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A kind of synthetic method of toluene-d8

A technology of -d8 and toluene, applied in the field of synthesis of toluene-d8, can solve the problems of high operating pressure, high price, complicated transportation process, etc., and achieve the effect of breaking the dependence on imports, reducing production costs, and high deuteration rate

Active Publication Date: 2021-03-05
BEIJING INSTITUTE OF TECHNOLOGYGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method also has obvious disadvantages. The operating pressure is high and the temperature is high, so it is not suitable for large-scale development and utilization under the existing conditions.
At present, domestic toluene-d8 mainly comes from foreign imports, which are expensive and the transportation process is complicated. Therefore, it is necessary to develop a method for preparing toluene-d8 with high isotope utilization rate, high product purity and easy operation.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Slowly add 13.2g of pentachlorotoluene to 1150g of anhydrous ether in a dry room temperature environment, stir at a rate of 250rpm, and after stirring for 0.6 hours, a clear solution A is obtained; the clear solution A is transferred to an autoclave with a volume of 3000mL 8.7g lithium deuterated aluminum was slowly added to the clear solution A under the protection of nitrogen. During the addition process, the temperature of the solution was kept not higher than 25°C. After the lithium deuterated aluminum was added, 1.3 g palladium carbon catalyst, after no bubbles emerge in the solution, seal the reaction system, check the airtightness of the device, then replace the gas in the kettle with deuterium gas, after replacing 3 times, fill the autoclave with deuterium gas, When the pressure reaches 1MPa, close the inlet valve, stir at a rate of 600rpm and raise the temperature to 45°C. After 24 hours of heat preservation, stop stirring and naturally cool to room temperature;...

Embodiment 2

[0026] Slowly add 29.1g of pentachlorotoluene to 2800g of anhydrous ether in a dry room temperature environment, stir at a rate of 300rpm, and after stirring for 0.5 hours, a clear solution A is obtained; the clear solution A is transferred to an autoclave with a volume of 6000mL 13.1g of lithium deuteride was slowly added to the clear solution A under the protection of nitrogen, and the temperature of the solution was maintained not higher than 25°C during the addition process. After the addition of lithium deuteride was completed, 2.9g of palladium was added to the mixed solution Carbon catalyst, after no bubbles emerge in the solution, seal the reaction system, check the airtightness of the device, then replace the gas in the autoclave with deuterium gas, after three replacements, fill the autoclave with deuterium gas, when the pressure in the autoclave reaches Close the inlet valve at 1.5MPa, stir at a rate of 600rpm and raise the temperature to 55°C. After 24 hours of heat...

Embodiment 3

[0028]Slowly add 43.8g of pentabromotoluene to 4000g of anhydrous tetrahydrofuran in a dry room temperature environment, and stir at a rate of 300rpm. After stirring for 1 hour, a clear solution A is obtained; the clear solution A is transferred to an autoclave with a volume of 10L 19.2g of sodium borodeuteride was slowly added to the clear solution A under the protection of nitrogen, and the temperature of the solution was maintained not higher than 25°C during the addition process. After the addition of sodium borodeuteride was completed, 4.4 g palladium carbon catalyst, after no bubbles emerge in the solution, seal the reaction system, check the airtightness of the device, then replace the gas in the kettle with deuterium gas, after replacing 3 times, fill the autoclave with deuterium gas, When the pressure reaches 2.5MPa, close the inlet valve, stir at a rate of 550rpm and raise the temperature to 65°C. After 24 hours of heat preservation, stop stirring and naturally cool t...

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Abstract

The invention relates to a method for synthesizing toluene-d8, which belongs to the synthesis technology of deuterated compounds. The pentahalogenated toluene is slowly added to the solvent to obtain a clear solution A; the solution A is transferred to the autoclave, and the deuterated reagent is slowly added to the solution in step 1 under nitrogen protection, and catalyst B is added. A mixed solution C was obtained, filtered and deionized water was added dropwise to obtain a filtrate D; after fractionation, heavy water, catalyst F and zeolite were added, and finally the solution was fractionated, and 110° C. fractions were taken to obtain toluene-d8. In the method, the halo-deuterium exchange reaction on the benzene ring and the hydrogen-deuterium exchange reaction on the methyl group are carried out step by step, which is conducive to the complete deuteration reaction, and the obtained product has a high deuteration rate; the use of the catalyst reduces the consumption of the deuterated reagent, It reduces the production cost and can effectively break the domestic market's dependence on imports.

Description

technical field [0001] The invention relates to a synthesis method of toluene-d8, which belongs to the synthesis technology of deuterated compounds. Background technique [0002] Due to the kinetic isotope effect, deuterated compounds play an important role in the study of reaction mechanism, the change of selectivity during synthesis, and the preparation of advanced functional materials. Especially in the pharmaceutical industry, since the incorporation of deuterium not only changes the absorption, distribution, and toxicological properties of the drug, but also retains the efficacy of the original drug and increases the residence time of the drug, it has attracted extensive research. Since the first deuteration of bioactive molecules to improve pharmacokinetic profiles in the 1960s, enormous efforts have been devoted to the synthesis of deuterium-labeled drugs. Since toluene is commonly used in drug synthesis, the utilization of toluene-d8 is expected to produce new drugs...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C1/26C07C7/00C07C15/06C07B59/00
CPCC07B59/001C07B2200/05C07C1/26C07C7/005C07C15/06
Inventor 刘吉平方祝青韩佳
Owner BEIJING INSTITUTE OF TECHNOLOGYGY
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