroxyphthalimide to yield a deuterated redox active ester.

3. The method of synthesis of claim 1, wherein, At room temperature, an alkaline solution is mixed with a deuterated butyrate compound and hydrolyzed to obtain deuterated butyric acid.

4. The method of synthesis of claim 1, wherein, The light is one of the following: red, orange, yellow, green, blue, or violet.

5. The method of synthesis of claim 1, wherein, The reaction temperature is 0~30℃, and stirring is carried out during the reaction.

6. The synthesis method according to claim 3, characterized in that, The alkaline solution is an aqueous solution of an alkali with a concentration of 5-25 wt%; the hydrolysis temperature is 20-70℃; the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, and triethylamine.

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