Synthesis method of deuterated butyric acid

Abstract

The invention discloses a synthetic method of deuterated butyric acid, and belongs to the technical field of chemical synthesis. According to the deuterated butyric acid, deuterated oxidation-reduction active ester and an acrylate compound are used as starting raw materials, a deuterated butyric acid ester compound is obtained after a reaction, and the deuterated butyric acid ester compound is hydrolyzed to obtain the deuterated butyric acid; the structure of the deuterated oxidation reduction active ester is # imgabs 0 # deuterated butyric acid ester compound is # imgabs 1 # deuterated butyric acid, the deuterated butyric acid is obtained by adopting a deuterated product which is low in cost and easy to obtain, the deuterated site is inert, hydrogen-deuterium exchange is not easy to occur, the selectivity is good, the yield is high, the reaction condition is mild, the operation is simple and easy, and the method is suitable for industrial production. The method is of great significance to the synthesis of deuterated alkyl carboxylic acid and derivatives thereof for scientific research and the research and development of deuterated drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing deuterated butyric acid. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Deuteration is a labeling technology widely used in many fields, such as reaction mechanism research, isotope tracing, drug 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 biosynthetic pathways of natural products. The development of these scientific research fields has led to an increasing demand for deuterated alkyl carboxylic acid synthesis methods; 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 deuterated alkyl carboxylic acids and their derivatives is of great significance for scientific research and the development of deuterated drugs.

[0004] The existing methods for synthesizing deuterated alkyl carboxylic acids include, first, deuterating the carbonyl ortho position, which is easy to exchange hydrogen and deuterium, but such deuterated products are easy to become non-deuterated products; the other synthesis method is to perform indiscriminate full deuteration modification on alkyl carboxylic acids, so that for more active sites, there is still a possibility of converting some non-deuterated products, which brings great difficulties to mass spectrometry analysis. Moreover, most of the existing methods for synthesizing deuterated alkyl carboxylic acids are carried out in deuterated solvents, and the yield of deuterated alkyl carboxylic acids is low. Summary of the invention

[0005] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a method for synthesizing deuterated butyric acid. The synthesis method provided by the present invention has the advantages of cheap reagents and raw materials, mild reaction conditions, simple and easy operation, etc.

[0006] In order to achieve the above object, the technical solution of the present invention is:

[0007] The first aspect of the present invention provides a method for synthesizing deuterated butyric acid, comprising:

[0008] The deuterated redox-active ester reacts with an acrylate compound to obtain a deuterated butyrate compound, which is hydrolyzed to obtain deuterated butyric acid;

[0009] The structure of the deuterated redox-active ester is as follows:

[0010]

[0011] The structure of the deuterated butyrate compound is as follows:

[0012]

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

[0014]

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

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

[0017] Tetradeuterated acetic acid reacts with N-hydroxyphthalimide to obtain a deuterated redox-active ester;

[0018] Alternatively, tetradeuterated acetic acid reacts with oxalyl chloride to obtain trideuterated acetyl chloride, and trideuterated acetyl chloride reacts with N-hydroxyphthalimide to obtain a deuterated redox-active ester.

[0019] In some embodiments of the present invention, the synthesis method comprises: under nitrogen protection, under the action of light, a catalyst and a reducing agent, reacting a deuterated redox-active ester with an acrylate compound to obtain a deuterated butyrate compound;

[0020] At room temperature, the alkaline solution is mixed with the deuterated butyrate compound for hydrolysis to obtain deuterated butyric acid.

[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 diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate.

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

[0025] Preferably, in the reaction, 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 alkaline solution is an aqueous solution of alkali with a concentration of 5 to 25 wt%.

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

[0029] In some embodiments of the present invention, the synthesis method comprises: under nitrogen protection, under heating and the action of a reducing agent, reacting a deuterated redox-active ester with an acrylate compound to obtain a deuterated butyrate compound;

[0030] At room temperature, the alkaline solution is mixed with the deuterated butyrate compound for hydrolysis to obtain deuterated butyric acid.

[0031] Preferably, the deuterated redox-active ester reacts with the acrylate compound by heating to 60-120°C.

