CN111440041B - Synthesis method of toluene-d 8 - Google Patents
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- CN111440041B CN111440041B CN202010422614.4A CN202010422614A CN111440041B CN 111440041 B CN111440041 B CN 111440041B CN 202010422614 A CN202010422614 A CN 202010422614A CN 111440041 B CN111440041 B CN 111440041B
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Abstract
The invention relates to a synthesis method of toluene-d 8, belonging to the synthesis technology of deuterated compounds. Slowly adding penta-halogenated toluene into a solvent to prepare a clear solution A; transferring the solution A into an autoclave, slowly adding a deuterated reagent into the solution obtained in the step one under the protection of nitrogen, adding a catalyst B to obtain a mixed solution C, filtering, and dropwise adding deionized water to obtain a filtrate D; after the fractionation, heavy water, catalyst F and zeolite are added, and finally the solution is fractionated, and the fraction at 110 ℃ is taken to obtain toluene-d 8. The method carries out the exchange reaction of halogen and deuterium on benzene ring and the exchange reaction of hydrogen and deuterium on methyl step by step, which is beneficial to complete deuterium generation reaction and high deuterium generation rate of the obtained product; the use of the catalyst reduces the dosage of the deuterated reagent, reduces the production cost and can effectively break the dependence of domestic markets on import.
Description
Technical Field
The invention relates to a synthesis method of toluene-d 8, belonging to the synthesis technology of deuterated compounds.
Background
Due to the kinetic isotope effect, the deuterated compound plays an important role in the aspects of reaction mechanism research, selective change in the synthetic process, preparation of advanced functional materials and the like. Particularly in the pharmaceutical industry, the deuterium incorporation has led to extensive research because it changes the absorption, distribution and toxicological properties of the drug, retains the efficacy of the original drug and increases the retention time of the drug. Since the first deuteration of bioactive molecules to improve pharmacokinetic profiles in the 60's of the 20 th century, great efforts have been put into the synthesis of deuterium-labeled drugs. Because of the common application of toluene in drug synthesis, the utilization of toluene-d 8 is expected to produce new drugs with higher therapeutic value.
The deuterium incorporation methods currently in common use are either metal-catalyzed or acid/base-promoted H/D exchange methods, which allow for the direct incorporation of deuterium without the need for preactivation of the starting materials and without the need for substantial changes in molecular structure. However, conventional H/D switching has some disadvantages. First, carbon-hydrogen bonds are often difficult to activate and multiple exchange processes are often required to achieve high deuterium content. Secondly, the method of activating carbon-hydrogen bonds with homogeneous noble metal catalysts is limited by the complexity and high cost of catalyst synthesis; supercritical deuterium oxide exchange, a process developed in recent years for preparing deuterides, has received much attention due to low cost, short reaction time, high probability of selectively deuterating or deuterating different organic compounds, and high yield. The application of the supercritical deuterium oxide exchange can adjust the physicochemical properties of the supercritical deuterium oxide by adjusting the temperature and the pressure, thereby further controlling the reaction efficiency, the reaction rate and the selectivity. However, the method has the obvious disadvantages of large operation pressure and high temperature, and is not suitable for large-scale development and utilization under the existing conditions. At present, the domestic toluene-d 8 is mainly imported from abroad, the price is high, and the transportation process is complex, so that the method for preparing the toluene-d 8, which has high isotope utilization rate, high product purity and simple and convenient operation, needs to be developed.
Disclosure of Invention
The invention aims to provide a preparation method of toluene-d 8. The method has the advantages of relatively simple operation, high isotope utilization rate, relatively high yield and high product purity, realizes the preparation of the p-toluene-d 8, and provides reference for the industrial production of the toluene-d 8.
The object of the present invention is achieved by the following steps.
