Preparation method of deuterated chloroform

Abstract

The invention discloses a preparation method of deuterated chloroform, which comprises the following steps: reacting hexachloroacetone and heavy water at 80-100 DEG C under the action of a cesium-containing catalyst, distilling while reacting, collecting fractions at 60-61 DEG C to obtain a deuterated chloroform crude product, and further post-treating to obtain a deuterated chloroform refined product, the cesium-containing catalyst is cesium salt or cesium oxide. The preparation method is high in yield and low in cost, the catalyst can be conveniently and mechanically used, and the loss of high-value heavy water is avoided.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of deuterated reagent production, and particularly relates to a preparation method of deuterated chloroform. BACKGROUND

[0002] Deuterated chloroform is the most commonly used solvent for nuclear magnetic resonance detection. With the rapid development of deuterated drugs, deuterated chloroform is also used as a deuterated reagent. At present, the preparation method of deuterated chloroform mainly uses sodium trichloroacetate and calcium oxide as raw materials to react with heavy water under the catalysis of a base to obtain deuterated chloroform.

[0003] Chinese Patent Application CN109096044B discloses a method for preparing deuterated chloroform by using sodium trichloroacetate, calcium oxide and heavy water as raw materials. During the reaction, equivalent amounts of sodium carbonate and calcium carbonate solid by-products are generated, which causes the catalyst to be unable to be continuously used. Chinese Patent Application CN107814686B discloses a method for preparing deuterated chloroform by using hexachloroacetone, calcium oxide and heavy water as raw materials. During the reaction, equivalent amounts of calcium carbonate solid by-products are generated, which causes the catalyst to be unable to be continuously used. Chinese Patent Application CN103408413B discloses a method for preparing deuterated chloroform by using hexachloroacetone, potassium carbonate and heavy water as raw materials. In the method, the potassium carbonate catalyst is converted into a potassium chloride by-product in a side reaction, which causes the catalyst to lose catalytic activity and be unable to be continuously used. Due to the inability of the catalyst to be used, the potassium chloride or calcium carbonate by-products generated during the reaction need to be removed after the reaction. The removal of the by-products or potassium chloride causes the loss of valuable heavy water. In order to avoid the loss of heavy water, the above-mentioned methods often increase the amount of hexachloroacetone to promote the conversion of heavy water. However, the above-mentioned methods still cannot fundamentally solve the problem of the loss of valuable heavy water, and the use of excessive hexachloroacetone also increases the cost.

[0004] In order to facilitate industrial production and avoid the loss of valuable heavy water and deuterated chloroform in the batch production process, a preparation method of deuterated chloroform with a catalyst that can be easily used is needed to be developed. SUMMARY

[0005] The purpose of the present application is to provide a preparation method of deuterated chloroform with high yield and low cost, and the catalyst of the preparation method can be easily used to avoid the loss of valuable heavy water.

[0006] The present application solves the technical problem by the following technical scheme:

[0007] A preparation method of deuterated chloroform, comprising the following steps:

[0008] Under the action of the cesium-containing catalyst, hexachloroacetone and heavy water are reacted at 80-100 DEG C, distillation is carried out at the same time, and then 60-61 DEG C fraction is collected under normal pressure, so that the crude deuterated chloroform is obtained; and through further post-treatment, the fine deuterated chloroform is obtained.

[0009] The cesium-containing catalyst is a cesium salt or an oxide of cesium.

[0010] The application uses hexachloroacetone and heavy water as raw materials, and uses a cesium salt or an oxide as a new catalyst, so that the deuterated chloroform can be efficiently prepared through only one step, the process is simple, the yield is high, the process can be continuous, the cost is low, and the cesium-containing catalyst is not deactivated after the reaction, so that the possibility of subsequent reuse is provided.

[0011] The cesium-containing catalyst is one or more of cesium chloride, cesium bromide, cesium iodide, cesium oxide, cesium nitrate, cesium carbonate, cesium sulfate and cesium phosphate, preferably one or more of cesium chloride, cesium carbonate and cesium phosphate, and further preferably cesium carbonate.

[0012] The molar ratio of the hexachloroacetone to the heavy water is 1.0:0.8-1.2, and further preferably 1.0:1.0.

