Synthesis method of deuterated alkyl carboxylic acid

Abstract

The invention discloses a synthetic method of deuterated alkyl carboxylic acid, and belongs to the technical field of chemical synthesis. The deuterated alkyl carboxylic acid is prepared by the following steps: reacting deuterated alkyl iodide with an acrylate compound to obtain an intermediate, and hydrolyzing to obtain the deuterated alkyl carboxylic acid; the structure of the deuterated alkyl iodide is R1-I; r1 is deuterated alkyl; the structure of the acrylate compound is # imgabs0 # R2 is selected from one of alkyl, substituted alkyl and aryl; the structure of the intermediate is # imgabs 1 #, the structure of the deuterated alkyl carboxylic acid is # imgabs 2 #, the deuterated site of the deuterated alkyl carboxylic acid is inert, hydrogen-deuterium exchange is not easy to occur, the selectivity is good, and the yield is high. And the long chain of the obtained deuterated alkyl carboxylic acid is variable, the deuterated alkyl iodide can be reasonably selected according to the structure of the target product, and the method has important significance on scientific research and 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 alkyl carboxylic 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] Selective deuterium labeling can greatly enhance the chemical stability and tolerance of drug molecules with little effect on their functions. And deuterium-labeled drugs are important tools for monitoring pharmacokinetics and elucidating metabolites. In addition, deuterium labeling is also widely used in synthetic organic chemistry to improve the stability of protecting groups and elucidate the mechanism of action. Therefore, exploring the chemical synthesis of deuterium-labeled molecules can open new doors for innovation and discovery of functional molecules in multiple scientific fields. Carboxylic acid is a common structural unit in medicinal chemistry and is present in various drugs, such as non-steroidal anti-inflammatory drugs (or NSAIDs) and natural products. The use of carboxylic acids is enhanced by their conversion into various valuable functions, and therefore, deuterium-labeled carboxylic acids are valuable deuterated compounds.

[0004] The existing method for synthesizing deuterated alkyl carboxylic acids is to deuterate at the ortho position of the carbonyl group, which is easy to exchange hydrogen and deuterium, but such deuterated products are easy to become non-deuterated products. For example, R. Yazaki et al. (Tanaka, T., Koga, Y., Honda, Y. et al. Ternary catalytic α-deuteration of carboxylic acids. Nat. Synth., 1, 824–830 (2022).) used a three-way catalytic system (K2CO3, Piv2O, DMAP) to efficiently achieve selective deuteration of the α position of carboxylic acid under mild conditions, but α-deuterated carboxylic acids can be easily converted into other labeled compounds, such as alcohols, aldehydes, esters and amides. Another synthetic method is to perform indiscriminate full deuteration modification on alkyl carboxylic acids, so that for more active sites, there is still the possibility of converting to partially non-deuterated products, which brings great difficulties to mass spectrometry analysis.

[0005] In summary, although people have been working hard to achieve efficient deuterium labeling methods for carboxylic acids, it remains a long-standing challenge to synthesize a deuterated alkyl carboxylic acid that is highly stable and not susceptible to hydrogen-deuterium exchange using a mild and simple method. Summary of the invention

[0006] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a method for synthesizing deuterated alkyl carboxylic acids. 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.

[0007] In order to achieve the above object, the technical solution of the present invention is:

[0008] The first aspect of the present invention provides a method for synthesizing a deuterated alkyl carboxylic acid, comprising:

[0009] The deuterated alkyl iodide reacts with an acrylate compound to obtain an intermediate, which is hydrolyzed to obtain a deuterated alkyl carboxylic acid;

[0010] The structure of the deuterated alkyl iodide is as follows:

[0011] R1-I;

[0012] R1 is a deuterated alkyl group;

[0013] The structure of the acrylate compound is as follows:

[0014]

[0015] R2 is selected from one of an alkyl group, a substituted alkyl group and an aromatic group;

[0016] The structure of the intermediate is as follows:

[0017]

[0018] The structure of the deuterated alkyl carboxylic acid is as follows:

[0019]

[0020] In some embodiments of the present invention, the R1 is selected from a C1-C6 deuterated alkyl group, and the R2 is selected from a C1-C6 alkyl group or an aromatic group.

[0021] In some embodiments of the present invention, the R1 is selected from a C1-C3 deuterated alkyl group, and the R2 is selected from a C1-C3 alkyl group or an aromatic group.

