Methods for preparing and purifying acetic acid-D

Abstract

The present invention provides a method for preparing acetic acid-D, comprising the step of reacting deuterium bromide with sodium acetate in a heavy water system to generate acetic acid-D.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for preparing and purifying acetic acid-D. BACKGROUND

[0002] Deuterated chemicals are a class of special compounds, which have important applications in the fields of reaction mechanism research, kinetics, drug metabolism and biological structure determination. Specifically, acetic acid-D (CH3COOD) is mainly used to adjust the pH value of deuterated system, or as a solvent to dissolve other deuterated compounds.

[0003] The current market common method for preparing deuterated chemicals is hydrogen-deuterium exchange method (H / D exchange method), that is, using catalyst to exchange hydrogen and deuterium source with target molecule. The catalyst is most commonly metal catalyst (palladium, platinum and rhodium, etc.). For example, Han Jun et al. (Han Jun, Guan Rui, Hu Sheng, et al. Hydrogen-deuterium exchange performance between methane and deuterium chloride on Pd / γ-Al2O3 catalyst [J]. Rare Metal Materials and Engineering, 2012, 41(1): 64-68) used Pd / γ-Al2O3 catalyst and DCl as deuterium source to exchange H / D with methane, and the conversion rate could reach 70%. Hironao Sajiki et al. (Sajiki H, Aoki F, Esaki H, et al. Palladium-catalyzed HD exchange into nucleic acids in deuterium oxide [C] / / Nucleic acids symposium series. Oxford University Press, 2003, 3(1): 55-56) used Pd / C as catalyst and D2O as deuterium source to exchange H / D with the methylene of valeric acid at 110℃ reflux, and the conversion rate could reach 95%. In addition, Yoshinari Sawama et al. (Sawama Y, Nakano A, Matsuda T, et al. H-D Exchange deuteration of arenes at room temperature [J]. Organic Process Research & Development, 2019, 23(4): 648-653) used Ir / C as catalyst and D2O as deuterium source to exchange H / D with the hydrogen atoms on the benzene ring of benzoic acid molecule at room temperature, and the conversion rate could reach 95% at most.

[0004] Although the currently common hydrogen-deuterium exchange reaction is a very attractive strategy, however, these methods face great challenges. First, the hydrogen-deuterium exchange reaction using catalysts is often deuterium gas as the deuterium source, and most processes involve high temperature, high pressure, strong acid, strong base conditions, so there is a high requirement for reaction equipment; second, the selectivity of hydrogen-deuterium exchange reaction is difficult to control, and in the process of hydrogen-deuterium exchange at specific sites of the molecule, it is difficult to accurately direct the replacement of deuterium atoms to the target functional group; third, the use of noble metal catalysts is costly, limiting large-scale industrial applications; finally, the conversion rate of hydrogen-deuterium exchange method is still low. Therefore, the existing deuterium strategy and technology need to be further improved and developed. SUMMARY

[0005] In view of the deficiencies of the prior art described above, the purpose of the present application is to provide a method for preparing and purifying acetic acid-D, which aims to solve the technical problems of the existing hydrogen-deuterium exchange reaction requiring the use of deuterium gas, high temperature, high pressure conditions, low selectivity and conversion rate, and high cost.

[0006] Sodium acetate is an organic salt, and the alpha-H on the acetate methyl group is relatively stable. At the same time, in the heavy water solution of deuterium bromide, deuterium bromide can be completely dissociated into deuterium ions and bromide ions as a strong acid, and acetic acid can be combined with deuterium ions to form acetate as a weak acid. This reaction is a process of making a weak acid from a strong acid, so it can proceed normally.

[0007] Therefore, in the heavy water system, deuterium bromide and sodium acetate can react to form acetic acid-D. This reaction does not require any catalyst, the reaction conditions are mild, and it can be carried out under laboratory conditions. The present inventors have unexpectedly found that by selecting a specific polar organic solvent to extract acetic acid-D, the present method can quickly and efficiently synthesize and purify acetic acid-D. The purity of the final product acetic acid-D can be as high as 99.8%, and the deuterium substitution rate of the hydroxyl group can be as high as 99.01%.

