Preparation method of deuterated acrylamide

Abstract

The invention belongs to the technical field of organic synthesis, and relates to a preparation method of deuterated acrylamide. Methyl acrylate and deuterium water are used as raw materials, deuterated acrylic acid is obtained through a hydrogen-deuterium exchange reaction, then deuterated methyl acrylate is generated through an acylating chlorination reaction and an esterification reaction, and deuterated acrylamide is prepared through an ammonolysis reaction of the deuterated methyl acrylate and an aminomethanol solution. According to the preparation method provided by the invention, the deuterated acrylamide with the deuteration rate not lower than 97% and the purity not lower than 99% can be prepared, and a method which is short in synthetic route, convenient and easy to obtain raw materials and high in synthetic product purity is provided for preparation of the deuterated acrylamide.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology and relates to a method for preparing deuterated acrylamide. Background Technology

[0002] Acrylamide (AM) is a white crystalline solid at room temperature and pressure, not easily volatile, with the chemical formula C3H5NO and a relative molecular mass of 71.08. Acrylamide is the most important and simplest of the acrylamide family, used as a raw material in organic synthesis and polymer materials, primarily for the production of polyacrylamide. Since its industrial application in 1954, demand has gradually increased. Acrylamide can also be used as an oil displacement agent and thickener in oil extraction, improving crude oil recovery and drilling fluid performance; as a reinforcing agent and retention aid in the paper industry, increasing paper strength and papermaking efficiency; and as a soil conditioner, increasing soil water permeability and moisture retention. Acrylamide exhibits multiple toxicities to humans and animals. The International Agency for Research on Cancer (IARC) classified it as a Group 2A carcinogen in 1994, with its main toxicities including neurotoxicity, reproductive toxicity, genotoxicity, and carcinogenicity.

[0003] Deuterated acrylamide is a deuterated derivative of acrylamide and has significant applications in scientific research and industry. In analytical methods such as gas chromatography-mass spectrometry (GC-MS), deuterated acrylamide can be used as an internal standard for the quantitative detection of acrylamide content in food and environmental samples. Its deuterated nature makes it less susceptible to interference from the sample matrix during analysis, improving the accuracy and sensitivity of detection. In metabolic studies, deuterated acrylamide can be used to track the metabolic pathways and kinetics of acrylamide in vivo, providing a scientific basis for assessing its toxicity. Deuterated acrylamide can also serve as an intermediate in the synthesis of other deuterated compounds, used to prepare deuterated polymers or drug molecules with specific properties.

[0004] However, there are few reported methods for synthesizing deuterated acrylamide, and commercially available deuterated acrylamide is expensive. Existing synthetic methods suffer from low deuteration rates and low purity of the products. Therefore, it is of great significance to study a synthetic method for deuterated acrylamide that can synthesize deuterated acrylamide with high deuteration rates and high purity. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a method for preparing deuterated acrylamide. The method uses methyl acrylate and deuterated water as raw materials, obtaining deuterated acrylic acid through a hydrogen-deuterium exchange reaction. Subsequently, methyl acrylate is generated through an acylation reaction and an esterification reaction. Deuterated acrylamide is then prepared by ammonolysis of the deuterated methyl acrylate with an ammonia-methanol solution. The preparation method provided by this invention can produce deuterated acrylamide with a deuteration rate of not less than 97% and a purity of not less than 99%, providing a method for the preparation of deuterated acrylamide with a short synthetic route, readily available raw materials, and high-purity synthesized products.

[0006] To achieve the technical objective of this invention, on one hand, this invention provides a method for preparing deuterated acrylamide, the synthetic route of which is shown below, specifically including the following steps:

[0007] S1: Under nitrogen protection, methyl acrylate, deuterated water, first solvent, strong base, and catalyst were heated and refluxed in an oil bath for 24 hours. After the deuteration rate was found to be qualified, the aqueous phase was extracted with diethyl ether, the organic phase was dried, and the organic phase was removed by evaporation at normal pressure to obtain deuterated acrylic acid.

[0008] Furthermore, the molar ratio of methyl acrylate to deuterium water is not less than 0.08:20, the volume ratio of deuterium water to the first solvent is 10~30:1, the molar ratio of methyl acrylate to the strong base is 1:0.1~0.3, and the weight ratio of methyl acrylate to 5wt% ruthenium carbon is 10~20:1. The first solvent is tert-butanol D1, the strong base is potassium tert-butoxide, and the catalyst is 5wt% ruthenium carbon.

[0009] S2: Dissolve the deuterated acrylic acid obtained in S1 in the second solvent, add sulfoxide dropwise under ice bath, remove the organic phase after the reaction is complete, and distill the mother liquor to obtain methyl deuterated acrylate.