[0022] In some embodiments of the present invention, the R1 is selected from one of deuterated methyl, deuterated ethyl or deuterated propyl, and the R2 is selected from one of methyl, ethyl, n-propyl, isopropyl, tert-butyl, phenyl or benzyl.

[0023] In some embodiments of the present invention, the R1 is selected from one of a perdeuterated methyl group or a deuterated propyl group, and the R2 is selected from one of a phenyl group or a benzyl group.

[0024] In some embodiments of the present invention, the synthesis method comprises:

[0025] Under the action of light, a catalyst and a reducing agent, the deuterated alkyl iodide reacts with the acrylate compound to obtain an intermediate;

[0026] At room temperature, a base solution is mixed with the intermediate to hydrolyze the intermediate to obtain a deuterated alkyl carboxylic acid.

[0027] In some embodiments of the present invention, the light source of the illumination is selected from one of red light, orange light, yellow light, green light, blue light or purple light;

[0028] The catalyst is selected from FeCl3, [(CH3CN)4Cu]PF6, Rh2(OAc)4, Mn(CO)5I, Mn(CO)5I or Mn2(CO 10 One of;

[0029] The reducing agent is selected from one of sodium borohydride, lithium aluminum hydride, trimethylsilane, tris(trimethylsilyl)silane or 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester;

[0030] The molar ratio of the deuterated alkyl iodide, the acrylate compound, the reducing agent and the catalyst is 1:(1-1.5):(1-2):(0.01-0.2).

[0031] In some embodiments of the present invention, in the reaction, the reaction solvent is selected from one of methanol, ethanol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylformamide.

[0032] In some embodiments of the present invention, the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or triethylamine;

[0033] The solvent of the alkaline solution is water, and the concentration is 5 to 25 wt%;

[0034] The hydrolysis temperature is 20~70℃.

[0035] In some embodiments of the present invention, the synthesis method further comprises the steps of adjusting the pH of the obtained solution to acidic, extracting, and concentrating to obtain deuterated alkyl carboxylic acid after the hydrolysis is completed.

[0036] The beneficial effects of the present invention are:

[0037] The present invention provides a method for synthesizing deuterated alkyl carboxylic acid, wherein deuterated alkyl iodide and acrylate compound are used as starting materials, a free radical addition reaction occurs in a solvent under light, and after hydrolysis, a deuterated alkyl carboxylic acid is obtained, and a relatively complex long-chain alkyl carboxylic acid is obtained by using a cheap and readily available deuterated product, the deuterated site is inert, hydrogen-deuterium exchange is not likely to occur, the selectivity is good, and the yield is high. Furthermore, the long chain of the deuterated alkyl carboxylic acid obtained by the present invention is variable, and the deuterated alkyl iodide can be reasonably selected according to the structure of the target product, which is of great significance for scientific research and the development of deuterated drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] 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.

[0039] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of deuterated butyric acid prepared in Example 1 of the present invention;

[0040] Figure 2 This is the carbon NMR spectrum of deuterated butyric acid prepared in Example 1 of the present invention;

[0041] Figure 3 This is the stability test hydrogen spectrum of deuterated butyric acid prepared in Example 1 of the present invention under chloroform dissolution conditions;

[0042] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of deuterated 4-methylpentanoic acid prepared in Example 2 of the present invention;

[0043] Figure 5 This is the carbon nuclear magnetic resonance spectrum of deuterated 4-methylpentanoic acid prepared in Example 2 of the present invention;

[0044] Figure 6 The stability test hydrogen spectrum of deuterated 4-methylpentanoic acid prepared in Example 2 of the present invention under chloroform dissolution conditions;

[0045] Figure 7 This is a hydrogen spectrum of the stability test of deuterated 4-methylpentanoic acid prepared in Example 2 of the present invention in aqueous solution. DETAILED DESCRIPTION

[0046] 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.

[0047] A first typical embodiment of the present invention provides a method for synthesizing a deuterated alkyl carboxylic acid, comprising:

[0048] The deuterated alkyl iodide reacts with an acrylate compound to obtain an intermediate, which is hydrolyzed to obtain a deuterated alkyl carboxylic acid;

[0049] The structure of the deuterated alkyl iodide is as follows:

[0050] R1-I;

[0051] R1 is a deuterated alkyl group;

[0052] The structure of the acrylate compound is as follows:

[0053]

[0054] R2 is selected from one of an alkyl group, a substituted alkyl group and an aromatic group;

[0055] The structure of the intermediate is as follows:

[0056]

[0057] The structure of the deuterated alkyl carboxylic acid is as follows:

[0058]

[0059] The synthesis route of deuterated butyric acid provided by the present invention is as follows:

[0060]

[0061] The invention uses cheap and readily available deuterated alkyl iodides and acrylate compounds as raw materials to obtain relatively complex deuterated long-chain alkyl carboxylic acids through free radical addition reaction and hydrolysis. The main chain length of the obtained deuterated alkyl carboxylic acid can be controlled by the main chain length of the deuterated alkyl iodide, and the chain length is variable, which provides a new research direction for scientific research and the development of deuterated drugs and is of great significance.

