A method for preparing deuterated 1,2-dibromoethane

Abstract

This invention discloses a method for preparing deuterated 1,2-dibromoethane, comprising the following steps: (1) adding tetradeuterium glycol, N-bromosuccinimide, and solvent into a reaction vessel; (2) controlling the temperature inside the reaction vessel at -5 to 20°C, and then adding a mixture of triphenylphosphine and solvent dropwise into the reaction vessel; (3) after the dropwise addition is completed, restoring the reaction vessel to room temperature, and controlling the reaction time to 0.5 to 1.5 h to obtain a product containing deuterated 1,2-dibromoethane. The reaction temperature of this invention is at room temperature, the reaction operation is simple, it meets the requirements of green chemistry, and it can be industrialized. Furthermore, the purity of deuterated 1,2-dibromoethane is above 98 wt%, and the yield of deuterated 1,2-dibromoethane is above 60 wt%.

Description

Technical Field

[0001] This invention relates to the field of deuterated compound production technology, and particularly to a method for preparing deuterated 1,2-dibromoethane. Background Technology

[0002] With increasing understanding of deuterium-containing organic compounds, they are becoming increasingly important. In medicinal chemistry, replacing hydrogen with deuterium at the active site of a drug affects its absorption, distribution, metabolism, and excretion. These effects were recognized by scientists in the 1970s and 1980s and applied to pharmaceuticals in the early 21st century. Due to their unique advantages in improving drug metabolism and pharmacokinetic characteristics, they are now becoming a hot area in new drug development. Deuterated reagents are commonly used as pharmaceutical intermediates in the synthesis of deuterated drugs.

[0003] Deuterated 1,2-dibromoethane is one of the deuterating reagents used in the synthesis of deuterated drugs. A 2002 article published in the *Journal of the American Chemical Society*, titled "Use of NMR in Chiral Anisotropic Solvents for the Synthesis of Deuterated Drugs with C3 and C4 Dibromoethanes," discussed its role in the synthesis of deuterated drugs. 3V The preparation of deuterated 1,2-dibromoethane was disclosed in the paper "Enantiomeric and Enantiomer Analysis of Symmetrical Conical Compounds". The specific method involved heating and stirring 24.0 g of ethylene glycol (~10% deuterated) and 5.3 g of red phosphorus at 140 °C while simultaneously adding 20.0 g of liquid bromine. The mixture was kept at this temperature for 1 hour, then cooled to room temperature. The mixture was diluted with water and diethyl ether, the solid residue was filtered, the ether layer was separated, and the solvent was distilled. After distillation, 23 g of 1,2-dibromoethane (~10% deuterated) was obtained. Although this method successfully prepared deuterated 1,2-dibromoethane, the reaction conditions were harsh, and the yield of deuterated 1,2-dibromoethane was only around 30%, which is low and not conducive to process scale-up.

[0004] Therefore, there is a need to develop a deuterated 1,2-dibromoethane with a simple synthesis process and high yield. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing deuterated 1,2-dibromoethane, which has a simple synthesis process and high yield.

[0006] The technical solution adopted by this invention to solve its technical problem is:

[0007] A method for preparing deuterated 1,2-dibromoethane includes the following steps:

[0008] (1) Add tetradeuterium glycol, N-bromosuccinimide, and solvent to the reaction vessel; the amount of solvent used in this step is 40-60% (by volume) of the total amount of solvent used;

[0009] (2) Control the temperature inside the reactor at -5 to 20°C, and then add the mixture of triphenylphosphine and solvent dropwise into the reactor; (3) After the dropwise addition is completed, restore the reactor to room temperature and control the reaction time to 0.5 to 1.5 h to obtain a product containing deuterated 1,2-dibromoethane.

[0010] The ratio of tetradeuterium glycol, N-bromosuccinimide, triphenylphosphine, and solvent is 1 mol: 2.0–3 mol: 2.0–3 mol: 0.8–1.5 L. The solvent volume refers to the total amount of solvent used.

[0011] The solvent is selected from one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, and chloroform.