[0013] The molar ratio of the heavy water to the cesium salt catalyst is 1.0:0.2-0.5.

[0014] The reaction temperature is further preferably 90-95 DEG C.

[0015] The post-treatment includes impurity removal and rectification.

[0016] The impurity removal is that a certain amount of concentrated sulfuric acid is added to the crude deuterated chloroform, and then stirring, standing and layer separation are carried out, and the upper organic phase, i.e., the impurity-removed crude deuterated chloroform, is collected.

[0017] In the impurity removal operation, the mass ratio of the crude deuterated chloroform to the concentrated sulfuric acid is 1.0:0.2-0.5.

[0018] The impurity removal operation can be repeated 1-3 times.

[0019] The rectification operation is that the impurity-removed crude deuterated chloroform is subjected to normal-pressure distillation, and then the fraction of 60-61 DEG C, i.e., the fine deuterated chloroform, is collected.

[0020] Preferably, the process also includes a catalyst reuse step, which involves adding hexachloroacetone and heavy water (the molar ratio of hexachloroacetone to heavy water is 1:0.8 to 1.2, preferably 1:1) to the reaction apparatus and repeating steps (1) and (2) to achieve intermittent continuous production of deuterated chloroform. The cesium-containing catalyst of this invention maintains high activity after the reaction is complete, eliminating the need to remove waste such as residue from the reactor. New raw materials can be added directly for subsequent reactions, avoiding the loss of heavy water or hexachloroacetone during operation, thus fully utilizing residual raw materials and reducing costs.

[0021] Preferably, the catalyst reuse step includes a catalyst replenishment step, that is, after the catalyst has been reused a certain number of times, when the product yield drops to or exceeds 10%, fresh catalyst equivalent to 15-25% of the initial catalyst addition is added to the reaction device, and the replenished catalyst system is recycled for reaction until the product yield drops to or exceeds 10% again, and then another 15-25% of fresh catalyst is added to achieve intermittent continuous production of deuterated chloroform.

[0022] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0023] (1) Cesium ions have large radius and low charge density, which weakens their electrostatic interaction with anions, making the anions nucleophilic and basic, and can efficiently catalyze the deuteration reaction of hexachloroacetone.

[0024] (2) Cesium salts do not transform into inert substances during the reaction, can always maintain catalytic activity, can be recycled, realize the continuous production of deuterated chloroform, and break through the bottleneck of deactivation of traditional alkali metal catalysts.

[0025] (3) Using cesium salt as a catalyst avoids the generation of insoluble byproducts such as calcium carbonate. After the reaction is completed, there is no need to remove byproducts, residues and other waste. On the one hand, it reduces the loss of high-value heavy water in post-processing and lowers production costs. On the other hand, it avoids stopping the reaction and allows for continuous feeding to achieve continuous production. Attached Figure Description

[0026] Figure 1 The image shows the 1H NMR spectrum of the product obtained in Example 1. Detailed Implementation

[0027] The technical solution of the present invention will be further described in detail below through specific embodiments.

[0028] Unless otherwise specified, the raw materials and equipment used in this invention can be purchased from the market or are commonly used in the field.

[0029] Unless otherwise specified, the methods described in the following embodiments are conventional methods in the art.

[0030] Example 1:

[0031] 10g of heavy water (0.5mol) and 30g of cesium chloride (0.178mol) were added to a 500mL three-necked flask equipped with a reflux condenser. 145g of hexachloroacetone (0.55mol) was added dropwise over approximately 10 minutes with stirring. The temperature was raised to 95℃, and the fraction distilled at 60-61℃ was collected under normal pressure. GC analysis showed a hexachloroacetone conversion rate >90%, indicating the reaction was complete and yielding 114.53g of crude deuterated chloroform. Concentrated sulfuric acid (25% by mass) was added to the crude deuterated chloroform, and the mixture was stirred for 20 minutes. After separation, the upper layer of crude deuterated chloroform was collected and purified. A second normal pressure distillation was then performed, collecting the fraction distilled at 60-61℃ to obtain 106.17g of a colorless, transparent liquid, which was the purified deuterated chloroform. A sample was taken. 1 The 1H NMR detection showed a deuteration degree of 99.88% and a yield of 88.33%. The 1H NMR spectrum is shown below. Figure 1 As shown, the 1H NMR data are 1 ¹H NMR (400MHz, CDCl₃) δ 7.26 (s, 1H). Subsequently, 0.5 mol of heavy water and 0.5 mol of hexachloroacetone were continuously added to the above three-necked flask, while the fraction at 60–61 °C was continuously collected at atmospheric pressure, which can realize the continuous preparation of deuterated chloroform. The results of catalyst utilization are shown in Table 1.