A preparation method of toluene-d 8 comprises the following steps:
step one, slowly adding penta-halogenated toluene into a solvent at room temperature, wherein the mass ratio of the penta-halogenated toluene to the solvent is 1: (80-100), stirring at the speed of 200-300 rpm for 0.5-1 hour to obtain a clear solution A;
step two, transferring the clear solution A obtained in the step one into an autoclave, slowly adding a deuterogen reagent into the solution obtained in the step one under the condition of nitrogen protection, wherein the molar ratio of the deuterogen reagent to penta-halogenated toluene is (2-12): 1, keeping the temperature of the solution not higher than 25 ℃ in the adding process, adding a catalyst B into the mixed solution after the deuterogen reagent is added, the mass ratio of the penta-halogenated toluene to the catalyst B is (5-15): 1, sealing the reaction system after no bubbles are emitted from the solution, checking the airtightness of the device, replacing the gas in the autoclave with deuterium, filling deuterium into the autoclave after 3-5 times of replacement, closing an air inlet valve when the pressure in the autoclave reaches 1-3 MPa, stirring at the speed of 400-600 rpm, heating to 35-70 ℃, keeping the temperature for 12-24 hours, stopping stirring and naturally cooling to room temperature, obtaining a mixed solution C;
step three, filtering the mixed liquid C obtained in the step two, transferring the filtrate into a container, placing the container into a high-precision medium-temperature circulating bath at the temperature of-5-0 ℃, slowly dripping deionized water with the temperature of not higher than 5 ℃ into the filtrate at the speed of 3-9 mL/min through a constant-pressure dropping funnel in a ventilated and dry environment, stopping dripping when no bubbles are generated, and filtering under the protection of nitrogen to obtain a filtrate D;
transferring the filtrate D into a new container, placing the new container into a high-precision constant-temperature tank at 25-30 ℃, adding 3-5 grains of zeolite, fractionating the solution, and collecting a fraction E at 110.3 ℃;
transferring the fraction E into a high-pressure reaction kettle, adding heavy water and a catalyst F into the high-pressure reaction kettle, wherein the mass ratio of the heavy water to the fraction E is (10-15): 1, and the mass ratio of the fraction E to the catalyst is (5-10): 1, replacing air in the kettle with deuterium gas, sealing the high-pressure reaction kettle, starting stirring at the speed of 400-700 rpm, heating to 110-170 ℃, reacting for 6-12 hours, cooling to 25-30 ℃, and filtering to obtain filtrate G;
and sixthly, transferring the filtrate G to a pressure-resistant device, placing the pressure-resistant device in a high-precision constant-temperature tank at the temperature of 25-30 ℃, adding 3-5 grains of zeolite into the solution, fractionating the solution, and collecting the fraction at the temperature of 110 ℃ to obtain toluene-d 8.
In the first step, the pentahalogenated toluene is one of pentafluorotoluene, pentachlorotoluene, pentabromotoluene and pentaiodotoluene.
In the step one, the solvent is one of anhydrous ether, anhydrous tetrahydrofuran, anhydrous dichloromethane, anhydrous chloroform and anhydrous acetone.
In the second step, the deuteration reagent is one of lithium aluminum deuteride, lithium deuteride and sodium boron deuteride.
In the second step, the catalyst B is one of a palladium carbon catalyst (with a palladium content of 10%), a platinum carbon catalyst (with a platinum content of 10%) and a Raney nickel catalyst.
In the fifth step, the catalyst F is one of palladium carbon catalyst (with palladium content of 10%) and platinum carbon catalyst (with platinum content of 10%).
All the steps are carried out in a drying chamber, and the relative humidity of the air in the drying chamber is 5-15%.