[0012] In this invention, triphenylphosphine is activated by the reaction with N-bromosuccinimide, followed by the attack of the oxygen atom of tetradeuterium glycol on the triphenylphosphine bromide to yield an oxophosphonium salt intermediate. The bromide ion undergoes an SN2 reaction, with triphenylphosphine bromide departing as a leaving group to give deuterated 1,2-dibromoethane. Configuration inversion occurs during this process, driven by the formation of triphenylphosphine bromide, which contains a strong P=O double bond, propelling the entire reaction system smoothly and allowing the reaction to proceed at room temperature.

[0013] In this invention, the addition amounts of tetradeuterium glycol and N-bromosuccinimide satisfy the ratio of 1 mol to 2.0–3 mol. Compared to tetradeuterium glycol, N-bromosuccinimide is added in excess. The purpose is to ensure that all hydroxyl groups in tetradeuterium glycol are brominated. However, when the amount of N-bromosuccinimide added is too high, the purity of the obtained product is reduced, and the difficulty of subsequent purification of the obtained product is increased.

[0014] In this invention, triphenylphosphine is added in excess, just like N-bromosuccinimide, to match the amount of N-bromosuccinimide added. The purpose is to fully activate N-bromosuccinimide, but adding too much can easily cause difficulties in subsequent purification.

[0015] The addition amounts of tetradeuterium glycol and solvent should meet the requirement of 1 mol: 0.8–1.5 L. Within this range, tetradeuterium glycol and N-bromosuccinimide can be fully mixed and the reaction efficiency can be improved.

[0016] The reaction time should be controlled between 0.5 and 1.5 hours. When the reaction time is less than 0.5 hours, the reaction is incomplete, with a large amount of raw materials remaining and a low product yield. When the reaction time is more than 1.5 hours, the risk of side reactions increases, and energy consumption also increases.

[0017] In step (2), 1 mol of triphenylphosphine is added dropwise over 0.05–0.15 h. This reaction is exothermic; therefore, triphenylphosphine is mixed with a portion of the solvent and added dropwise. The temperature inside the reactor is controlled between -5 and 20°C to avoid generating excessive heat. The dropping rate must also be controlled; too rapid a drop results in severe exothermic reactions and increased side reactions. Too slow a drop results in prolonged reaction time and increased energy consumption.

[0018] It also includes product purification procedures, specifically:

[0019] (4) The product containing deuterated 1,2-dibromoethane obtained in step (3) is washed with an inorganic salt solution and / or water, and then allowed to stand for separation. The lower organic phase is taken out; the purpose is to separate out excess N-bromosuccinimide.

[0020] (5) Add the organic phase into the distillation vessel. The internal temperature of the distillation vessel is controlled at 43-50℃ and the top temperature is controlled at 35-42℃. Distill off part of the solvent under normal pressure, then add n-hexane dropwise. At the same time, continue to distill off the solvent under normal pressure for a second time, and keep the volume ratio of the added n-hexane to the volume of the second distilled solvent at 1.5-3:1.

[0021] (6) After the addition is completed, the internal temperature of the distillation vessel is first controlled at 35-42℃, and the mixture is stirred. Then the internal temperature of the distillation vessel is controlled below 30℃, and the organic phase is filtered to obtain the filtrate. In this step, after the addition is completed, the internal temperature of the distillation vessel is first controlled at 35-42℃. At this temperature, it is convenient for the growth of triphenyloxyphosphine crystal nuclei. The internal temperature of the distillation vessel is controlled below 30℃ so that triphenyloxyphosphine crystals crystallize and precipitate.

[0022] (7) Add the filtrate to another distillation vessel and control the internal temperature of the distillation vessel to 55℃~65℃ and the vacuum degree to 500~700mmbar until no liquid flows out. The purpose of controlling the appropriate temperature and vacuum degree is to distill off the solvent first, while avoiding the azeotropic distillation of deuterated 1,2-dibromoethane with the solvent, thereby improving the distillation yield of deuterated 1,2-dibromoethane.

[0023] (8) Adjust the internal temperature of the distillation vessel to 70℃~80℃ and the vacuum degree to less than 100mmbar to obtain purified deuterated 1,2-dibromoethane. By controlling the appropriate temperature and vacuum degree, high-purity deuterated 1,2-dibromoethane is obtained by distillation.