[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 acrylate 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 alkaline solution is an aqueous solution of alkali with a concentration of 5 to 25 wt%.

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

[0037] The beneficial effects of the present invention are:

[0038] The present invention provides a method for synthesizing deuterated butyric acid, using deuterated redox active ester and acrylate compound as starting materials, undergoing free radical addition reaction in a solvent, and then obtaining a target product by ester hydrolysis. Compared with the existing process, the method for synthesizing deuterated butyric acid provided by the present invention uses cheap deuterated iodide as raw material, efficiently synthesizes long-chain deuterated alkyl carboxylic acid with higher value, does not require a 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 safety is higher; the deuterated site of the obtained deuterated butyric acid is inert, not prone to hydrogen-deuterium exchange, has good selectivity, high yield, purity up to 98%, and yield up to 87%, and has good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0040] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of deuterated butyric acid prepared in Example 1 of the present invention;

[0041] Figure 2 This is the carbon NMR spectrum of deuterated butyric acid prepared in Example 1 of the present invention;

[0042] Figure 3 This is a hydrogen spectrum of the stability test of deuterated butyric acid prepared in Example 1 of the present invention under chloroform dissolution conditions. DETAILED DESCRIPTION

[0043] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0044] A first typical embodiment of the present invention provides a method for synthesizing deuterated butyric acid, comprising:

[0045] The deuterated redox-active ester reacts with an acrylate compound to obtain a deuterated butyrate compound, which is hydrolyzed to obtain deuterated butyric acid;

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

[0047]

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

[0049]

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

[0051]

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

[0053]

[0054] The deuterated butyric acid synthesized by the present invention is butyric acid deuterated at an inert site, which is not prone to hydrogen-deuterium exchange, has good selectivity and high yield. The deuterated butyric acid synthesized by the present invention can be used in the fields of instrumental analysis, isotope labeling, mechanism research, drug development, and materials science.

[0055] In some examples of this embodiment, R in the deuterated butyrate compound includes but is not limited to one of an alkyl group, an alkoxy group, and an aromatic group, such as one of a methyl group, an ethyl group, a tert-butyl group, a phenyl group, or a benzyl group; preferably an aromatic group, and more preferably one of a phenyl group or a benzyl group.

[0056] It should be noted that when R is an alkyl group, an alkoxy group or an aromatic group, the reaction between the deuterated redox active ester and the acrylate compound can proceed. When R is an aromatic group, especially a phenyl group or a benzyl group, the reaction effect is good and the yield of the deuterated butyrate compound is high.

[0057] In some examples of this embodiment, the method for preparing the deuterated redox-active ester comprises the following steps:

[0058] Tetradeuterated acetic acid reacts with N-hydroxyphthalimide to give a deuterated redox-active ester.

[0059] Its synthetic route is as follows:

[0060]

[0061] In some examples of this embodiment, the method for preparing the deuterated redox-active ester comprises the following steps:

[0062] Tetradeuterated acetic acid reacts with oxalyl chloride to obtain trideuterated acetyl chloride, and trideuterated acetyl chloride reacts with N-hydroxyphthalimide to obtain a deuterated redox-active ester.

[0063] Its synthetic route is as follows:

[0064]

[0065] In some examples of this embodiment, deuterated butyric acid may be synthesized by a photocatalytic method. Specifically, the synthesis method comprises: under nitrogen protection, under the action of light, a catalyst and a reducing agent, a deuterated redox-active ester reacts with an acrylate compound to obtain a deuterated butyrate compound;

[0066] At room temperature, the alkaline solution is mixed with the deuterated butyrate compound for hydrolysis to obtain deuterated butyric acid.

[0067] The photocatalytic synthesis route is as follows:

[0068]

[0069] Specifically, under the protection of nitrogen, under the action of light, a catalyst and a reducing agent, a deuterated redox active ester and an acrylate compound undergo a free radical addition reaction, and after the reaction is completed, the deuterated butyrate compound is separated;

[0070] At room temperature, an alkali solution is added to the deuterated butyrate compound for hydrolysis to obtain deuterated butyric acid.