Advantageous effects
(1) According to the preparation method of the toluene-d 8, the exchange reaction of halogen deuterium on a benzene ring and the exchange reaction of hydrogen deuterium on a methyl are carried out step by step, so that the complete deuterium generation reaction is facilitated, and the obtained product has high deuteration rate;
(2) the use of the catalyst reduces the dosage of the deuterated reagent, reduces the production cost and can effectively break the dependence of domestic markets on import.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
Slowly adding 13.2g of pentachlorotoluene into 1150g of anhydrous ether in a dry room temperature environment, stirring at the speed of 250rpm for 0.6 hour to obtain a clear solution A; transferring the clear solution A into an autoclave with the volume of 3000mL, slowly adding 8.7g of lithium aluminum deuteride into the clear solution A under the protection of nitrogen, maintaining the temperature of the solution to be not higher than 25 ℃ in the adding process, adding 1.3g of palladium-carbon catalyst into the mixed solution after the lithium aluminum deuteride is added, sealing the reaction system after no bubble emerges from the solution, checking the air tightness of the device, replacing the gas in the autoclave with deuterium, filling deuterium into the autoclave after 3 times of replacement, closing an air inlet valve when the pressure in the autoclave reaches 1MPa, stirring at the speed of 600rpm, heating to 45 ℃, preserving heat for 24 hours, stopping stirring and naturally cooling to room temperature; filtering, transferring the filtrate into a three-port pressure-resistant device with the volume of 3000mL, placing the three-port pressure-resistant device in a high-precision medium-temperature circulating bath at the temperature of-5 ℃, slowly dripping 5 ℃ deionized water into the filtrate at the speed of 3mL/min through a constant-pressure dropping funnel in a ventilation drying environment, stopping dripping when no bubbles are generated, and filtering under the protection of nitrogen to obtain a filtrate D; transferring the filtrate D into a three-port pressure-resistant device with the volume of 3000mL, placing the three-port pressure-resistant device into a high-precision constant-temperature tank with the temperature of 25 ℃, adding 5 grains of zeolite into the solution, fractionating the solution, slowly heating the solution to 125 ℃ at the heating rate of 3 ℃/min, and receiving a fraction E with the temperature of 110.3 ℃; transferring 3.6G of fraction E into a high-pressure reaction kettle, adding 40G of heavy water and 0.4G of platinum-carbon catalyst into the high-pressure reaction kettle, replacing air in the kettle with deuterium gas, sealing the high-pressure reaction kettle, starting stirring at 700rpm, raising the temperature to 120 ℃, reacting for 12 hours, cooling to 25 ℃, and filtering to obtain filtrate G; transferring the filtrate G to a three-port pressure-resistant device, placing the three-port pressure-resistant device in a high-precision constant temperature tank at 25 ℃, adding 5 grains of zeolite into the solution, fractionating the solution, heating the solution at the heating rate of 3 ℃/min, and collecting the fraction at 110 ℃ to obtain 3.12G of toluene-d 8, wherein the deuteration rate is 99.1 percent, and the yield is 62.4 percent.
Example 2
Slowly adding 29.1g of pentachlorotoluene into 2800g of anhydrous ether in a dry room temperature environment, stirring at the speed of 300rpm for 0.5 hour to obtain a clear solution A; transferring the clear solution A into an autoclave with the volume of 6000mL, slowly adding 13.1g of lithium deuteride into the clear solution A under the protection of nitrogen, maintaining the temperature of the solution to be not higher than 25 ℃ in the adding process, adding 2.9g of palladium-carbon catalyst into the mixed solution after the lithium deuteride is added, sealing the reaction system after no bubbles in the solution emerge, checking the air tightness of the device, replacing the gas in the autoclave with deuterium, filling deuterium into the autoclave after 3 times of replacement, closing an air inlet valve when the pressure in the autoclave reaches 1.5MPa, stirring at the speed of 600rpm, heating to 55 ℃, preserving heat for 24 hours, stopping stirring and naturally cooling to room temperature; filtering, transferring the filtrate into a three-port pressure-resistant device with the volume of 6000mL, placing the three-port pressure-resistant device in a high-precision medium-temperature circulating bath at the temperature of-5 ℃, slowly dripping 5 ℃ deionized water into the filtrate at the speed of 4mL/min through a constant-pressure dropping funnel in a ventilation drying environment, stopping dripping when no bubbles are generated, and filtering under the protection of nitrogen to obtain filtrate D; transferring the filtrate D to a three-port pressure-resistant device with the volume of 6000mL, placing the three-port pressure-resistant device in a high-precision thermostatic bath at 25 ℃, adding 5 grains of zeolite into the solution, fractionating the solution, slowly heating the solution to 125 ℃ at the heating rate of 3 ℃/min, and taking a fraction E at 110.3 ℃; transferring 6.5G of fraction E into a high-pressure reaction kettle, adding 70G of heavy water and 0.7G of platinum-carbon catalyst into the high-pressure reaction kettle, replacing air in the kettle with deuterium gas, sealing the high-pressure reaction kettle, starting stirring at the speed of 700rpm, heating to 140 ℃, reacting for 12 hours, cooling to 25 ℃, and filtering to obtain filtrate G; transferring the filtrate G to a three-port pressure-resistant device, placing the three-port pressure-resistant device in a high-precision constant temperature tank at 25 ℃, adding 5 grains of zeolite into the solution, fractionating the solution, heating the solution at the heating rate of 3 ℃/min, and collecting the fraction at 110 ℃ to obtain 5.9G of toluene-d 8, wherein the deuteration rate is 99.2 percent, and the yield is 53.7 percent.