[0024] A key technical challenge of this invention is the purification of the product. The product contains deuterated 1,2-dibromoethane, N-bromosuccinimide, triphenylphosphine oxide, and a solvent. At room temperature, this system is miscible, and the reaction product, deuterated 1,2-dibromoethane, is also a haloalkane, exhibiting excellent solubility for triphenylphosphine oxide. Therefore, conventional solvent evaporation cannot yield the product. Removing triphenylphosphine oxide from this system is thus the purification process's challenge. This invention removes triphenylphosphine oxide by adding n-hexane during solvent evaporation to reduce its solubility, thereby achieving crystallization. Through multiple operations, separation and purification are achieved, yielding qualified deuterated 1,2-dibromoethane.

[0025] In step (5), the solvent distilled off in one step accounts for 40% to 60% of the total volume of solvent used in the reaction.

[0026] In step (5), the amount of n-hexane added accounts for 40% to 60% of the total volume of the solvent used in the reaction.

[0027] The purpose of distilling off a portion of the solvent at atmospheric pressure is to reduce the solubility of triphenyloxyphosphine, which facilitates its crystallization and precipitation. The solvent distilled off in one step accounts for 40% to 60% of the total solvent volume, allowing triphenyloxyphosphine to crystallize better and form a solid, which is easier to filter.

[0028] Then, hexane is added dropwise while the solvent is distilled off a second time. This is to replace the solvent with hexane, thereby increasing the crystallization yield of triphenylphosphine oxide. The amount of hexane added is 40% to 60% of the total solvent volume, which is more conducive to the fluidity of the entire system.

[0029] The volume ratio of the added hexane to the secondary distilled solvent should be maintained at 1.5 to 3:1. This is to avoid explosive precipitation during the crystallization process of triphenylphosphine oxide, otherwise the solid will be in lumps, increasing the difficulty of filtration.

[0030] In step (8), the purity of the deuterated 1,2-dibromoethane obtained is above 98 wt%.

[0031] Step (4) is as follows:

[0032] a) The product containing deuterated 1,2-dibromoethane obtained in step (3) is first washed with sodium sulfite aqueous solution, then washed with sodium bicarbonate aqueous solution. After the pH is measured to 7-8, the product is allowed to stand and separated, and the lower organic phase is retained.

[0033] b) Wash the organic phase obtained in step a) with water, check the pH to 7-8, let it stand and separate the layers, retaining the lower organic phase; c) Wash the organic phase obtained in step b) with sodium chloride aqueous solution, let it stand and separate the layers, retaining the lower organic phase.

[0034] The amounts of sodium sulfite aqueous solution, sodium bicarbonate aqueous solution, water, and sodium chloride aqueous solution used are based on N-bromosuccinimide, and the ratio of N-bromosuccinimide:sodium sulfite aqueous solution:sodium bicarbonate aqueous solution:water:sodium chloride aqueous solution = 1 mol:0.08-0.2 L:0.08-0.2 L:0.08-0.2 L:0.08-0.2 L. The concentration of the sodium sulfite aqueous solution is 10 wt%-25 wt%, the concentration of the sodium bicarbonate aqueous solution is 5 wt%-8 wt%, and the concentration of the sodium chloride aqueous solution is 5 wt%-30 wt%.

[0035] The beneficial effects of this invention are: by controlling the amount of tetradeuterium glycol, N-bromosuccinimide, and solvent added, and by controlling the reaction temperature and reaction time, easily brominated deuterated 1,2-dibromoethane can be finally obtained. The reaction temperature is at room temperature, the reaction operation is simple, meets the requirements of green chemistry, and can be industrialized. The purity of deuterated 1,2-dibromoethane is above 98 wt%, and the yield of deuterated 1,2-dibromoethane is above 60 wt%. Attached Figure Description

[0036] Figure 1 This is the molecular structural formula of tetradeuterium ethylene glycol of the present invention;

[0037] Figure 2 This is the molecular structural formula of deuterated 1,2-dibromoethane of the present invention;

[0038] Figure 3 This is a synthetic route diagram for deuterated 1,2-dibromoethane according to the present invention;

[0039] Figure 4 This refers to the GC detection data from Embodiment 1 of the present invention;

[0040] Figure 5 This is the NMR spectrum of the deuteration degree in Example 1 of the present invention. Detailed Implementation

[0041] The technical solution of the present invention will be further described in detail below through specific embodiments.