[0062] The deuterated alkyl carboxylic acid synthesized by the present invention is deuterated at an inert site, is not prone to hydrogen-deuterium exchange, has high stability, good selectivity and high yield. The uses of the deuterated alkyl carboxylic acid obtained by the present invention include but are not limited to instrumental analysis, isotope labeling, mechanism research, drug development and material science and other fields.

[0063] It should be noted that only deuterated alkyl iodides can react with acrylate compounds to obtain the corresponding target product. If they are replaced with deuterated alkyl chlorides, deuterated alkyl bromides, etc., the reaction cannot proceed smoothly and the target product cannot be obtained smoothly.

[0064] It should be noted that the present invention does not impose any limitation on the type of deuterated alkyl, and it can be any deuterated alkyl, which can be specifically determined according to the structure of the target product. For example, if the target product is deuterated butyric acid, the deuterated alkyl is a deuterated methyl group; if the target product is deuterated pentanoic acid, the deuterated alkyl is a deuterated ethyl group containing one carbon atom.

[0065] In some examples of this embodiment, in order to reduce production costs, the R1 is selected from low-cost C1-C6 deuterated alkyl groups, such as deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated n-butyl, deuterated isobutyl, deuterated sec-butyl, deuterated tert-butyl, deuterated n-pentyl, deuterated n-hexyl, and the like; the R2 is selected from one of the C1-C6 alkyl or aromatic groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, phenyl, benzyl, o-tolyl, 1-naphthyl (or α-naphthyl), 2-naphthyl, and the like.

[0066] More specifically, R1 is selected from C1-C3 deuterated alkyl, specifically deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl; R2 is selected from C1-C3 alkyl or aromatic groups, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, and the like.

[0067] More specifically, the R1 is selected from one of deuterated methyl, deuterated ethyl or deuterated propyl, and the R2 is selected from one of methyl, ethyl, tert-butyl, phenyl or benzyl.

[0068] More specifically, the inventors found that when R2 is an aromatic group, the yield of the reaction of deuterated alkyl iodide and acrylate compound is higher, therefore, R1 is selected from one of perdeuterated methyl or deuterated propyl, and R2 is selected from one of phenyl or benzyl.

[0069] In some embodiments of the present invention, the deuterated alkyl iodide is selected from one of perdeuterated iodomethane and deuterated 2-iodopropane, and the acrylate compound is methyl acrylate.

[0070] It should be noted that the CAS number of the perdeuterated iodomethane is 865-50-9, and its molecular formula is CD3I. It is an existing product and can be purchased, such as from Shanghai Haohong.

[0071] The molecular formula of the deuterated 2-iodopropane is C3D6HI, and the structure is as follows:

[0072]

[0073] The synthetic route of the deuterated 2-iodopropane is as follows:

[0074]

[0075] Specifically, it can be prepared by the following method:

[0076] Dissolve deuterated acetone in a dichloromethane solution, dissolve NaBH4 in a methanol solution, and add the mixture dropwise to the dichloromethane solution containing deuterated acetone under ice bath conditions to react, then extract with DCM / H2O, retain the organic phase, and spin dry to obtain deuterated isopropanol;

[0077] Dissolve triphenylphosphine and elemental iodine in diethylene glycol dimethyl ether, stir at room temperature, add imidazole, stir at room temperature, add deuterated isopropanol obtained in the previous step, react at room temperature, and then obtain deuterated 2-iodopropane by atmospheric distillation.

[0078] In some embodiments of the present invention, the synthesis method comprises:

[0079] Under the action of light, a catalyst and a reducing agent, the deuterated alkyl iodide reacts with the acrylate compound to obtain an intermediate;

[0080] At room temperature, a base solution is mixed with the intermediate to hydrolyze the intermediate to obtain a deuterated alkyl carboxylic acid.