Example 3
Slowly adding 43.8g of pentabromotoluene into 4000g of anhydrous tetrahydrofuran in a dry room temperature environment, stirring at the speed of 300rpm for 1 hour to obtain a clear solution A; transferring the clear solution A into an autoclave with the volume of 10L, slowly adding 19.2g of boron sodium deuteride into the clear solution A under the protection of nitrogen, maintaining the temperature of the solution to be not higher than 25 ℃ in the adding process, adding 4.4g of palladium carbon catalyst into the mixed solution after the addition of the boron sodium deuteride is finished, sealing the reaction system after no bubbles in the solution emerge, checking the airtightness of the device, replacing the gas in the autoclave with deuterium gas, filling the deuterium gas into the autoclave after 3 times of replacement, closing an air inlet valve when the pressure in the autoclave reaches 2.5MPa, stirring at the speed of 550rpm, heating to 65 ℃, preserving the temperature for 24 hours, stopping stirring and naturally cooling to room temperature; filtering, transferring the filtrate into a three-port pressure-resistant device with the volume of 10L, placing the three-port pressure-resistant device in a high-precision medium-temperature circulating bath at the temperature of-5 ℃, slowly dripping 5 ℃ deionized water into the filtrate at the speed of 4mL/min through a constant-pressure dropping funnel in a ventilation drying environment, stopping dripping when no bubbles are generated, and filtering under the protection of nitrogen to obtain a filtrate D; transferring the filtrate D to a three-port pressure-resistant device with the volume of 10L, placing the three-port pressure-resistant device in a high-precision constant-temperature tank with the temperature of 25 ℃, adding 5 grains of zeolite into the solution, fractionating the solution, slowly heating the solution to 125 ℃ at the heating rate of 3 ℃/min, and taking a fraction E with the temperature of 110.3 ℃; transferring 7.1G of fraction E into a high-pressure reaction kettle, adding 75G of heavy water and 0.75G of palladium-carbon catalyst into the high-pressure reaction kettle, replacing air in the kettle with deuterium gas, sealing the high-pressure reaction kettle, starting stirring at 700rpm, heating to 150 ℃, reacting for 11 hours, cooling to 25 ℃, and filtering to obtain filtrate G; transferring the filtrate G to a three-port pressure-resistant device, placing the three-port pressure-resistant device in a high-precision constant temperature tank at 25 ℃, adding 5 grains of zeolite into the solution, fractionating the solution, heating the solution at the heating rate of 3 ℃/min, and collecting the 110 ℃ fraction to obtain 7.1G of toluene-d 8, wherein the deuteration rate is 99.7 percent, and the yield is 78.8 percent.