[0008] Therefore, in one aspect, the present application provides a method for preparing acetic acid-D, comprising the step of reacting deuterium bromide with sodium acetate in a heavy water system to form acetic acid-D.

[0009] As described above, sodium acetate is an organic salt, and the alpha-H on the acetate methyl group is relatively stable. At the same time, in the heavy water solution of deuterium bromide, deuterium bromide can be completely dissociated into deuterium ions and bromide ions as a strong acid, and acetic acid can be combined with deuterium ions to form acetate as a weak acid. This reaction is a process of making a weak acid from a strong acid, so it can proceed normally. The reaction of deuterium bromide and sodium acetate in a heavy water system to form acetic acid-D is as follows:

[0010] DBr + CH3COONa → CH3COOD + NaBr

[0011] In the method for preparing acetic acid-D according to the present application, sodium acetate can be added to the heavy water solution of deuterium bromide at one time for reaction. The one-time addition of sodium acetate results in an increase in reaction temperature and a decrease in the deuterium substitution rate of hydroxyl group. Therefore, according to a preferred embodiment, sodium acetate is added to the heavy water solution of deuterium bromide in several portions for reaction. For example, sodium acetate is added to the heavy water solution of deuterium bromide in three to five equal portions for reaction.

[0012] Since the method for preparing acetic acid-D according to the present application is an exothermic reaction, in order to prevent the system temperature from being too high due to the heat released by the reaction, which affects the deuterium substitution rate of hydroxyl group, sodium acetate is added in portions.

[0013] According to a preferred embodiment, the method according to the present application further comprises a step of extracting the acetic acid-D in the aqueous phase by a polar organic solvent.

[0014] The selection of the polar organic solvent used for extraction should meet the following requirements: acetic acid-D is a polar molecule, and according to the principle of "like dissolves like", the extractant should also be a polar solvent; the solvent molecules should not contain active conventional H to prevent affecting the isotopic abundance of the product; and the extractant molecules should have a larger boiling point difference compared with acetic acid-D and not azeotrope with acetic acid-D, so as to facilitate the purification of the target product and the recovery of the extractant. Therefore, the solvents that can be used as the extractant in the method according to the present application include, but are not limited to, deuterated dichloromethane, diethyl ether, ethyl acetate, deuterated chloroform (CDCl3), etc., or a mixture of one or more of the above solvents. Considering the cost and the requirements of downstream customers for the deuterium substitution rate of product impurities, deuterated chloroform is preferably used to extract the acetic acid-D from the aqueous phase.

[0015] According to a preferred embodiment, the volume ratio of the polar organic solvent to the aqueous phase can be 0.8:1 to 1.2:1.

[0016] According to a preferred embodiment, the method according to the present application further comprises a step of purifying the acetic acid-D by distillation at normal temperature and reduced pressure.

[0017] According to a preferred embodiment, the isotopic deuterium abundance of the heavy water is greater than 99.5%.

[0018] According to a particularly preferred embodiment, the method according to the present application comprises the following steps:

[0019] a) chemically reacting deuterium bromide with sodium acetate in a heavy water system to generate acetic acid-D;

[0020] b) adding a polar organic solvent to the above reaction mixture to extract the acetic acid-D in the aqueous phase; and

[0021] c) purifying the acetic acid-D by distillation at normal temperature and reduced pressure.

[0022] According to a preferred embodiment, the method of the present invention includes the following steps:

[0023] a) Sodium acetate is added in portions to a heavy aqueous solution of deuterium bromide to generate acetic acid-D;

[0024] b) Add deuterated chloroform to the above reaction mixture to extract acetic acid-D from the aqueous phase; and

[0025] c) Purify the acetic acid-D by distillation under reduced pressure at room temperature.

[0026] The hydroxyl deuteration rate of acetic acid-D prepared by the method of the present invention can reach up to 99.01%, and its purity can reach up to 99.8%.

[0027] The method of this invention is an exothermic reaction, and the reaction temperature can be varied from -11℃ to 12℃ of the heavy aqueous solution of deuterium bromide before the reaction to 15℃ to 28℃.