[0081] The detailed synthetic route is as follows:

[0082]

[0083] More specifically, deuterated alkyl iodide, acrylate compound, catalyst and reducing agent are added to the reaction solvent, and the mixture is irradiated with light and stirred under nitrogen protection. After the reaction is complete, the mixture is separated to obtain an intermediate;

[0084] At room temperature, the intermediate is added to an alkaline solution for hydrolysis to obtain a deuterated alkyl carboxylic acid.

[0085] It should be noted that the separation can be carried out by column chromatography or by atmospheric distillation. If atmospheric distillation is used for separation, the fraction at 100-105° C. is collected to obtain an intermediate.

[0086] In some embodiments of the present invention, the light source of the illumination is selected from one of red light, orange light, yellow light, green light, blue light or purple light, preferably blue light.

[0087] It should be noted that under light, the deuterated alkyl iodide 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.

[0088] In some embodiments of the present invention, the catalyst is a metal catalyst, including but not limited to FeCl3, [(CH3CN)4Cu]PF6, Rh2(OAc)4, Mn(CO)5I, Mn(CO)5I or Mn2(CO) 10 One of them.

[0089] In some embodiments of the present invention, the reducing agent is selected from 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.

[0090] In some embodiments of the present invention, the molar ratio of the deuterated alkyl iodide, the acrylate compound, the reducing agent and the catalyst is 1:(1-1.5):(1-2):(0.01-0.2).

[0091] In some embodiments of the present invention, the reaction temperature is 0-60°C, specifically 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, etc., and stirring is carried out during the reaction at a speed of 800r / min.

[0092] In some embodiments of the present invention, the reaction solvent is selected from one of methanol, ethanol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide (DMSO) or N,N-dimethylformamide, preferably one of methanol, acetonitrile or DMSO.

[0093] In some embodiments of the present invention, 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.

[0094] In some embodiments of the present invention, the solvent of the alkaline solution is water, and the concentration is 5 to 25 wt %;

[0095] In some embodiments of the present invention, the hydrolysis temperature is 20-70°C.

[0096] 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 min, to ensure rapid and complete hydrolysis of the intermediate.

[0097] In some embodiments of the present invention, the synthesis method further comprises the steps of adjusting the pH of the obtained solution to acidic, extracting, and concentrating to obtain deuterated alkyl carboxylic acid after the hydrolysis is completed.

[0098] It should be noted that the present invention has no particular restrictions on the method and parameters for adjusting the pH of the obtained solution to acidity, and the method and parameters for adjusting the pH of the obtained solution to acidity well known to those skilled in the art can be used. The present invention has no particular restrictions on the method and parameters for extraction, and the method and parameters for extraction well known to those skilled in the art can be used.

[0099] It should be noted that the concentration is vacuum concentration or reduced pressure distillation. The present invention has no particular limitation on the method of vacuum concentration or reduced pressure distillation, and any vacuum concentration or reduced pressure distillation method known to those skilled in the art can be used.

[0100] Compared with the existing process, the synthesis method of deuterated alkyl carboxylic acid provided by the invention adopts cheap deuterated alkyl iodide as raw material, efficiently synthesizes long-chain deuterated alkyl carboxylic acid with higher value, does not require high temperature and high pressure environment, and has mild reaction conditions; at the same time, strong reducing agent and strong oxidizing agent are not used, and the reaction safety is higher; the deuterated site of the obtained deuterated alkyl carboxylic acid is inert, hydrogen-deuterium exchange is not easy to occur, the selectivity is good, the yield is high, the purity can reach up to 98%, and the yield can reach up to 85%, and the method has good application prospects.

[0101] 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.

[0102] 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.

[0103] The deuterated iodomethane used in the following examples was purchased from Shanghai Haohong, and the deuterated 2-iodopropane was prepared as follows:

[0104]

[0105] 1.12 g of deuterated acetone was dissolved in 20 mL of dichloromethane solution, 380 mg of NaBH4 was dissolved in 5 mL of methanol solution, and the mixture was added dropwise to the dichloromethane solution containing deuterated acetone under ice bath conditions. The mixture was reacted for 1 h, and then extracted with DCM / H2O. The organic phase was retained and dried to obtain deuterated isopropanol with a yield of 100%.

[0106] 6.2 g of triphenylphosphine and 6.01 g of elemental iodine were dissolved in diethylene glycol dimethyl ether, stirred at room temperature for 10 min, and then 1.63 g of imidazole was added. After stirring at room temperature for 10 min, deuterated isopropanol obtained in the previous step was added, and the reaction was carried out at room temperature for 5 h. Subsequently, 2.34 g of deuterated 2-iodopropane was obtained by atmospheric distillation with a yield of 67%.