Example 4
Slowly adding 58.4g of pentabromotoluene into 6000g of anhydrous tetrahydrofuran in a dry room temperature environment, stirring at the speed of 250rpm for 1 hour to obtain a clear solution A; transferring the clear solution A into an autoclave with the volume of 12L, slowly adding 27.3g of lithium aluminum deuteride into the clear solution A under the protection of nitrogen, maintaining the temperature of the solution to be not higher than 25 ℃ in the adding process, adding 6.0g of platinum-carbon catalyst into the mixed solution after the lithium aluminum deuteride is added, sealing the reaction system after no bubble emerges from the solution, checking the air tightness of the device, replacing the gas in the autoclave with deuterium, filling deuterium into the autoclave after 3 times of replacement, closing an air inlet valve when the pressure in the autoclave reaches 2.5MPa, stirring at the speed of 600rpm, heating to 65 ℃, preserving heat for 24 hours, stopping stirring and naturally cooling to room temperature; filtering, transferring the filtrate into a three-port pressure-resistant device with the volume of 12L, placing the three-port pressure-resistant device in a high-precision medium-temperature circulating bath at the temperature of-5 ℃, slowly dripping 5 ℃ deionized water into the filtrate at the speed of 4mL/min through a constant-pressure dropping funnel in a ventilation drying environment, stopping dripping when no bubbles are generated, and filtering under the protection of nitrogen to obtain a filtrate D; transferring the filtrate D to a three-port pressure-resistant device with the volume of 12L, placing the three-port pressure-resistant device in a high-precision thermostatic bath at the temperature of 25 ℃, adding 5 grains of zeolite into the solution, fractionating the solution, slowly heating the solution to 125 ℃ at the heating rate of 3 ℃/min, and taking a fraction E at the temperature of 110.3 ℃; transferring 8.6G of fraction E into a high-pressure reaction kettle, adding 90G of heavy water and 0.8G of palladium-carbon catalyst into the high-pressure reaction kettle, replacing air in the kettle with deuterium gas, sealing the high-pressure reaction kettle, starting stirring at 700rpm, heating to 160 ℃, reacting for 10 hours, cooling to 25 ℃, and filtering to obtain filtrate G; transferring the filtrate G to a three-port pressure-resistant device, placing the three-port pressure-resistant device in a high-precision constant temperature tank at 25 ℃, adding 5 grains of zeolite into the solution, fractionating the solution, heating the solution at the heating rate of 3 ℃/min, and collecting the fraction at 110 ℃ to obtain 8.2G of toluene-d 8, wherein the deuteration rate is 99.6 percent, and the yield is 68.3 percent.
Example 5
Slowly adding 21.8g of pentafluorotoluene into 2500g of anhydrous tetrahydrofuran in a dry room temperature environment, stirring at the speed of 250rpm for 1 hour to obtain a clear solution A; transferring the clear solution A into an autoclave with the volume of 6L, slowly adding 74.1g of lithium aluminum deuteride into the clear solution A under the protection of nitrogen, maintaining the temperature of the solution to be not higher than 25 ℃ in the adding process, adding 4g of Raney nickel catalyst into the mixed solution after the lithium aluminum deuteride is added, sealing the reaction system after no bubble in the solution emerges, checking the air tightness of the device, replacing the gas in the autoclave with deuterium gas, filling the deuterium gas into the autoclave after 3 times of replacement, closing an air inlet valve when the pressure in the autoclave reaches 3MPa, stirring at the speed of 600rpm, heating to 70 ℃, preserving the temperature for 24 hours, stopping stirring and naturally cooling to room temperature; filtering, transferring the filtrate into a three-port pressure-resistant device with the volume of 6L, placing the three-port pressure-resistant device in a high-precision medium-temperature circulating bath at the temperature of-5 ℃, slowly dripping 5 ℃ deionized water into the filtrate through a constant-pressure dropping funnel at the speed of 5mL/min in a ventilation drying environment, stopping dripping when no bubbles are generated, and filtering under the protection of nitrogen to obtain a filtrate D; transferring the filtrate D to a three-port pressure-resistant device with the volume of 6L, placing the three-port pressure-resistant device in a high-precision thermostatic bath at 25 ℃, adding 5 grains of zeolite into the solution, fractionating the solution, slowly heating the solution to 125 ℃ at the heating rate of 3 ℃/min, and taking a fraction E at the temperature of 110.3 ℃; transferring 7.2G of fraction E into a high-pressure reaction kettle, adding 80G of heavy water and 0.8G of palladium-carbon catalyst into the high-pressure reaction kettle, replacing air in the kettle with deuterium gas, sealing the high-pressure reaction kettle, starting stirring at the speed of 700rpm, heating to 170 ℃, reacting for 9 hours, cooling to 25 ℃, and filtering to obtain filtrate G; transferring the filtrate G to a three-port pressure-resistant device, placing the three-port pressure-resistant device in a high-precision constant temperature tank at 25 ℃, adding 5 grains of zeolite into the solution, fractionating the solution, heating the solution at the heating rate of 3 ℃/min, and collecting the 110 ℃ fraction to obtain 7.1G of toluene-d 8, wherein the deuteration rate is 99.6 percent, and the yield is 59.2 percent.