[0010] Furthermore, the molar ratio of deuterated acrylic acid to the second solvent is 1:10~30, and the molar ratio of thionyl chloride to deuterated acrylic acid is 0.8~1.2:1. The second solvent is methanol D1.

[0011] S3: Dissolve methyl deuterated acrylate in a 7M ammonia-methanol solution, add it to a 100mL pressure vessel, heat and stir at 30~55℃ for 18~72h. After the reaction is complete, remove the solvent by evaporation, and perform column chromatography on the crude product. The chromatographic solution is petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain the final product, deuterated acrylamide.

[0012] Furthermore, the molar ratio of methyl deuterated acrylate to ammonia in a methanol solution of 7M ammonia is 1:3~10.

[0013] On the other hand, the present invention claims protection for a deuterated acrylamide prepared by the above-described preparation method.

[0014] Specifically, the deuterated acrylamide prepared by this method has a deuteration rate of not less than 97% and a purity of not less than 99%.

[0015] On the other hand, the present invention seeks protection for the use of the above-mentioned deuterated acrylamide in the quantitative detection of acrylamide content in samples.

[0016] Furthermore, this invention seeks protection for the use of the aforementioned deuterated acrylamide in the synthesis of deuterated polymeric materials / deuterated polymeric drugs.

[0017] Compared with the prior art, the technical solution provided by the present invention has at least the following beneficial effects or advantages: (1) This invention provides a method for preparing deuterated acrylamide with high deuteration rate, short synthetic route, readily available raw materials, and high purity of the synthesized product. This invention uses methyl acrylate and deuterated water as raw materials, and obtains deuterated acrylic acid through a hydrogen-deuterium exchange reaction. Subsequently, it generates deuterated methyl acrylate through an acylation reaction and an esterification reaction. The deuterated methyl acrylate is then reacted with an ammonia-methanol solution through an ammonolysis reaction to prepare deuterated acrylamide. The preparation method provided by this invention can produce deuterated acrylamide with a deuteration rate of not less than 97% and a purity of not less than 99%.

[0018] (2) In this invention, the addition of a strong base to the isotope transesterification reaction promotes the deuteration reaction. The strong base removes the α-proton from methyl acrylate, forming an enol anion intermediate, thereby enhancing its nucleophilicity and promoting the deuteration reaction of methyl acrylate with deuterated water. In the ammonolysis reaction of this invention, an ammonia-methanol solution is added. Ammonia, as a strong nucleophile, attacks the carbonyl carbon of the deuterated methyl acrylate, initiating a nucleophilic addition-elimination reaction to generate acrylamide. High concentrations of ammonia can also stabilize the reaction intermediate through hydrogen-deuterium exchange, preventing the deuterated group from being lost at high temperatures. Methanol, as a solvent, promotes the dissolution of ammonia and the uniformity of the reaction. The polar environment it provides helps maintain the stability of the deuterated product. Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0020] Figure 1 This is the 1H NMR spectrum of deuterated methyl acrylate.

[0021] Figure 2 This is the 1H NMR spectrum of deuterated acrylamide. Detailed Implementation

[0022] The technical solution of the present invention will be described below with reference to embodiments. However, the present invention is not limited to the following embodiments. Unless otherwise specified, the experimental methods and detection methods described in each embodiment are conventional methods; unless otherwise specified, the reagents and materials can be purchased commercially. Unless otherwise specified, the percentages in the following embodiments refer to mass percentages.

[0023] The method for preparing deuterated acrylamide of the present invention specifically includes the following steps: S1: Under nitrogen protection, methyl acrylate, deuterium water, first solvent, strong base, and 500 mg of 5 wt% ruthenium carbon were heated and refluxed in an oil bath for 24 h. After the deuteration rate was found to be qualified, the aqueous phase was extracted with diethyl ether, the organic phase was dried, and the organic phase was evaporated at atmospheric pressure to obtain deuterated acrylic acid.

[0024] Furthermore, the molar ratio of methyl acrylate to deuterium water is not less than 0.08:20, the volume ratio of deuterium water to the first solvent is 10~30:1, the molar ratio of methyl acrylate to the strong base is 1:0.1~0.3, and the weight ratio of methyl acrylate to 5wt% ruthenium carbon is 10~20:1. The first solvent is tert-butanol D1, and the strong base is potassium tert-butoxide.

[0025] S2: Dissolve the deuterated acrylic acid obtained in S1 in the second solvent, add sulfoxide dropwise under ice bath, remove the organic phase after the reaction is complete, and distill the mother liquor to obtain methyl deuterated acrylate.