[0028] The technical advantages of the method for preparing and purifying acetic acid-D in this invention are summarized as follows:

[0029] 1) The method of the present invention does not require a catalyst, the reaction conditions are mild, it can be carried out in the laboratory, and it does not have high requirements for reaction equipment, thus reducing costs;

[0030] 2) The method of this invention achieves site-specific deuteration of the number of deuterium atoms and key sites in the deuterated product acetic acid-D, wherein the deuteration rate of the hydroxyl groups in acetic acid-D can reach up to 99.01%; and

[0031] 3) By selecting a specific polar organic solvent for extracting acetic acid-D, the method of the present invention can synthesize acetic acid-D quickly and efficiently, with a purity of up to 99.8%. Attached Figure Description

[0032] Figure 1 This is the mass spectrum of acetic acid-D prepared in Example 1 of the present invention.

[0033] Figure 2 This is a gas chromatogram of acetic acid-D prepared in Example 1 of the present invention.

[0034] Figure 3 This is the hydrogen spectrum of acetic acid-D prepared in Example 1 of this invention. Figure 3 As shown, the peak at 2.079 min is the α-methyl peak, and the peak at 11.669 min is the hydroxyl peak (deuterated position).

[0035] The calculation method for the deuteration rate of the product's hydroxyl groups is as follows:

[0036] Product hydroxyl deuteration rate = 1 - product hydroxyl peak area / (standard hydroxyl peak area / (1 - standard hydroxyl deuteration rate)).

[0037] Figure 4 This is a flowchart of a preferred embodiment of the method according to the present invention.

[0038] Figure 5 This is a schematic diagram of the reaction apparatus for the method of the present invention.

[0039] Figure 6 This is a schematic diagram of a distillation apparatus for a preferred embodiment of the method of the present invention. Detailed Implementation

[0040] The present invention will be further described below with reference to specific embodiments. It should be noted that the following embodiments are merely illustrative examples of the present invention, but the scope of protection of the present invention is not limited thereto. All equivalent substitutions made by those skilled in the art in accordance with the spirit of the present invention fall within the scope of protection of the present invention.

[0041] Experimental reagents and instruments:

[0042] Deuterium bromide was purchased from Shanghai Maclean Biochemical Technology Co., Ltd.

[0043] The heavy water solution was purchased from Shanghai Maclean Biochemical Technology Co., Ltd.

[0044] Sodium acetate was purchased from Tianjin Oubokai Chemical Co., Ltd.

[0045] Deuterated chloroform was purchased from Shanghai Maclean Biochemical Technology Co., Ltd.

[0046] The refrigeration unit is DLSB-5 / 25 from Zhengzhou Yuda Instrument Technology Co., Ltd.

[0047] The peristaltic pump is the BT600LC from Ruichuang Pumps.

[0048] The vacuum pump is a 2XZ-2 manufactured by Zhejiang Huangyan Tianlong Vacuum Pump Factory.

[0049] Example 1

[0050] 396.8 g of deuterium bromide was placed in 595 g of a heavy aqueous solution to obtain 992 g (746 ml) of a 40% deuterium bromide heavy aqueous solution. This solution was then transferred to a 2 L Erlenmeyer flask and continuously stirred using an electric stirrer. The flask was placed in a refrigeration system (e.g., one where the ambient temperature is -11°C and ethylene glycol is the working fluid) to achieve the desired temperature. Figure 5(As shown). 1190.4 g of sodium acetate was slowly added in three equal portions to a heavy aqueous solution of deuterium bromide. After the addition was complete, the reaction continued for 30 minutes. The reaction was exothermic, and the temperature change within the system was measured to be 15-25℃. After the reaction, the liquid phase was transferred to a 5L glass bottle, and 1259.1 g (832 ml) of deuterated chloroform (purity >99.9%) was added. The mixture was shaken and allowed to stand to separate into layers. The aqueous phase was in the lower layer, and the organic phase of deuterated chloroform was in the upper layer. A portion of the organic phase (1562.9 g) was extracted using a peristaltic pump. Gas chromatography analysis showed that the mass fraction of deuterated chloroform was 71.49%, and the mass fraction of acetic acid-D was 27.9%. A vacuum distillation apparatus (such as...) was constructed. Figure 6 As shown, the internal pressure was reduced to -75 mmHg using a vacuum pump, the reboiler temperature was 23°C, and the condensation temperature was -6.1°C. Finally, 104.34 g of liquid phase was obtained from the reboiler, in which the mass fraction of acetic acid-D was 99.1%, and the hydroxyl deuteration rate was tested to be 99.01%.

