Preparation method of carbon isotope labeled diester carbonate
13CO2 and 1,1-dialkoxytrimethylamine compounds were added to the reaction system under vacuum, and the reaction was reacted at 100°C for 3 days, followed by adding water and extracting with a hydrocarbon solvent, washing with dilute hydrochloric acid, drying with anhydrous sodium sulfate, and then blasting column chromatography to obtain the pure product. The problem of expensive and complex operation of carbonate diester preparation materials in the prior art is solved, and efficient and inexpensive carbonate diester-13C preparation is achieved.
Patent Information
- Application Number
- CN202311284812.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-10-07
- Publication Date
- 2025-04-08
AI Technical Summary
The prior art is difficult to provide a method for preparing carbon isotope-labeled carbonate diesters with inexpensive raw materials and simple operation.
13CO2 and 1,1-dialkoxytrimethylamine compounds were added to the reaction system under vacuum, and the reaction was reacted at 100°C for 3 days, followed by water and extracted with a hydrocarbon solvent, washed with dilute hydrochloric acid, dried over anhydrous sodium sulfate, and obtained by flash column chromatography.
It realizes efficient preparation of carbonate diester-13C, with simple operation, mild conditions, easy separation and purification of the product, and high yield.
Smart Images
Figure CN119775140A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the field of organic synthesis preparation chemistry, and in particular to a method for preparing a carbon isotope-labeled carbonic acid diester. Background Art
[0002] Carbonic acid diester is an organic compound, a low-toxic, environmentally friendly, widely used chemical raw material, and an important organic synthesis intermediate. Because its molecular structure contains carbonyl, alkyl and alkoxy functional groups, it has a variety of reaction properties and can also be used as a drug synthesis intermediate. Carbonic acid diester with low molecular weight has excellent solubility, narrow melting and boiling point range, high surface tension, low viscosity, small dielectric constant, high evaporation temperature and fast evaporation rate, so it can be used as a low-toxic solvent in the coating industry and the pharmaceutical industry, and is a green solvent.
[0003] Carbonic acid diesters have similar nucleophilic reaction centers. When the carbonyl group of carbonic acid diesters is attacked by nucleophilic attack, the acyl-oxygen bond breaks to form a carbonyl compound, and the by-product is an alkyl alcohol. Therefore, carbonic acid diesters can be a safe reaction reagent for the synthesis of carbonic acid derivatives. Taking dimethyl carbonate (DMC) as an example, it is used to synthesize carbamate pesticides, polycarbonates, isocyanates, etc., among which polycarbonate will be the field with the largest demand for DMC. When the alkyl carbon of carbonic acid diesters is attacked by nucleophilic attack, its alkyl-oxygen bond breaks and alkylated products are also generated. The main uses include the synthesis of organic intermediates, pharmaceutical products, pesticide products, etc.
[0004] In view of the important application value of carbonic acid diesters in medicine, their carbonyl carbon is labeled. During the reaction, the labeled carbon can be introduced into the drug molecule, which is more conducive to studying the metabolic process of the drug. At the same time, carbon labeling also has great application value in mass spectrometry (MS) analysis and nuclear magnetic resonance. In any clinical setting, accurate and precise results are crucial for correct diagnosis and treatment. Therefore, in MS detection, the use of stable isotope labeled standards can obtain the best reliable results. Summary of the invention
[0005] The technical problem to be solved by the present invention is to provide a method for preparing carbon isotope-labeled carbonic acid diester with cheap raw materials and simple operation.
[0006] In order to solve the above problems, the present invention provides a method for preparing a carbon isotope labeled carbonic acid diester, characterized in that: a container equipped with a stirrer is evacuated to a vacuum state by a vacuum pump, 13 CO2 is used as a reference amount, 1,1-dialkoxytrimethylamine compounds and solvents are added to the reaction system, and then the main raw material is charged into the reaction system. 13CO2 until it returns to normal pressure to obtain a reaction mixture; the reaction mixture is placed at 100°C for reaction for 3 days. After the reaction is completed, it is returned to room temperature, water is first added to the system, and then extracted with a hydrocarbon solvent. The obtained organic phase is washed with dilute hydrochloric acid, dried with anhydrous sodium sulfate, and then passed through a flash column chromatography to obtain a pure product.