[0026] Furthermore, the molar ratio of deuterated acrylic acid to the second solvent is 1:10~40, and the molar ratio of thionyl chloride to deuterated acrylic acid is 0.8~1.2:1. The second solvent is methanol D1.

[0027] S3: Dissolve methyl deuterated acrylate in a 7M ammonia-methanol solution, add it to a 100mL pressure vessel, heat and stir at 30~55℃ for 36h. After the reaction is complete, remove the solvent by evaporation, and perform column chromatography on the crude product. The chromatographic solution is petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain the final product, deuterated acrylamide.

[0028] Furthermore, the molar ratio of methyl deuterated acrylate to ammonia in a methanol solution of 7M ammonia is 1:3~10.

[0029] Example 1 This embodiment provides the preparation of deuterated acrylamide. The synthetic route is shown below, and specifically includes the following steps:

[0030] S1: Under nitrogen protection, methyl acrylate (6.93 g, 0.08 mol), deuterated water (100 mL), tert-butanol D1 (5 mL), potassium tert-butoxide (1 g, 0.0089 mol), and 500 mg of 5 wt% ruthenium carbon were heated to reflux in an oil bath for 24 h. After the deuteration rate was found to be qualified, the aqueous phase was extracted with diethyl ether, the organic phase was dried, and the organic phase was evaporated at atmospheric pressure to obtain 5.5 g of crude deuterated acrylic acid, which was directly used in the next step.

[0031] S2: Deuterated acrylic acid was dissolved in 100 mL of methanol D1 (2.46 mol), and 5 mL of sulfoxide (0.071 mol) was added dropwise under ice bath conditions. The reaction progress was monitored. After the reaction was completed, the organic phase was removed, and the mother liquor was distilled to obtain compound 3, methyl deuterated acrylate (6.2 g, yield 92%). The 1H NMR spectrum of compound 3 is shown below. Figure 1 The results of the proton nuclear magnetic resonance spectrum are shown below: ¹H NMR (600 MHz, Chloroform-d) δ 6.37 – 6.25 (m, 0.02H), 6.05 (d, J = 3.6 Hz, 0.02H), 5.74 (d, J = 2.2 Hz, 0.02H), 3.69 (s, 3H).

[0032] S3: Deuterated methyl acrylate (6 g, 0.067 mol) was dissolved in 50 mL of 7 M ammonia in methanol solution, added to a 100 mL pressure vessel, heated and stirred at 45 °C for 36 h. After the reaction was completed, the solvent was evaporated, and the crude product was subjected to column chromatography (Pe:EA = 2:1) to obtain the final product deuterated acrylamide (4 g, yield 80%).

[0033] Determination of the deuteration degree and purity of the product: 7.1 mg (0.0959 mmol) of the prepared deuterated acrylamide and 11.1 g (0.1009 mmol) of the internal standard hydroquinone were weighed and placed in an NMR tube. 0.5 mL of DMSO-d6 was added. The resulting 1H NMR spectrum of the deuterated acrylamide is shown below. Figure 2 The 1H NMR spectrum results are shown below: 1H NMR (600 MHz, DMSO-d6) δ 8.60 (s, 2H), 7.50 (s, 0.95H), 7.05 (s, 0.95H), 6.56 (s, 4H), 6.17 (s, 0.02H), 6.05 (s, 0.02H), 5.57 (s, 0.02H). The deuteration degree and purity were calculated based on the integrated areas of the corresponding peaks. The deuteration degree is: 1 - (0.02 / 0.95) = 97.9%; the purity is: 0.95% × 1.009 ÷ 0.959 = 99.9%.

[0034] Example 2 This embodiment provides the preparation of deuterated acrylamide, specifically including the following steps: S1: Under nitrogen protection, methyl acrylate (6.93 g, 0.08 mol), deuterated water (150 mL, 30 mol), tert-butanol D1 (15 mL), potassium tert-butoxide (1.8 g, 0.016 mol), and 5 wt% ruthenium carbon 690 mg were heated to reflux in an oil bath for 24 h. After the deuteration rate was found to be qualified, the aqueous phase was extracted with diethyl ether, the organic phase was dried, and the organic phase was evaporated at atmospheric pressure to obtain 5.6 g of crude deuterated acrylic acid, which was directly used in the next step.

[0035] S2: Dissolve deuterated acrylic acid in 35 mL of methanol D1 (0.86 mol), add 4.5 mL of thionyl chloride (0.062 mol) dropwise under ice bath, monitor the reaction progress, remove the organic phase after the reaction is completed, and distill the mother liquor to obtain compound methyl 3-deuterated acrylate (6.3 g, yield 94%).