[0032] After the catalyst was reused 20 times, the yield of deuterated chloroform decreased by 11.37%. 4.5 g of cesium chloride (i.e., 15 wt% fresh catalyst) was added to the three-necked flask reactor. After the 21st reaction, 107.32 g of deuterated chloroform product was obtained, with a yield of 89.28%.

[0033] Example 2:

[0034] 10g of heavy water (0.5mol) and 30g of cesium chloride (0.178mol) were added to a 500ml three-necked flask equipped with a reflux condenser. 145g of hexachloroacetone (0.55mol) was added dropwise over approximately 10 minutes with stirring. The temperature was raised to 95℃, and the fraction distilled at 60-61℃ was collected under normal pressure. GC analysis showed a hexachloroacetone conversion rate >90%, indicating the reaction was complete and yielding 112.48g of crude deuterated chloroform. Concentrated sulfuric acid (25% by mass of the crude deuterated chloroform) was added to the crude deuterated chloroform. After stirring for 20 minutes, the mixture was allowed to separate into layers. The upper layer of deuterated chloroform was collected. This crude product was purified three times and then subjected to a second atmospheric distillation. The fraction distilled at 60-61℃ was collected, yielding 101.59g of a colorless, transparent liquid, which was the purified deuterated chloroform. A sample was taken. 1¹H NMR analysis showed a deuteration degree of 99.81% and a yield of 84.51%. Subsequently, 0.5 mol of heavy water and 0.5 mol of hexachloroacetone were continuously added to the three-necked flask, while the fraction at 60–61 °C was continuously collected under normal pressure, enabling the continuous preparation of deuterated chloroform.

[0035] Example 3:

[0036] 10g of heavy water (0.5mol) and 42g of cesium chloride (0.25mol) were added to a 500ml three-necked flask equipped with a reflux condenser. 145g of hexachloroacetone (0.55mol) was added dropwise over approximately 10 minutes with stirring. The temperature was raised to 95℃ for the reaction, while the fraction distilled at 60-61℃ was collected under normal pressure. GC analysis showed a hexachloroacetone conversion rate >90%, indicating the reaction was complete and yielding 110.88g of crude deuterated chloroform. Concentrated sulfuric acid (25% by mass of the crude deuterated chloroform) was added to the crude deuterated chloroform. After stirring for 20 minutes, the mixture was allowed to separate into layers. The upper layer of crude deuterated chloroform, after impurity removal, was collected and subjected to a second atmospheric distillation. The fraction distilled at 60-61℃ was collected, yielding 103.15g of a colorless, transparent liquid, which was the purified deuterated chloroform. A sample was taken. 1 ¹H NMR analysis showed a deuteration degree of 99.81% and a yield of 85.81%. Subsequently, 0.5 mol of heavy water and 0.5 mol of hexachloroacetone were continuously added to the three-necked flask, while the fraction at 60–61 °C was continuously collected under normal pressure, enabling the continuous preparation of deuterated chloroform.