[0107] Example 1

[0108] A method for synthesizing deuterated butyric acid, the synthetic route is as follows:

[0109]

[0110] To 20 mL of methanol solution, deuterated iodomethane (1.44 g, 10.0 mmol), Mn2(CO) 10 (398mg, 1mmol), 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (5.08g, 20mmol), methyl acrylate (1.29g, 15mmol), under nitrogen protection, continuously irradiated with a 40W blue light lamp, stirred at 800r / min for 12 hours. After the reaction is complete, the 100-105℃ fraction is collected by atmospheric distillation to obtain 0.73g of the intermediate, with a yield of 69%.

[0111] At room temperature, the intermediate of the previous step was added to 20 mL of 1 M sodium hydroxide solution, the temperature was raised to 60° C. and stirred rapidly for 30 min, and then the pH was adjusted to acidic with 3 M hydrochloric acid, followed by extraction, vacuum concentration / reduced pressure distillation to obtain deuterated butyric acid with a yield of 100%.

[0112] 1 H NMR (500MHz, Chloroform-d) δ2.36 (t, J = 7.4Hz, 2H), 1.68 (t, J = 7.4Hz, 2H).

[0113] 13 C NMR (126MHz, CDCl3) δ179.0,35.7,17.9.

[0114] Stability test:

[0115] The deuterated butyric acid obtained in Example 1 was stored at room temperature for 7 days under chloroform dissolution conditions, and then re-NMR detection was performed. No deterioration occurred, and the obtained NMR hydrogen spectrum data were as follows:

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

[0117] Example 2

[0118] A method for synthesizing deuterated 4-methylpentanoic acid, the synthetic route is as follows:

[0119]

[0120] To 20 mL of methanol solution, deuterated 2-iodopropane (1.76 g, 10.0 mmol), Mn2(CO) 10 (398mg, 1mmol), 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (5.08g, 20mmol), methyl acrylate (1.29g, 15mmol), under nitrogen protection, continuously irradiated with a 40W blue light lamp, and rapidly stirred for 12 hours. After the reaction is complete, the 140-145°C fraction is collected by atmospheric distillation to obtain 1.03g of the intermediate, with a yield of 76%.

[0121] At room temperature, the intermediate of the previous step was added to 20 mL of 1 M sodium hydroxide solution, the temperature was raised to 60 ° C and stirred rapidly for 30 min, and then the pH was adjusted to acidic with 3 M hydrochloric acid, followed by extraction, vacuum concentration / reduced pressure distillation to obtain deuterated 4-methylpentanoic acid with a yield of 100%.

[0122] 1 H NMR(500MHz,Chloroform-d)δ7.42–7.34(m,8H),7.21–7.16(m,2H),7.13(t,J=7.6 Hz, 1H), 6.30 (s, 1H), 5.59 (s, 1H), 5.21 (s, 2H), 3.77 (s, 3H), 3.14 (d, J = 7.6Hz, 2H).

[0123] 13C NMR (126MHz, CDCl3) δ167.4,166.2,140.7,137.8,135.8,135.4,134.7,129.5,128.6,128.3,128.2,128.2,127.8,126.7,66.7,52.2,31.8.

[0124] Stability test:

[0125] The deuterated 4-methylpentanoic acid obtained in Example 2 was stored at room temperature for 7 days under chloroform dissolution conditions, and then re-NMR detection was performed. No deterioration occurred, and the obtained NMR hydrogen spectrum data were as follows:

[0126] 1 H NMR (500MHz, Chloroform-d) δ2.28 (dd, J=8.4, 6.7Hz, 2H).

[0127] The deuterated 4-methylpentanoic acid obtained in Example 2 was stored in an aqueous solution at room temperature for 30 days, and then purified and re-tested by nuclear magnetic resonance. No deterioration occurred, and the obtained nuclear magnetic hydrogen spectrum data were as follows:

[0128] 1 H NMR (500MHz, Chloroform-d) δ2.28 (dd, J=8.4, 6.7Hz, 2H).

[0129] Example 3

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

[0131]

[0132] To 20 mL of acetonitrile solution, add deuterated iodomethane (1.44 g, 10.0 mmol), Mn2(CO) 10 (398mg, 1mmol), 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (5.08g, 20mmol), methyl acrylate (1.29g, 15mmol), under nitrogen protection, continuously irradiated with a 40W blue light lamp, and rapidly stirred for 12 hours. After the reaction is complete, the 100-105°C fraction is collected by atmospheric distillation to obtain 0.65g of the intermediate with a yield of 62%.