[0042] In this invention, unless otherwise specified, all raw materials and equipment used are commercially available or commonly used in the field. The methods described in the following embodiments are conventional methods in the field, unless otherwise specified.

[0043] Example:

[0044] This invention provides 15 examples and 4 comparative examples for preparing deuterated 1,2-dibromoethane, wherein the examples include the following preparation steps ( Figure 3 ):

[0045] 1) Tetradeuterium glycol ( Figure 1N-bromosuccinimide and solvent were added to the reaction vessel;

[0046] 2) Control the temperature inside the reactor at -5 to 20°C, and then add the mixture of triphenylphosphine and solvent dropwise into the reactor; the addition time of triphenylphosphine should meet the requirement of 1 mol: 0.05 to 0.15 h;

[0047] 3) After the addition is complete, the reactor is brought back to room temperature, and the reaction time is controlled at 0.5 to 1.5 h to obtain the product containing deuterated 1,2-dibromoethane;

[0048] The amounts of tetradeuterium glycol, N-bromosuccinimide, triphenylphosphine, and solvent added meet the following ratios: 1 mol: 2.0–3 mol: 2.0–3 mol: 0.8–1.5 L. The solvent is selected from one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, and chloroform. Key parameter controls are shown in Table 1. In all embodiments of the present invention, the amount of solvent used in step 1) is half of the total amount of solvent used.

[0049] The amounts of tetradeuterium glycol, N-bromosuccinimide, triphenylphosphine, and solvent added satisfy A;

[0050] The addition time of triphenylphosphine satisfies C.

[0051] The 15 examples of deuterated 1,2-dibromoethane were purified according to the purification method of the present invention, including the following purification steps:

[0052] 4) Wash the obtained product as follows, then allow it to stand and separate the layers to obtain the lower organic phase; specifically:

[0053] a) Wash the obtained product with sodium sulfite aqueous solution, then wash with sodium bicarbonate aqueous solution. After checking the pH to 7-8, let it stand and separate the liquid, retaining the lower organic phase.

[0054] b) Wash the organic phase obtained in step a) with water again, check the pH to 7-8, let it stand and separate the liquid, retaining the lower organic phase;

[0055] c) Wash the organic phase obtained in step b) with sodium chloride aqueous solution, let it stand and separate the layers, retaining the lower organic phase; the addition amounts of N-bromosuccinimide, sodium sulfite aqueous solution, sodium bicarbonate aqueous solution, water, and sodium chloride aqueous solution meet the following ratios: 1 mol: 0.08–0.2 L: 0.08–0.2 L: 0.08–0.2 L: 0.08–0.2 L, the concentration of sodium sulfite aqueous solution is 10 wt%–25 wt%, the concentration of sodium bicarbonate aqueous solution is 5 wt%–8 wt%, and the concentration of sodium chloride aqueous solution is 5 wt%–30 wt%.

[0056] 5) Add the organic phase to the distillation vessel. The internal temperature of the distillation vessel is controlled at 43-50℃, and the top temperature is controlled at 35-42℃. Distill off part of the solvent under normal pressure, and then add n-hexane dropwise. At the same time, continue to distill off the solvent a second time under normal pressure, and maintain the volume ratio of the added n-hexane to the secondary distilled solvent at 1.5-3:1. The solvent distilled off in the first stage accounts for 40%-60% of the total solvent volume, and the amount of n-hexane added accounts for 40%-60% of the total solvent volume.

[0057] 6) After the addition is complete, the internal temperature of the distillation vessel is first controlled at 35-42℃, and the mixture is stirred. Then the internal temperature of the distillation vessel is controlled below 30℃, and the organic phase is filtered to obtain the filtrate.

[0058] 7) Add the filtrate to the distillation vessel, and control the internal temperature of the distillation vessel to be 55℃~65℃ and the vacuum degree to be 500~700mmbar until no liquid flows out;

[0059] 8) Adjust the internal temperature of the distillation vessel to 70℃~80℃ and the vacuum degree to below 100mmbar to obtain purified deuterated 1,2-dibromoethane. Figure 2 The analytical data for the deuterated 1,2-dibromoethane (d4) compound are as follows: ¹H NMR (399MHz, Chloroform-d) δ 3.81 (s, 0.02H) MS (EI) 186.1.