[0051] Example 2

[0052] 1190.4 g of deuterium bromide was placed in 1785 g of a heavy aqueous solution to obtain 2976 g (2283 ml) of a 40% deuterium bromide heavy aqueous solution. This solution was then transferred to a 2 L Erlenmeyer flask and continuously stirred with an electric stirrer. The flask was placed in a refrigerator with an ambient temperature of 9°C and ethylene glycol as the working fluid. 1845 g of sodium acetate was slowly added to the deuterium bromide heavy aqueous solution in three equal portions. After the addition was complete, the reaction continued for 1 hour, and the temperature change within the system was measured to be 17-28°C. After the reaction was complete, 2300 ml of deuterated chloroform was added to the liquid phase system, and the mixture was shaken to mix. After separation, 3250 ml of the upper organic phase was extracted using a peristaltic pump. Gas chromatography analysis revealed that the mass fraction of deuterated chloroform was 85%, and the mass fraction of acetic acid-D was 13%. After vacuum distillation, 330.54 g of liquid phase was obtained from the bottom of the column, which contained 99.4% acetic acid-D by mass, and the hydroxyl deuteration rate was tested to be 99.00%.

[0053] Example 3

[0054] 726.1 g of deuterium bromide was placed in 1106.7 g of a heavy aqueous solution to obtain 1845 g (1370 ml) of a 40% deuterium bromide heavy aqueous solution. This solution was then transferred to a 2 L Erlenmeyer flask and continuously stirred with an electric stirrer. The flask was placed in a refrigerator with ethylene glycol as the working fluid at an ambient temperature of 12 °C. 1110 g of sodium acetate was slowly added to the deuterium bromide heavy aqueous solution in three equal portions. After each addition, the reaction continued for 40 min. The reaction was exothermic, and the temperature change within the system was measured to be 19-23 °C. After the reaction was complete, 1400 ml of deuterated chloroform was added, and the mixture was shaken to mix thoroughly. After separation, 1700 ml of the upper organic phase was extracted using a peristaltic pump. Gas chromatography analysis revealed that the mass fraction of deuterated chloroform was 74%, and the mass fraction of acetic acid-D was 25%. After vacuum distillation, 158.3 g of liquid phase was obtained from the bottom of the column, which contained 99.8% acetic acid-D by mass, and the hydroxyl deuteration rate was tested to be 99.01%.

[0055] Example 4

[0056] 400.8 g of deuterium bromide was placed in 601.0 g of a heavy aqueous solution to obtain 1000.0 g (753.5 ml) of a 40% deuterium bromide heavy aqueous solution. 1202.3 g of sodium acetate was slowly added to the deuterium bromide heavy aqueous solution in three equal portions. After the addition was complete, the reaction continued for 30 min. After the reaction was complete, the liquid phase was transferred to a 5 L glass bottle, and 1884.0 g (1244.32 ml) of deuterated dichloromethane (purity >99.9%) was added. The mixture was shaken and then allowed to stand for separation. A portion of the organic phase (1578.5 g) was extracted using a peristaltic pump. The solution was then purified using a vacuum distillation apparatus (e.g.,...). Figure 6 As shown in the figure, the final product obtained in the bottom of the column was 64.75 g of liquid phase, of which the mass fraction of acetic acid-D was 99.04% and the hydroxyl deuteration rate was tested to be 99.02%.