[0007] The main raw material 13 The molar ratio of CO2 to the 1,1-dialkoxytrimethylamine is 1.0: 1.0 to 5.0 eq.
[0008] The 1,1-dialkoxytrimethylamine compound has a structure as shown in formula (I): Wherein, R is selected from any one of an alkyl group, an alkenyl group, an alkynyl group or an aryl group having 1 to 42 carbon atoms.
[0009] The solvent is dimethyl sulfoxide (DMSO), N -Methyl pyrrolidone (NMP) or 1,3-dimethyl-2-imidazolidinone (DMI); per mole of main raw material 13 According to CO2, the dosage is 1 to 5 mL.
[0010] The hydrocarbon solvent is one of petroleum ether, n-pentane, n-hexane or cyclohexane.
[0011] Compared with the prior art, the present invention has the following advantages: 1. The present invention selects commercially available 13 CO2 and 1,1-dialkoxytrimethylamine are used as starting materials to generate carbonic acid diester- 13 C. The entire reaction operation is simple and easy, the conditions are relatively mild, the product is easy to separate and purify, and the yield is high.
[0012] 2. The raw materials of the present invention adopt the most basic 13 C1 Reagent 13 CO2 as 13 C source, of which 1,1-dialkoxytrimethylamine is cheap and readily available and can be purchased in large quantities.
[0013] 3. The synthesis method of the present invention can be scaled up to tens of grams, which is suitable for medium-scale production. 13 C-labeled carbonic acid diesters provide a feasible synthetic method. BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The specific implementation modes of the present invention are further described in detail below in conjunction with the accompanying drawings.
[0015] Figure 1 Synthesized for the present invention 13Chemical reaction process diagram of carbonic acid diester labeled with C. DETAILED DESCRIPTION
[0016] like Figure 1 As shown in the figure, a method for preparing a carbon isotope labeled carbonic acid diester is as follows: in a container equipped with a stirrer, a vacuum pump is used to evacuate the container to a vacuum state, 13 CO2 is used as a reference amount, 1,1-dialkoxytrimethylamine compounds and solvents are added to the reaction system, and then the main raw material is charged into the reaction system. 13 CO2 until it returns to normal pressure to obtain a reaction mixture; the reaction mixture is placed at 100 °C for reaction for 3 days (72 h). After the reaction is completed, it is returned to room temperature, water is first added to the system, and then extracted with a hydrocarbon solvent. The obtained organic phase is washed with dilute hydrochloric acid, dried with anhydrous sodium sulfate, and then passed through a flash column chromatography (detergent: petroleum ether) to obtain a pure product.
[0017] Among them: Main raw materials 13 The molar ratio of CO2 to 1,1-dialkoxytrimethylamine is 1.0: 1.0 to 5.0 eq, preferably 1.0: 2.0 to 4.0 eq.
[0018] The 1,1-dialkoxytrimethylamine compounds have a structure as shown in formula (I): Wherein, R is selected from any one of an alkyl group, an alkenyl group, an alkynyl group or an aryl group having 1 to 42 carbon atoms.
[0019] The solvent was dimethyl sulfoxide (DMSO), N -methyl pyrrolidone (NMP) or 1,3-dimethyl-2-imidazolidinone (DMI), preferably dimethyl sulfoxide; per mole of main raw material 13 In terms of CO2, the amount used is 1 to 5 mL, preferably 2 to 3 mL.
[0020] The hydrocarbon solvent is one of petroleum ether, n-pentane, n-hexane or cyclohexane, preferably petroleum ether.
[0021] Example 1 A method for preparing a carbon isotope labeled carbonic acid diester: In a round-bottom flask equipped with a stirrer, a vacuum pump was used to evacuate the flask, 1,1-dimethoxytrimethylamine (30 mmol) and dimethyl sulfoxide (20 mL) were added to the reaction flask, and the main raw materials were then charged into the reaction system. 13CO2 (10 mmol) was added until the pressure returned to normal to obtain a reaction mixture; the reaction mixture was placed at 100 °C for 3 days (72 h). After the reaction was completed, it was restored to room temperature. Water was first added to the system, and then extracted three times with petroleum ether. The obtained organic phase was washed with dilute hydrochloric acid, dried over anhydrous sodium sulfate, and then passed through a flash column chromatography to obtain a pure product (0.77 g, yield 85%).