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

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

[0073] It should be noted that under light, the deuterated redox-active ester and the acrylate compound undergo a free radical addition reaction, and the light exposure time is the same as the reaction time. If the reaction time is 5 minutes to 24 hours, the light exposure time is also 5 minutes to 24 hours.

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

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

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

[0077] In which, the reaction solvent is one of methanol, ethanol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylacetamide or N,N-dimethylformamide, 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 speed is 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, preferably sodium hydroxide.

[0080] Wherein, the alkaline solution is an aqueous solution of alkali, and the concentration of the alkali is 5-25wt%.

[0081] Wherein, the hydrolysis temperature is 20~70℃.

[0082] It should be noted that, in order to accelerate the hydrolysis rate, stirring may be performed during the hydrolysis process, such as stirring at 20 to 70° C. for 20 to 30 minutes, to ensure that the deuterated butyrate compound is rapidly and completely hydrolyzed.

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

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

[0085] Preferably, the solvent can be removed by vacuum concentration or reduced pressure distillation.

[0086] In some examples of this embodiment, deuterated butyric acid may be synthesized by a thermal catalytic method. Specifically, the synthesis method comprises: under nitrogen protection, under heating and the action of a reducing agent, reacting a deuterated redox-active ester with an acrylate compound to obtain a deuterated butyrate compound;

[0087] At room temperature, the alkaline solution is mixed with the deuterated butyrate compound for hydrolysis to obtain deuterated butyric acid.

[0088] The photocatalytic synthesis route is as follows:

[0089]

[0090] Specifically, under the protection of nitrogen, under the action of heating and a reducing agent, the deuterated redox-active ester undergoes free radical homolysis and a free radical addition reaction with the acrylate compound, and after the reaction is completed, separation is performed to obtain a deuterated butyrate compound;

[0091] At room temperature, an alkali solution is added to the deuterated butyrate compound for hydrolysis to obtain deuterated butyric acid.

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

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

[0094] Wherein, the reducing agent is one of sodium borohydride, lithium aluminum hydride, trimethylsilane, tris(trimethylsilyl)silane or 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester, preferably 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic 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] Wherein, the base includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or triethylamine, preferably sodium hydroxide.

[0098] Wherein, the alkaline solution is an aqueous solution of alkali with a concentration of 5 to 25 wt%.

[0099] Wherein, the hydrolysis temperature is 20~70℃.

[0100] The synthesis method further comprises the step of separating and purifying to obtain deuterated butyric acid after the hydrolysis is completed;

[0101] The separation and purification comprises the steps of: after the hydrolysis is completed, adjusting the pH of the solution after the reaction to acidity, extracting, and removing the solvent to obtain 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 solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0104] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the art or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products available on the market. There is no particular restriction on the purity of all raw materials in the present invention, and analytical grade is preferably used in the present invention.

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

[0106]

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

[0108]

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

[0110] Example 1

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

[0112]

[0113] The steps include:

[0114] To 20mL of methanol solution, deuterated redox active ester (2.50g, 12.0mmol), tetrabutylammonium iodide (369mg, 1mmol), 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (5.08g, 20mmol), benzyl acrylate (1.62g, 10mmol) were added, and under nitrogen protection, 40W blue light lamp was used for continuous illumination, and stirred at 800r / min for 12 hours. After the reaction was complete, 0.80g of deuterated benzyl butyrate was obtained by column chromatography separation with a yield of 87%.

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

[0116] 1 H NMR (500MHz, Chloroform-d) δ2.36 (t, J = 7.4Hz, 2H), 1.68 (t, J = 7.4Hz, 2H).

[0117] 13 C NMR (126MHz, CDCl3) δ179.0,35.7,17.9.

[0118] Stability test:

[0119] The deuterated butyric acid obtained in Example 1 was dissolved in chloroform and stored at room temperature for 7 days. The nuclear magnetic resonance (NMR) test was performed again and no deterioration occurred. The obtained NMR hydrogen spectrum was as follows: Figure 3 As shown, the H NMR spectrum data are as follows:

[0120] 1H NMR (500MHz, Chloroform-d) δ2.36 (t, J = 7.4Hz, 2H), 1.68 (t, J = 7.4Hz, 2H).

