阅读说明：本技术 一种稳定性同位素13c标记二氯乙酸的合成方法 (Stable isotope13Method for synthesizing C-marked dichloroacetic acid ) 是由 伍君 陈雨雷 方宁静 张�雄 阮善龙 刘大成 于 2020-05-11 设计创作，主要内容包括：一种稳定性同位素<Sup>13</Sup>C标记二氯乙酸的合成方法,包括以下步骤：(1)利用<Sup>13</Sup>C标记乙酸为原料,加入氯化亚砜和氯气进行反应得中间体<Sup>13</Sup>C标记一氯乙酸；(2)在步骤(1)所得中间体<Sup>13</Sup>C标记一氯乙酸中加入硫磺和氯气进行循环反应,所得反应液中用饱和碳酸钠调至pH值,加入等摩尔量的硫代硫酸钠进行反应,当中间体<Sup>13</Sup>C标记一氯乙酸反应完全后,所得反应液用乙酸乙酯进行萃取去掉有机杂质,水相加入浓盐酸调至pH值,再次用乙酸乙酯萃取,有机相旋干,得<Sup>13</Sup>C标记二氯乙酸。本发明为稳定性同位素<Sup>13</Sup>C标记二氯乙酸的合成提供了一种条件温和,易控制、易操作的合成方法,同样也适用于放射性同位素<Sup>14</Sup>C标记二氯乙酸的合成。(Stable isotope 13 The method for synthesizing the C-labeled dichloroacetic acid comprises the following steps of: (1) by using 13 Adding thionyl chloride and chlorine into C-labeled acetic acid as a raw material to react to obtain an intermediate 13 C, marking monochloroacetic acid; (2) the intermediate obtained in step (1) 13 C-marked monochloroacetic acid is added with sulfur and chlorine for cyclic reaction, the obtained reaction liquid is adjusted to pH value by saturated sodium carbonate, and equimolar sodium thiosulfate is added for reaction, and an intermediate is obtained 13 After the reaction of the C-labeled monochloroacetic acid is completed, the obtained reaction liquid is used for ethyl acetateExtracting to remove organic impurities, adding concentrated hydrochloric acid into water phase to adjust pH value, extracting with ethyl acetate, and spin drying organic phase to obtain 13 C denotes dichloroacetic acid. The invention relates to stable isotopes 13 The synthesis of C-labeled dichloroacetic acid provides a synthesis method with mild conditions, easy control and operation, and is also suitable for radioactive isotopes 14 C marks the synthesis of dichloroacetic acid.)

1. Stable isotope¹³The method for synthesizing the C-marked dichloroacetic acid is characterized by comprising the following steps: the method comprises the following steps:

(1) adding into a dry two-neck flask¹³C-labeled acetic acid is taken as a raw material, thionyl chloride is added, the air in the flask is replaced by argon, the temperature is raised, chlorine is introduced for reaction, the reaction process is monitored by HPLC, and the reaction is carried out until the reaction is finished¹³After the C-marked acetic acid completely reacts, the redundant thionyl chloride in the reaction solution is dried by spinning to obtain an intermediate¹³C, marking monochloroacetic acid;

(2) adding the intermediate obtained in the step (1) into a dry two-neck flask¹³C marking monochloroacetic acid, adding sulfur, replacing air in the flask with argon, heating, introducing chlorine for reaction, monitoring the reaction by HPLC (high performance liquid chromatography), stopping the reaction until trichloroacetic acid is generated, adding petroleum ether into the obtained reaction liquid for low-temperature recrystallization, filtering, adding sulfur into the obtained filter cake again, replacing the air in the flask with argon, heating, introducing chlorine for reaction, circulating for 3-5 times, adjusting the pH value of the obtained reaction liquid to be the same as the pH value by using saturated sodium carbonate, adding sodium thiosulfate with equal molar weight for reaction, and preparing an intermediate¹³C, after the monochloroacetic acid marked by the mark C completely reacts, the obtained reaction liquid is extracted by ethyl acetate to remove organic impurities, the water phase is added with concentrated hydrochloric acid to adjust the pH value, the ethyl acetate is used for extraction again, and the organic phase is dried by spinning to obtain the product¹³C denotes dichloroacetic acid.

2. According to claim1 the stable isotope¹³The method for synthesizing the C-marked dichloroacetic acid is characterized by comprising the following steps: in the step (1), the¹³C-labeled acetic acid as [1-¹³C]-acetic acid, [2-¹³C]-acetic acid or [1,2-¹³C₂]-one of acetic acids.