[0022] 1 (400 MHz, CDCl3) δ 3.79 (td, J = 7.2, 2.8 Hz,, 6H) ppm; 13 C NMR (101 MHz, CDCl3) δ 156.4, 54.7 (d, J = 3.0 Hz) ppm. Example 2 A method for preparing a carbon isotope labeled carbonic acid diester: In a round-bottom flask equipped with a stirrer, a vacuum pump was used to evacuate the flask, 1,1-dibutoxytrimethylamine (30 mmol) and dimethyl sulfoxide (20 mL) were added to the reaction flask, and the main raw materials were then charged into the reaction system. 13 CO2 (10 mmol) was added until the pressure returned to normal to obtain a reaction mixture; the reaction mixture was placed at 100 °C for 3 days (72 h). After the reaction was completed, it was restored to room temperature. Water was first added to the system, and then extracted three times with petroleum ether. The obtained organic phase was washed with dilute hydrochloric acid, dried over anhydrous sodium sulfate, and then passed through a flash column chromatography to obtain a pure product (1.44 g, yield 82%).
[0023] 1 (400 MHz, CDCl3) δ 4.13 (td, J = 6.8, 2.4 Hz, 4H), 1.69 – 1.62 (m, 4H), 1.45 – 1.36 (m, 4H), 1.00 – 0.87 (m, 6H) ppm; 13 C NMR(101 MHz, CDCl3) δ 155.4,67.7, 30.7 (d, J = 3.0 Hz), 18.9, 13.6 (d, J = 1.0 Hz) ppm. It should be understood that the technical solution of the present invention is not limited to the above specific implementation cases. 11 C. 12 C. 14Carbonic acid diesters labeled with carbon isotopes such as C can also be prepared by this scheme. Any technical variations made according to the technical scheme of the present invention without departing from the spirit of the present invention and the scope of protection of the claims shall fall within the scope of protection of the present invention.
Claims
1. A method for preparing a carbon isotope-labeled carbonic acid diester, characterized in that: In a container equipped with a stirrer, a vacuum pump is used to evacuate the container to 13 CO2 is used as a reference amount, 1,1-dialkoxytrimethylamine compounds and solvents are added to the reaction system, and then the main raw material is charged into the reaction system. 13 CO2 until it returns to normal pressure to obtain a reaction mixture; the reaction mixture is placed at 100°C for reaction for 3 days. After the reaction is completed, it is returned to room temperature, water is first added to the system, and then extracted with a hydrocarbon solvent. The obtained organic phase is washed with dilute hydrochloric acid, dried with anhydrous sodium sulfate, and then passed through a flash column chromatography to obtain a pure product.
2. The method for preparing a carbon isotope-labeled carbonic acid diester according to claim 1, characterized in that: The main raw material 13 The molar ratio of CO2 to the 1,1-dialkoxytrimethylamine is 1.0: 1.0 to 5.0 eq.
3. The method for preparing a carbon isotope-labeled carbonic acid diester according to claim 1 or 2, characterized in that: The 1,1-dialkoxytrimethylamine compound has a structure as shown in formula (I): Wherein, R is selected from any one of an alkyl group, an alkenyl group, an alkynyl group or an aryl group having 1 to 42 carbon atoms.
4. The method for preparing a carbon isotope-labeled carbonic acid diester according to claim 1, characterized in that: The solvent is dimethyl sulfoxide, N -methyl pyrrolidone or 1,3-dimethyl-2-imidazolidinone; per mole of main raw material 13 According to CO2, the dosage is 1 to 5 mL.
5. The method for preparing a carbon isotope-labeled carbonic acid diester according to claim 1, characterized in that: The hydrocarbon solvent is one of petroleum ether, n-pentane, n-hexane or cyclohexane.