[0036] S3: Deuterated methyl acrylate (6 g, 0.067 mol) was dissolved in 30 mL of 7 M ammonia in methanol solution, added to a 100 mL pressure vessel, heated and stirred at 30 °C for 72 h. After the reaction was completed, the solvent was evaporated, and the crude product was subjected to column chromatography (Pe:EA = 2:1) to obtain the final product deuterated acrylamide (4.3 g, yield 86%).

[0037] Example 3 This embodiment provides the preparation of deuterated acrylamide, specifically including the following steps: S1: Under nitrogen protection, methyl acrylate (6.93 g, 0.08 mol), deuterated water (125 mL, 25 mol), tert-butanol D1 (4 mL), potassium tert-butoxide (2.7 g, 0.024 mol), and 350 mg of 5 wt% ruthenium carbon were heated to reflux in an oil bath for 24 h. After the deuteration rate was found to be qualified, the aqueous phase was extracted with diethyl ether, the organic phase was dried, and the organic phase was evaporated at atmospheric pressure to obtain 5.3 g of crude deuterated acrylic acid, which was directly used in the next step.

[0038] S2: Dissolve deuterated acrylic acid in 40 mL of methanol D1 (1.49 mol), add 6.5 mL of thionyl chloride (0.089 mol) dropwise under ice bath, monitor the reaction progress, remove the organic phase after the reaction is completed, and distill the mother liquor to obtain compound methyl 3-deuterated acrylate (6 g, yield 91%).

[0039] S3: Deuterated methyl acrylate (6 g, 0.067 mol) was dissolved in 30 mL of 7 M ammonia in methanol solution, added to a 100 mL pressure vessel, heated and stirred at 55 °C for 18 h. After the reaction was completed, the solvent was evaporated, and the crude product was subjected to column chromatography (Pe:EA = 2:1) to obtain the final product deuterated acrylamide (4.1 g, yield 82%).

[0040] As described above, the basic principles, main features, and advantages of the present invention have been well described. The above embodiments and specifications are merely descriptions of preferred embodiments of the present invention, and the present invention is not limited to the above embodiments. Various changes and improvements made to the technical solutions of the present invention by those skilled in the art without departing from the spirit and scope of the present invention should fall within the protection scope defined by the present invention.

Claims

1. A method for preparing deuterated acrylamide, characterized in that, include: S1: Using methyl acrylate and deuterium water as raw materials, a first solvent, a strong base and a catalyst are added, and the mixture is heated in an oil bath under reflux for 24 hours to produce deuterated acrylic acid; S2: Dissolve the deuterated acrylic acid in a second solvent, add sulfoxide dropwise under ice bath, and after the reaction is complete, obtain methyl deuterated acrylate; S3: Dissolve the deuterated methyl acrylate in a 7M ammonia-methanol solution, and heat and stir the mixture in a pressure vessel to obtain the deuterated acrylamide.

2. The method for preparing deuterated acrylamide according to claim 1, characterized in that, The first solvent is tert-butanol D1; The strong base is potassium tert-butoxide; The catalyst is 5 wt% ruthenium carbon; The second solvent is methanol D1.

3. The method for preparing deuterated acrylamide according to claim 1, characterized in that, The molar ratio of methyl acrylate to deuterium water is not less than 0.08:20; The volume ratio of the deuterium water to the first solvent is 10~30:1; The molar ratio of methyl acrylate to strong alkali is 1:0.1~0.3; The weight ratio of methyl acrylate to catalyst is 10~20:

1.

4. The method for preparing deuterated acrylamide according to claim 1, characterized in that, The molar ratio of the deuterated acrylic acid to the second solvent is 1:10~30; The molar ratio of thionyl chloride to deuterated acrylic acid is 0.8~1.2:

1.

5. The method for preparing deuterated acrylamide according to claim 1, characterized in that, The reaction temperature for the heating and stirring reaction is 30~55℃, and the reaction time is 18~72h.

6. The method for preparing deuterated acrylamide according to claim 1, characterized in that, The heating and stirring reaction is followed by column chromatography, in which the chromatographic solvent is petroleum ether and ethyl acetate in a volume ratio of 2:

1.

7. The method for preparing deuterated acrylamide according to claim 1, characterized in that, The molar ratio of ammonia in the methanol solution of deuterated methyl acrylate and 7M ammonia is 1:3~10.

8. A deuterated acrylamide, characterized in that, It is prepared by the method for preparing deuterated acrylamide according to any one of claims 1 to 6; The structural formula of the deuterated acrylamide is shown below. .

9. The application of the deuterated acrylamide according to claim 8 in the quantitative detection of acrylamide content in a sample.

10. The use of the deuterated acrylamide according to claim 8 in the synthesis of deuterated polymer materials / deuterated polymer drugs.

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