[0037] Example 4:

[0038] 10g of heavy water (0.5mol) and 30g of cesium chloride (0.178mol) were added to a 500ml three-necked flask equipped with a reflux condenser. 110g of hexachloroacetone (0.42mol) was added dropwise over approximately 10 minutes with stirring. The temperature was raised to 95℃ for the reaction, while the fraction distilled at 60-61℃ was collected under normal pressure. GC analysis showed a hexachloroacetone conversion rate >99%. The reaction was then complete, yielding 95.41g of crude deuterated chloroform. Concentrated sulfuric acid (25% by mass of the crude deuterated chloroform) was added to the crude deuterated chloroform. After stirring for 20 minutes, the mixture was allowed to separate into layers. The upper layer of crude deuterated chloroform, after impurity removal, was collected and subjected to a second atmospheric distillation. The fraction distilled at 60-61℃ was collected, yielding 86.79g of a colorless, transparent liquid, which was the purified deuterated chloroform. A sample was taken. 1 ¹H NMR analysis showed a deuteration degree of 99.87% and a yield of 72.21%. Subsequently, 0.42 mol of heavy water and 0.5 mol of hexachloroacetone were continuously added to the three-necked flask, while the fraction collected at 60–61 °C under normal pressure was continuously collected. GC analysis showed a hexachloroacetone conversion rate >99%, at which point the reaction was terminated. The above post-processing procedure was repeated to obtain 105.35 g of purified deuterated chloroform. A sample was taken. 1¹H NMR analysis showed a deuteration degree of 99.85% and a yield of 87.65%. Subsequently, 0.5 mol of heavy water and 0.5 mol of hexachloroacetone were continuously added to the three-necked flask, while the fraction at 60–61 °C was continuously collected under normal pressure, thus enabling the continuous preparation of deuterated chloroform.

[0039] Example 5:

[0040] 10 g of heavy water (0.5 mol) and 32.53 g of cesium carbonate (0.15 mol) were added to a 500 ml three-necked flask equipped with a reflux condenser. 145 g of hexachloroacetone (0.55 mol) was added dropwise over approximately 10 minutes with stirring. The temperature was raised to 90 °C, and the fraction distilled at 60–61 °C was collected under normal pressure. GC analysis showed a hexachloroacetone conversion rate >90%, indicating the reaction was complete. 116.84 g of crude deuterated chloroform was obtained. Concentrated sulfuric acid (25% by mass of the crude deuterated chloroform) was added to the crude deuterated chloroform. After stirring for 20 minutes, the mixture was allowed to separate into layers. The upper layer of crude deuterated chloroform, after impurity removal, was collected and subjected to a second atmospheric distillation. The fraction distilled at 60–61 °C was collected, yielding 107.45 g of a colorless, transparent liquid, which was the purified deuterated chloroform. A sample was taken. 1 ¹H NMR analysis showed a deuteration degree of 99.82% and a yield of 89.38%. Subsequently, 0.5 mol of heavy water and 0.5 mol of hexachloroacetone were continuously added to the three-necked flask, while the fraction at 60–61 °C was continuously collected at atmospheric pressure. This enabled the continuous preparation of deuterated chloroform. The results of catalyst utilization are shown in Table 1.

[0041] Example 6:

[0042] 10g of heavy water (0.5mol) and 49.3g of cesium phosphate (0.1mol) were added to a 500ml three-necked flask equipped with a reflux condenser. 106g of hexachloroacetone (0.4mol) was added dropwise over approximately 10 minutes with stirring. The temperature was raised to 90℃, and the fraction distilled at 60-61℃ was collected under normal pressure. GC analysis showed a hexachloroacetone conversion rate >99%. The reaction was then complete, yielding 97.42g of crude deuterated chloroform. Concentrated sulfuric acid (25% by mass of the crude deuterated chloroform) was added to the crude deuterated chloroform. After stirring for 20 minutes, the mixture was allowed to separate into layers. The upper layer of crude deuterated chloroform, after impurity removal, was collected and subjected to a second atmospheric distillation. The fraction distilled at 60-61℃ was collected, yielding 87.64g of a colorless, transparent liquid, which was the purified deuterated chloroform. A sample was taken. 1 ¹H NMR analysis showed a deuteration degree of 99.72% and a yield of 72.90%. Subsequently, 0.5 mol of heavy water and 0.5 mol of hexachloroacetone were continuously added to the three-necked flask, while the fraction at 60–61 °C was continuously collected at atmospheric pressure. This enabled the continuous preparation of deuterated chloroform. The results of catalyst utilization are shown in Table 1.