[0121] pass Figure 1 and Figure 3 By comparison, it can be seen that the deuterated butyric acid obtained in Example 1 is deuterated at an inert site, has stable properties, and is not prone to hydrogen-deuterium exchange.

[0122] Example 2

[0123] A method for synthesizing deuterated butyric acid, the synthetic route is as follows:

[0124]

[0125] The steps include:

[0126] To 20mL DMSO solution, deuterated redox active ester (2.50g, 12.0mmol), tetrabutylammonium iodide (369mg, 1mmol), 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (5.08g, 20mmol), benzyl acrylate (1.62g, 10mmol) were added, and under nitrogen protection, 40W blue light lamp was used for continuous irradiation, and stirred at 800r / min for 12 hours. After the reaction was complete, 0.72g of deuterated benzyl butyrate was obtained by column chromatography, with a yield of 79%.

[0127] At room temperature, benzyl deuterated butyrate from the previous step was added to 20 mL of 1 M sodium hydroxide solution, the temperature was raised to 60° C., and stirred at 800 r / min for 30 min. The aqueous phase was then extracted and retained, and the pH was adjusted to acidic with 3 M hydrochloric acid. Deuterated butyric acid was then obtained by extraction and reduced pressure distillation with a yield of 100%.

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

[0129] Example 3

[0130] A method for synthesizing deuterated butyric acid, the synthetic route is as follows:

[0131]

[0132] The steps include:

[0133] To 20mL DMSO solution, deuterated redox active ester (2.50g, 12.0mmol), tetrabutylammonium iodide (369mg, 1mmol), 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (5.08g, 20mmol), benzyl acrylate (1.62g, 10mmol) were added, and under nitrogen protection, 40W blue light lamp was used for continuous irradiation, and stirred at 800r / min for 12 hours. After the reaction was complete, 0.77g of deuterated benzyl butyrate was obtained by column chromatography separation, with a yield of 85%.

[0134] At room temperature, benzyl deuterated butyrate from the previous step was added to 20 mL of 1 M sodium hydroxide solution, the temperature was raised to 60° C., and stirred at 800 r / min for 30 min. The aqueous phase was then extracted and retained, and the pH was adjusted to acidic with 3 M hydrochloric acid. Deuterated butyric acid was then obtained by extraction and vacuum concentration with a yield of 100%.

[0135] The H NMR spectrum of the deuterated butyric acid obtained in Example 3 is consistent with that in Example 1.

[0136] Example 4

[0137] A method for synthesizing deuterated butyric acid, the synthetic route is as follows:

[0138]

[0139] The steps include:

[0140] To 20 mL of tetrahydrofuran solution, 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) were added, and stirred at 60°C, 800 r / min for 12 hours under nitrogen protection. After the reaction was complete, 1.28 g of deuterated benzyl butyrate was obtained by column chromatography separation with a yield of 73%.

[0141] At room temperature, benzyl deuterated butyrate from the previous step was added to 20 mL of 1 M sodium hydroxide solution, the temperature was raised to 60° C., and stirred at 800 r / min for 30 min. The aqueous phase was then extracted and retained, and the pH was adjusted to acidic with 3 M hydrochloric acid. Deuterated butyric acid was then obtained by extraction and vacuum concentration with a yield of 100%.

[0142] The H NMR spectrum of the deuterated butyric acid obtained in Example 4 is consistent with that in Example 1.

[0143] Example 5

[0144] A method for synthesizing deuterated butyric acid, the synthetic route is as follows:

[0145]

[0146] The steps include:

[0147] To 20 mL of DMSO solution, 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) were added, and stirred at 60 ° C, 800 r / min for 12 hours under nitrogen protection. After the reaction was completed, 1.02 g of deuterated benzyl butyrate was separated by column chromatography, with a yield of 57%.

[0148] At room temperature, benzyl deuterated butyrate from the previous step was added to 20 mL of 1 M sodium hydroxide solution, the temperature was raised to 60° C., and stirred at 800 r / min for 30 min. The aqueous phase was then extracted and retained, and the pH was adjusted to acidic with 3 M hydrochloric acid. Deuterated butyric acid was then obtained by extraction and reduced pressure distillation with a yield of 100%.