3. The stable isotope of claim 1 or 2¹³The method for synthesizing the C-marked dichloroacetic acid is characterized by comprising the following steps: in the step (1), the¹³The feeding molar ratio of the C-marked acetic acid to the thionyl chloride to the chlorine is 1: 0.3-0.5: 3.8-4.2.

4. The stable isotope of claim 1 or 2¹³The method for synthesizing the C-marked dichloroacetic acid is characterized by comprising the following steps: in the step (2), the intermediate¹³C, the feeding molar ratio of the monochloroacetic acid marked by C, the sulfur and the chlorine is 1: 0.4-0.6: 1.8-2.2.

5. The stable isotope of claim 1 or 2¹³The method for synthesizing the C-marked dichloroacetic acid is characterized by comprising the following steps: in the step (1), the chlorine gas was introduced for 2 days, and 2eq of chlorine gas was introduced every day.

6. The stable isotope of claim 1 or 2¹³The method for synthesizing the C-marked dichloroacetic acid is characterized by comprising the following steps: and (3) in the step (2), the chlorine gas is introduced within 1 day.

7. The stable isotope of claim 1 or 2¹³The method for synthesizing the C-marked dichloroacetic acid is characterized by comprising the following steps: in the step (2), the pH value is adjusted to 9.5 by saturated sodium carbonate; and adding concentrated hydrochloric acid into the water phase to adjust the pH value to be less than or equal to 1.

8. The stable isotope of claim 1 or 2¹³The method for synthesizing the C-marked dichloroacetic acid is characterized by comprising the following steps: in the step (1), the temperature rise is 110-120 ℃.

9. The stable isotope of claim 1 or 2¹³The method for synthesizing the C-marked dichloroacetic acid is characterized by comprising the following steps: in the step (2), the temperature rise is 130-140 ℃.

10. A stable isotope as claimed in any of claims 1 to 9¹³Method for synthesizing C-labeled dichloroacetic acid in radioactive isotope¹⁴Label C is the application of dichloroacetic acid synthesis.

Technical Field

The invention relates to a method for synthesizing dichloroacetic acid by isotope labeling, in particular to a stable isotope¹³Method for synthesizing C-labeled dichloroacetic acid.

Background

The dichloroacetic acid is an important organic chemical raw material and intermediate, has wide markets in the industries of medicine, pesticide, fine chemical industry, organic synthesis and the like, and has great development prospects.

At present, the method for producing dichloroacetic acid in China mainly adopts chloroacetic acid mother liquor to separate and purify to obtain dichloroacetic acid, the yield of the dichloroacetic acid obtained by the reaction of the method is low, the operation is complex during separation, time and labor are wasted, the cost for synthesizing the dichloroacetic acid by isotope labeling is high, and the isotope labeling is seriously hindered¹³C、¹⁴The C-labeled dichloroacetic acid and derivative compounds thereof are used for toxicological research, metabolic research and research on animal, plant and environmental influence of research objects.

For example, CN1109862 discloses a method for co-producing dichloroacetic acid and thioglycollic acid, which belongs to the technical field of haloacid separation and organic chemical preparation, mother liquor in the production of the chloroacetic acid is taken as a raw material, the mother liquor is subjected to distillation and neutralization pretreatment, then reacts with sodium thiosulfate at the temperature of 60-100 ℃, dichloroacetic acid is extracted by ethyl acetate and the like after reaction liquid is acidified, and the extraction solution is distilled off an extraction agent to obtain the dichloroacetic acid with the purity of more than or equal to 97%; the raffinate is hydrolyzed and reduced, and then the generated thioglycollic acid is extracted by using an extracting agent such as ethyl acetate and the like, and the yield is more than 80%. The method mainly comprises the steps of using chloroacetic acid mother liquor as a raw material, carrying out distillation and neutralization pretreatment, reacting with sodium thiosulfate at the temperature of 60-100 ℃, acidifying reaction liquid, and extracting with ethyl acetate to obtain dichloroacetic acid.

For example, CN102363593A discloses a process and an apparatus for co-producing thioglycolic acid and dichloroacetic acid by using a chloroacetic acid mother liquor as a raw material, distilling to separate acetic acid and low boiling point substances contained in the mother liquor, and then using Ca (OH) to remove the mother liquor₂Neutralizing with water solution. Adding a certain amount of thiourea solution into the neutralization solution for reaction. Separating the reaction liquid with centrifuge, the filtrate mainly contains calcium dichloroacetate and calcium chloride, acidifying the filtrate with concentrated hydrochloric acid, and extracting with organic solvent. Removing the solvent from the organic phase by a falling film evaporator to obtain the dichloroacetic acid. Reacting S-carboxymethyl isothiourea with barium hydroxide, centrifuging to obtain barium thioglycolate precipitate, acidifying and dissolving the white precipitate with hydrochloric acid, extracting with organic solvent, and removing solvent with falling film evaporator to obtain thioglycolic acid. The method mainly uses the by-product mother liquor produced in chloroacetic acid production as a raw material, and comprises the steps of distilling and neutralizing, adding a certain amount of thiourea for reaction, filtering, and extracting the filtrate to obtain dichloroacetic acid.