The above detailed description is intended to illustrate the objects, aspects and advantages of the present invention, and it should be understood that the above detailed description is only exemplary of the present invention and is not intended to limit the scope of the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (4)
1. A method for preparing toluene-d 8, which is characterized in that: the method comprises the following steps:
step one, slowly adding penta-halogenated toluene into a solvent at room temperature, wherein the mass ratio of the penta-halogenated toluene to the solvent is 1: (80-100), stirring at the speed of 200-300 rpm for 0.5-1 hour to obtain a clear solution A;
step two, transferring the clear solution A obtained in the step one into an autoclave, slowly adding a deuterogen reagent into the solution obtained in the step one under the condition of nitrogen protection, wherein the molar ratio of the deuterogen reagent to penta-halogenated toluene is (2-12): 1, keeping the temperature of the solution not higher than 25 ℃ in the adding process, adding a catalyst B into the mixed solution after the deuterogen reagent is added, the mass ratio of the penta-halogenated toluene to the catalyst B is (5-15): 1, sealing the reaction system after no bubbles are emitted from the solution, checking the airtightness of the device, replacing the gas in the autoclave with deuterium, filling deuterium into the autoclave after 3-5 times of replacement, closing an air inlet valve when the pressure in the autoclave reaches 1-3 MPa, stirring at the speed of 400-600 rpm, heating to 35-70 ℃, keeping the temperature for 12-24 hours, stopping stirring and naturally cooling to room temperature, obtaining a mixed solution C;
step three, filtering the mixed liquid C obtained in the step two, transferring the filtrate into a container, placing the container into a high-precision medium-temperature circulating bath at the temperature of-5-0 ℃, slowly dripping deionized water with the temperature of not higher than 5 ℃ into the filtrate at the speed of 3-9 mL/min through a constant-pressure dropping funnel in a ventilated and dry environment, stopping dripping when no bubbles are generated, and filtering under the protection of nitrogen to obtain a filtrate D;
transferring the filtrate D into a new container, placing the new container into a high-precision constant-temperature tank at 25-30 ℃, adding 3-5 grains of zeolite, fractionating the solution, and collecting a fraction E at 110.3 ℃;
transferring the fraction E into a high-pressure reaction kettle, adding heavy water and a catalyst F into the high-pressure reaction kettle, wherein the mass ratio of the heavy water to the fraction E is (10-15): 1, and the mass ratio of the fraction E to the catalyst is (5-10): 1, replacing air in the kettle with deuterium gas, sealing the high-pressure reaction kettle, starting stirring at the speed of 400-700 rpm, heating to 110-170 ℃, reacting for 6-12 hours, cooling to 25-30 ℃, and filtering to obtain filtrate G;
sixthly, transferring the filtrate G to a pressure-resistant device, placing the pressure-resistant device in a high-precision constant-temperature tank at the temperature of 25-30 ℃, adding 3-5 grains of zeolite into the solution, fractionating the solution, and collecting fractions at the temperature of 110 ℃ to obtain toluene-d 8;
in the step one, the solvent is one of anhydrous ether, anhydrous tetrahydrofuran, anhydrous dichloromethane, anhydrous chloroform and anhydrous acetone;
in the second step, the catalyst B is one of palladium carbon catalyst, platinum carbon catalyst and Raney nickel catalyst;
in the fifth step, the catalyst F is a palladium-carbon catalyst with 10 percent of palladium content or a platinum-carbon catalyst with 10 percent of platinum content.
2. The method of claim 1, wherein: in the first step, the pentahalogenated toluene is pentafluorotoluene, pentachlorotoluene, pentabromotoluene or pentaiodotoluene.
3. The method of claim 1, wherein: in the second step, the deuteration reagent is one of lithium aluminum deuteride, lithium deuteride and sodium boron deuteride.
4. The method of claim 1, wherein: all the steps are carried out in a drying chamber, and the relative humidity of the air in the drying chamber is 5-15%.
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| 《High enrichment of heavy water and NMR-solvents to ≥ 99.95 at. % deuterium》;Ch. Jonas和G. Möbius;《Isotopenpraxis》;19871231;第 23卷(第7期);第245-248页 * |
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