[0149] The H NMR spectrum of deuterated butyric acid obtained in Example 5 is consistent with that in Example 1.

[0150] Example 6

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

[0152]

[0153] The steps include:

[0154] To 20 mL of DMA solution, 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) were added, and stirred at 60 ° C, 800 r / min for 12 hours under nitrogen protection. After the reaction was completed, 0.77 g of deuterated benzyl butyrate was separated by column chromatography, with a yield of 43%.

[0155] At room temperature, benzyl deuterated butyrate from the previous step was added to 20 mL of 1 M sodium hydroxide solution, the temperature was raised to 60° C., and stirred at 800 r / min for 30 min. The aqueous phase was then extracted and retained, and the pH was adjusted to acidic with 3 M hydrochloric acid. Deuterated butyric acid was then obtained by extraction and vacuum concentration with a yield of 100%.

[0156] The H NMR spectrum of the deuterated butyric acid obtained in Example 6 is consistent with that in Example 1.

[0157] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing deuterated butyric acid, characterized in that: include: The deuterated redox-active ester reacts with an acrylate compound to obtain a deuterated butyrate compound, which is hydrolyzed to obtain deuterated butyric acid; The structure of the deuterated redox-active ester is as follows: The structure of the deuterated butyrate compound is as follows: The structure of the deuterated butyric acid is as follows:

2. The synthesis method according to claim 1, characterized in that In the deuterated butyrate compound, R is selected from one of methyl, ethyl, tert-butyl, phenyl or benzyl.

3. The synthesis method according to claim 1, characterized in that The method for preparing the deuterated redox-active ester comprises the following steps: Tetradeuterated acetic acid reacts with N-hydroxyphthalimide to obtain a deuterated redox-active ester; Alternatively, tetradeuterated acetic acid reacts with oxalyl chloride to obtain trideuterated acetyl chloride, and trideuterated acetyl chloride reacts with N-hydroxyphthalimide to obtain a deuterated redox-active ester.

4. The synthesis method according to any one of claims 1 to 3, characterized in that: The synthesis method comprises: under the protection of nitrogen, under the action of light, a catalyst and a reducing agent, reacting a deuterated redox active ester with an acrylate compound to obtain a deuterated butyrate compound; At room temperature, the alkaline solution is mixed with the deuterated butyrate compound for hydrolysis to obtain deuterated butyric acid.

5. The synthesis method according to claim 4, characterized in that The light is one of red light, orange light, yellow light, green light, blue light or purple light; The catalyst is one of sodium iodide, potassium iodide, lithium iodide, tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium fluoride; The reducing agent is one of sodium borohydride, lithium aluminum hydride, trimethylsilane, tris(trimethylsilyl)silane or 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester; The molar ratio of the deuterated redox active ester, the acrylic acid ester compound, the reducing agent and the catalyst is 1:(1-1.5):(1-2):(0.01-0.2).

6. The synthesis method according to claim 4, characterized in that In the reaction, 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.

7. The synthesis method according to claim 4, characterized in that The base includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or triethylamine; The alkaline solution is an aqueous solution of alkali with a concentration of 5 to 25 wt%; The hydrolysis temperature is 20~70℃.

8. The synthesis method according to any one of claims 1 to 3, characterized in that: The synthesis method comprises: under the protection of nitrogen, under the action of heating and a reducing agent, reacting a deuterated redox active ester with an acrylate compound to obtain a deuterated butyrate compound; At room temperature, the alkaline solution is mixed with the deuterated butyrate compound for hydrolysis to obtain deuterated butyric acid.

9. The synthesis method according to claim 8, characterized in that Heating to 60-120°C, the deuterated redox active ester reacts with the acrylate compound; The reducing agent is one of sodium borohydride, lithium aluminum hydride, trimethylsilane, tris(trimethylsilyl)silane or 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester; The molar ratio of the deuterated redox active ester, the acrylic acid ester compound and the reducing agent is 1:(1-1.5):(1-2).

10. The synthesis method according to claim 8, characterized in that The base includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or triethylamine; The alkaline solution is an aqueous solution of alkali with a concentration of 5 to 25 wt%; The hydrolysis temperature is 20~70℃.

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