None of the above methods can realize isotopes¹³C、¹⁴The simple synthesis of C-labeled dichloroacetic acid has high equipment requirement, complex process and high cost.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects in the prior art and provide a stable isotope with simple operation, low cost, mild reaction conditions, high yield and high purity¹³Method for synthesizing C-labeled dichloroacetic acid.

The technical scheme adopted by the invention for solving the technical problems is as follows: stable isotope¹³The method for synthesizing the C-labeled dichloroacetic acid comprises the following steps of:

(1) adding into a dry two-neck flask¹³C-labeled acetic acid is taken as a raw material, thionyl chloride is added, the air in the flask is replaced by argon, the temperature is raised, chlorine is introduced for reaction, the reaction process is monitored by HPLC, and the reaction is carried out until the reaction is finished¹³After the reaction of C-labeled acetic acid is completed, spin-drying reactionExcess thionyl chloride in the solution to give an intermediate¹³C, marking monochloroacetic acid;

(2) adding the intermediate obtained in the step (1) into a dry two-neck flask¹³C marking monochloroacetic acid, adding sulfur, replacing air in the flask with argon, heating, introducing chlorine for reaction, monitoring the reaction by HPLC (high performance liquid chromatography), stopping the reaction until trichloroacetic acid is generated, adding petroleum ether into the obtained reaction liquid for low-temperature recrystallization, filtering, adding sulfur into the obtained filter cake again, replacing the air in the flask with argon, heating, introducing chlorine for reaction, circulating for 3-5 times, adjusting the pH value of the obtained reaction liquid to be the same as the pH value by using saturated sodium carbonate, adding sodium thiosulfate with equal molar weight for reaction, and preparing an intermediate¹³C, after the monochloroacetic acid marked by the mark C completely reacts, the obtained reaction liquid is extracted by ethyl acetate to remove organic impurities, the water phase is added with concentrated hydrochloric acid to adjust the pH value, the ethyl acetate is used for extraction again, and the organic phase is dried by spinning to obtain the product¹³C denotes dichloroacetic acid.

Preferably, in step (1), the¹³C-labeled acetic acid is [1,2-¹³C₂]-acetic acid.

Preferably, in step (1), the¹³The feeding molar ratio of the C-marked acetic acid to the thionyl chloride to the chlorine is 1: 0.3-0.5: 3.8-4.2.

Preferably, in step (2), the intermediate¹³C, the feeding molar ratio of the monochloroacetic acid marked by C, the sulfur and the chlorine is 1: 0.4-0.6: 1.8-2.2.

Preferably, in the step (1), chlorine gas is introduced for 2 days, and 2eq of chlorine gas is introduced per day.

Preferably, in step (2), the chlorine gas is introduced for 1 day.

Preferably, in step (2), the pH of the reaction mixture obtained is adjusted to 9.5 with saturated sodium carbonate.

Preferably, in step (2), the pH value of the water phase is adjusted to be less than or equal to 1 by adding concentrated hydrochloric acid.

Preferably, in the step (1), the temperature rise is 110-120 ℃.

Preferably, in the step (2), the temperature rise is 130-140 ℃.

Stable isotopes of the invention¹³Method for synthesizing C-labeled dichloroacetic acid in radioactive isotope¹⁴Label C is the application of dichloroacetic acid synthesis.

The reaction process of the invention is as follows:

note: is a stable isotope¹³C-labels or radioisotopes¹⁴And C, marking.

Compared with the prior art, the invention has the following beneficial effects: (1) the complex or difficultly obtained labeled compound is avoided being used as the starting material, and the labeled acetic acid on the market is directly used as the starting material, so that the synthesis process of the dichloroacetic acid is simplified, and the cost is lower; the adopted reaction device is simple, the whole reaction can be carried out in one device, the material loss in the transfer process is avoided, the safety and the high efficiency are realized, and the method is particularly suitable for micro and semi-micro laboratory reactions; the method has mild reaction conditions, can realize the maximized obtaining of the high-purity dichloroacetic acid, has high efficiency and energy conservation, and is also suitable for the radioactive isotope¹⁴C marks the synthesis of dichloroacetic acid.

Detailed Description

The present invention will be further described with reference to the following examples.

The chemical reagents used in the examples of the present invention, unless otherwise specified, are commercially available in a conventional manner.