[0043] Example 7:

[0044] 10 g of heavy water (0.5 mol) and 56.28 g of cesium oxide (0.2 mol) were added to a 500 ml three-necked flask equipped with a reflux condenser. 145 g of hexachloroacetone (0.55 mol) was added dropwise over approximately 10 minutes with stirring. The temperature was raised to 80 °C for the reaction, while the fraction distilled at 60–61 °C was collected under normal pressure. GC analysis showed a hexachloroacetone conversion rate >90%, indicating the reaction was complete and yielding 102.17 g of crude deuterated chloroform. Concentrated sulfuric acid (25% by mass of the crude deuterated chloroform) was added to the crude deuterated chloroform. After stirring for 20 minutes, the mixture was allowed to separate into layers. The upper layer of crude deuterated chloroform, after impurity removal, was collected and subjected to a second atmospheric distillation. The fraction distilled at 60–61 °C yielded 96.51 g of a colorless, transparent liquid, which was the purified deuterated chloroform. A sample was taken. 1 ¹H NMR analysis showed a deuteration degree of 99.89% and a yield of 80.28%. Subsequently, 0.5 mol of heavy water and 0.5 mol of hexachloroacetone were continuously added to the three-necked flask, while the fraction at 60–61 °C was continuously collected at atmospheric pressure. This enabled the continuous preparation of deuterated chloroform. The results of catalyst utilization are shown in Table 1.

[0045] Example 8:

[0046] 10 g of heavy water (0.5 mol) and 64.41 g of cesium nitrate (0.178 mol) were added to a 500 ml three-necked flask equipped with a reflux condenser. 145 g of hexachloroacetone (0.55 mol) was added dropwise over approximately 10 minutes with stirring. The temperature was raised to 100 °C for the reaction, while the fraction distilled at 60–61 °C was collected under normal pressure. GC analysis showed a hexachloroacetone conversion rate >90%, indicating the reaction was complete and yielding 97.44 g of crude deuterated chloroform. Concentrated sulfuric acid (25% by mass of the crude deuterated chloroform) was added to the crude deuterated chloroform, and the mixture was stirred for 20 minutes. After settling, the layers were separated, and the upper layer of crude deuterated chloroform was collected after impurity removal. A second normal pressure distillation was then performed, collecting the fraction distilled at 60–61 °C to obtain 90.16 g of a colorless, transparent liquid, which was the purified deuterated chloroform. A sample was taken. 1 ¹H NMR analysis showed a deuteration degree of 99.83% and a yield of 75.00%. Subsequently, 0.5 mol of heavy water and 0.5 mol of hexachloroacetone were continuously added to the three-necked flask, while the fraction at 60–61 °C was continuously collected at atmospheric pressure. This enabled the continuous preparation of deuterated chloroform. The results of catalyst utilization are shown in Table 1.

[0047] Comparative Example 1:

[0048] 10 g of heavy water (0.5 mol) and 10.09 g of calcium oxide (0.178 mol) were added to a 500 mL three-necked flask equipped with a reflux condenser. 145 g of hexachloroacetone (0.55 mol) was added dropwise over approximately 10 minutes with stirring. The temperature was raised to 95 °C for the reaction, while the fraction distilled at 60–61 °C was collected under normal pressure. GC analysis showed a hexachloroacetone conversion rate >90%, indicating the reaction was complete and yielding 118.77 g of crude deuterated chloroform. Concentrated sulfuric acid (25% by mass of the crude deuterated chloroform) was added to the crude deuterated chloroform. After stirring for 20 minutes, the mixture was allowed to separate into layers. The upper layer of crude deuterated chloroform, after impurity removal, was collected and subjected to a second atmospheric distillation. The fraction distilled at 60–61 °C yielded 109.48 g of a colorless, transparent liquid, which was the purified deuterated chloroform. A sample was taken. 1 The H NMR analysis showed a deuteration degree of 99.85% and a yield of 91.07%. Subsequently, 0.5 mol of heavy water and 0.5 mol of hexachloroacetone were continuously added to the three-necked flask to conduct a catalyst reuse experiment. The results of the catalyst reuse are shown in Table 1.