[0133] At room temperature, the intermediate of the previous step was added to 20 mL of 1 M sodium hydroxide solution, the temperature was raised to 60° C. and stirred rapidly for 30 min, and then the pH was adjusted to acidic with 3 M hydrochloric acid, followed by extraction and reduced pressure distillation to obtain deuterated butyric acid with a yield of 100%.

[0134] The NMR spectrum of deuterated butyric acid obtained in Example 3 is consistent with that in Example 1.

[0135] Example 4

[0136] A method for synthesizing deuterated butyric acid, the synthetic route is as follows:

[0137]

[0138] To 20 mL of DMSO solution, add deuterated iodomethane (1.44 g, 10.0 mmol), Mn2(CO) 10 (398mg, 1mmol), 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (5.08g, 20mmol), methyl acrylate (1.29g, 15mmol), under nitrogen protection, continuously irradiated with a 40W blue light lamp, and rapidly stirred for 12 hours. After the reaction is complete, the 100-105°C fraction is collected by atmospheric distillation to obtain 0.77g of the intermediate with a yield of 85%.

[0139] At room temperature, the intermediate of the previous step was added to 20 mL of 1 M sodium hydroxide solution, the temperature was raised to 60° C. and stirred rapidly for 30 min, and then the pH was adjusted to acidic with 3 M hydrochloric acid, followed by extraction and vacuum concentration to obtain deuterated butyric acid with a yield of 100%.

[0140] The NMR spectrum of deuterated butyric acid obtained in Example 4 is consistent with that in Example 1.

[0141] 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 a deuterated alkyl carboxylic acid, characterized in that: include: The deuterated alkyl iodide reacts with an acrylate compound to obtain an intermediate, which is hydrolyzed to obtain a deuterated alkyl carboxylic acid; The structure of the deuterated alkyl iodide is as follows: R1-I; R1 is a deuterated alkyl group; The structure of the acrylate compound is as follows: R2 is selected from one of an alkyl group, a substituted alkyl group and an aromatic group; The structure of the intermediate is as follows: The structure of the deuterated alkyl carboxylic acid is as follows:

2. The synthesis method according to claim 1, characterized in that The R1 is selected from a C1-C6 deuterated alkyl group, and the R2 is selected from a C1-C6 alkyl group or an aromatic group.

3. The synthesis method according to claim 1, characterized in that The R1 is selected from a C1-C3 deuterated alkyl group, and the R2 is selected from a C1-C3 alkyl group or an aromatic group.

4. The synthesis method according to claim 1, characterized in that The R1 is selected from one of deuterated methyl, deuterated ethyl or deuterated propyl, and the R2 is selected from one of methyl, ethyl, n-propyl, isopropyl, tert-butyl, phenyl or benzyl.

5. The synthesis method according to claim 1, characterized in that The R1 is selected from one of a perdeuterated methyl group or a deuterated propyl group, and the R2 is selected from one of a phenyl group or a benzyl group.

6. The synthesis method according to any one of claims 1 to 5, characterized in that: The synthesis method comprises: Under the action of light, a catalyst and a reducing agent, the deuterated alkyl iodide reacts with the acrylate compound to obtain an intermediate; At room temperature, a base solution is mixed with the intermediate to hydrolyze the intermediate to obtain a deuterated alkyl carboxylic acid.

7. The synthesis method according to claim 6, characterized in that The light source of the illumination is selected from one of red light, orange light, yellow light, green light, blue light or purple light; The catalyst is selected from FeCl3, [(CH3CN)4Cu]PF6, Rh2(OAc)4, Mn(CO)5I, Mn(CO)5I or Mn2(CO 10 One of; The reducing agent is selected from 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 alkyl iodide, the acrylate compound, the reducing agent and the catalyst is 1:(1-1.5):(1-2):(0.01-0.2).

8. The synthesis method according to claim 6, characterized in that In the reaction, the reaction solvent is selected from one of methanol, ethanol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylformamide.

9. The synthesis method according to claim 6, characterized in that The base includes one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate or triethylamine; The solvent of the alkaline solution is water, and the concentration is 5 to 25 wt%; The hydrolysis temperature is 20~70℃.

10. The synthesis method according to claim 6, characterized in that The synthesis method further comprises the steps of adjusting the pH of the obtained solution to acidity, extracting, and concentrating to obtain deuterated alkyl carboxylic acid after the hydrolysis is completed.

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