[0057] Comparative Example 1

[0058] 396.8 g of deuterium bromide was placed in 589 g of a heavy aqueous solution to obtain 982 g (738.5 ml) of a 40% deuterium bromide heavy aqueous solution. 1178.5 g of sodium acetate was slowly added to the deuterium bromide heavy aqueous solution in three equal portions, and the reaction was continued for 30 min after each addition. After the reaction was complete, the liquid phase was transferred to a 5 L glass bottle, and 856.26 g (565.5 ml) of deuterated chloroform (purity >99.9%) was added. The mixture was shaken and allowed to stand to separate into layers. The aqueous phase was in the lower layer, and the organic phase of deuterated chloroform was in the upper layer. A portion of the organic phase (797 g) was extracted using a peristaltic pump. The solution was then purified using a vacuum distillation apparatus (e.g., Figure 6 (As shown) The final product obtained in the bottom of the column was 34.42 g of liquid phase, of which the mass fraction of acetic acid-D was 99.3%, and the hydroxyl deuteration rate was tested to be 99.01%.

[0059] Comparative Example 2

[0060] 394.8 g of deuterium bromide was placed in 592.0 g of a heavy aqueous solution to obtain 987.0 g (742.3 ml) of a 40% deuterium bromide heavy aqueous solution. 1184.4 g of sodium acetate was slowly added to the deuterium bromide heavy aqueous solution in three equal portions, and the reaction was continued for 30 min after each addition. After the reaction was complete, the liquid phase was transferred to a 5 L glass bottle, and 2798.1 g (1849 ml) of deuterated chloroform (purity >99.9%) was added. The mixture was shaken and allowed to stand for separation. A portion of the organic phase (2328.3 g) was extracted using a peristaltic pump. The solution was then purified using a vacuum distillation apparatus (e.g.,...). Figure 6 As shown in the figure, the final product obtained in the bottom of the column was 73.04 g of liquid phase, of which the mass fraction of acetic acid-D was 99.2%, and the hydroxyl deuteration rate was tested to be 99.01%.

[0061] Comparative Example 3

[0062] 398.8 g of deuterium bromide was placed in 598 g of a heavy aqueous solution to obtain 997 g (750 ml) of a 40% deuterium bromide heavy aqueous solution. 1190.4 g of sodium acetate was added to the deuterium bromide heavy aqueous solution in one step. After the addition was complete, the reaction continued for 30 min. The reaction was exothermic, and the temperature change within the system was measured to be 15-75℃. After the reaction was complete, the liquid phase system was transferred to a 5 L glass bottle, and 1265.4 g (836.16 ml) of deuterated chloroform (purity >99.9%) was added. The mixture was shaken and then allowed to stand for separation. A portion of the organic phase (1570.7 g) was extracted using a peristaltic pump. A vacuum distillation apparatus (such as...) was then constructed. Figure 6 As shown in the figure, the internal pressure was reduced to -75 mmHg using a vacuum pump, and 104.86 g of liquid phase was finally obtained in the column bottom, of which the mass fraction of acetic acid-D was 99.1%, and the hydroxyl deuteration rate was tested to be 97.50%.

Claims

1. A process for the preparation of acetic acid-D, comprising the steps of: a) chemically reacting deuterium bromide with sodium acetate in a heavy water system to produce acetic acid-D; b) adding a polar organic solvent to the above reaction mixture to extract the acetic acid-D from the aqueous phase; and c) purifying the acetic acid-D by rectification at normal temperature and reduced pressure; wherein the temperature of the heavy water system in step a) is between -11 °C and 12 °C, and the sodium acetate is added in portions to the heavy water system; and wherein the polar organic solvent in step b) is selected from the group consisting of deuterated dichloromethane, diethyl ether, ethyl acetate, deuterated chloroform or a mixture thereof.

2. The process according to claim 1, wherein the isotopic deuterium abundance of the heavy water is greater than 99.5%.

3. The process according to claim 1, wherein the polar organic solvent is deuterated chloroform.

4. The process according to claim 3, wherein the purity of the deuterated chloroform is greater than 99.9%.

5. The process according to claim 1, wherein the volume ratio of the polar organic solvent to the aqueous phase is between 0.8:1 and 1.2:1.

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