[0049] Comparative Example 2

[0050] 10 g of heavy water (0.5 mol) and 24.88 g of potassium carbonate (0.178 mol) were added to a 500 mL three-necked flask equipped with a reflux condenser. 145 g of hexachloroacetone (0.55 mol) was added dropwise over approximately 10 minutes with stirring. The temperature was raised to 95 °C for the reaction, while the fraction distilled at 60–61 °C was collected under normal pressure. GC analysis showed a hexachloroacetone conversion rate >90%, indicating the reaction was complete and yielding 98.74 g of crude deuterated chloroform. Concentrated sulfuric acid (25% by mass of the crude deuterated chloroform) was added to the crude deuterated chloroform, and the mixture was stirred for 20 minutes. After settling, the layers were separated, and the upper layer of crude deuterated chloroform was collected after impurity removal. A second normal pressure distillation was then performed, collecting the fraction distilled at 60–61 °C to obtain 91.52 g of a colorless, transparent liquid, which was the purified deuterated chloroform. A sample was taken. 1 The H NMR analysis showed a deuteration degree of 99.80% and a yield of 76.13%. Subsequently, 0.5 mol of heavy water and 0.5 mol of hexachloroacetone were continuously added to the three-necked flask to conduct a catalyst reuse experiment. The results of the catalyst reuse are shown in Table 1.

[0051] Table 1

[0052]

[0053]

[0054] The embodiments described above are merely preferred embodiments of the present invention and are not intended to modify the present invention in any way.

[0055] The invention is limited to variations and modifications that do not exceed the scope of the technical solutions described in the claims.

Claims

1. A method for preparing deuterated chloroform, characterized in that, Includes the following steps: Under the action of a cesium-containing catalyst, hexachloroacetone and heavy water react at 80-100℃. Distillation is carried out simultaneously with the reaction, and the fraction at 60-61℃ is collected to obtain crude deuterated chloroform. After further post-processing, refined deuterated chloroform is obtained. The cesium-containing catalyst is a cesium salt or a cesium oxide.

2. The method for preparing deuterated chloroform according to claim 1, characterized in that, The cesium-containing catalyst is one or more of cesium chloride, cesium bromide, cesium iodide, cesium oxide, cesium nitrate, cesium carbonate, cesium sulfate, and cesium phosphate, preferably one or more of cesium chloride, cesium carbonate, and cesium phosphate, and more preferably cesium carbonate.

3. The method for preparing deuterated chloroform according to claim 1, characterized in that, The molar ratio of hexachloroacetone to heavy water is 1.0:0.8 to 1.2, more preferably 1.0:1.0; The molar ratio of heavy water to cesium-containing catalyst is 1.0:0.2 to 0.

5.

4. The method for preparing deuterated chloroform according to claim 1, characterized in that, The reaction temperature is 90–95℃.

5. The method for preparing deuterated chloroform according to claim 1, characterized in that, The post-processing includes impurity removal and distillation; The impurity removal process involves adding concentrated sulfuric acid, stirring, allowing the mixture to stand and separate into layers, and collecting the upper organic phase. The distillation is atmospheric distillation, collecting the fraction at 60-61℃.

6. The method for preparing deuterated chloroform according to claim 5, characterized in that, In the impurity removal operation, the mass ratio of crude deuterated chloroform to concentrated sulfuric acid is 1.0:0.2-0.5; The impurity removal operation can be repeated 1-3 times.

7. The method for preparing deuterated chloroform according to any one of claims 1 to 6, characterized in that, The post-processing also includes a catalyst reprocessing step: Add hexachloroacetone and heavy water to the reaction apparatus and continue heating to produce deuterated chloroform.

8. The method for preparing deuterated chloroform according to claim 7, characterized in that, The molar ratio of the added hexachloroacetone to heavy water is 1:0.8 to 1.2, preferably 1:

1.

9. The method for preparing deuterated chloroform according to claim 7, characterized in that, The catalyst application step also includes a catalyst replenishment step: After the catalyst has been used a certain number of times, when the product yield drops by 10% or more, fresh cesium-containing catalyst equivalent to 15-25% of the initial catalyst addition is added to the reaction device. The catalyst system is then recycled until the product yield drops by 10% or more again. At this point, another 15-25% of fresh catalyst is added to achieve intermittent continuous production of deuterated chloroform.

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