[0060] Let D be the ratio of the volume of n-hexane added to the volume of the solvent removed during the second distillation.

[0061] Let E be the percentage of solvent extracted during the first distillation relative to the total volume of solvent.

[0062] Let F be the percentage of n-hexane added relative to the total volume of the solvent;

[0063] After the addition is complete, the internal temperature of the distillation vessel should be controlled at G; stir, and then the internal temperature of the distillation vessel should be controlled at H.

[0064] The addition amounts of N-bromosuccinimide, sodium sulfite aqueous solution, sodium bicarbonate aqueous solution, water, and sodium chloride aqueous solution meet the requirements of I; key parameter controls are shown in Tables 2 and 3.

[0065] The difference between Comparative Example 1 and Example 1 is that the temperature inside the reactor is controlled at 25°C;

[0066] The difference between Comparative Example 2 and Example 1 is that the reaction time is 3 hours;

[0067] The difference between Comparative Example 3 and Example 1 is that the triphenylphosphine addition time satisfies the ratio of 1 mol to 0.03 h.

[0068] The difference between Comparative Example 4 and Example 1 is that step 2 in the purification process is omitted.

[0069] The obtained embodiments and comparative examples were subjected to the following tests:

[0070] 1) Purity detection: Gas chromatograph is used for detection.

[0071] The GC detection data for Example 1 are shown below. Figure 4 .

[0072] 2) Yield detection: The calculation formula is: actual weight of 1,2-dibromoethane / theoretical weight of 1,2-dibromoethane *%.

[0073] The NMR spectrum of the deuteration degree in Example 1 is shown below. Figure 5 .

[0074] The specific test results are shown in Table 4.

[0075] Table 1 Key parameter control in the preparation of embodiments of the present invention

[0076]

[0077] Table 2. Control of key purification parameters in embodiments of the present invention.

[0078]

[0079] Table 3 Key Parameter Control for Purification in Embodiments of the Invention

[0080]

[0081] Table 4. Detection results of embodiments and comparative examples of the present invention.

[0082] serial number Yield / % purity / % Example 1 70.3 99.4 Example 2 87.5 99.0 Example 3 88.8 99.2 Example 4 80.1 98.8 Example 5 78.9 99.2 Example 6 78.3 98.3 Example 7 87.5 98.7 Example 8 89.2 99.1 Example 9 83.3 98.5 Example 10 88.5 98.2 Example 11 89.3 98.8 Example 12 79.2 99.5 Example 13 78.8 99.0 Example 14 88.6 98.5 Example 15 87.8 98.9 Comparative Example 1 65 83.4 Comparative Example 2 68 85.6 Comparative Example 3 61 90.1 Comparative Example 4 70 80.7 .

[0083] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Other variations and modifications are possible without departing from the technical solutions described in the claims.

Claims

1. A method for preparing deuterated 1,2-dibromoethane, characterized in that, Includes the following steps: (1) Add tetradeuterium glycol, N-bromosuccinimide, and solvent to the reaction vessel; (2) Control the temperature inside the reactor at -5 to 20°C, and then add the mixture of triphenylphosphine and solvent dropwise into the reactor; the time for adding 1 mol of triphenylphosphine is 0.05 to 0.15 h. (3) After the addition is complete, the reactor is brought back to room temperature and the reaction time is controlled to be 0.5 to 1.5 h to obtain a product containing deuterated 1,2-dibromoethane; It also includes product purification procedures, specifically: (4) Wash the product containing deuterated 1,2-dibromoethane obtained in step (3) with an inorganic salt solution and / or water, then let it stand and separate the layers, and take the lower organic phase. (5) Add the organic phase into the distillation vessel. The internal temperature of the distillation vessel is controlled at 43-50℃ and the top temperature is controlled at 35-42℃. Distill off part of the solvent under normal pressure, then add n-hexane dropwise. At the same time, continue to distill off the solvent under normal pressure for a second time, and keep the volume ratio of the added n-hexane to the volume of the second distilled solvent at 1.5-3:

1. (6) After the addition is completed, the internal temperature of the distillation vessel is first controlled at 35-42℃, stirred, and then the internal temperature of the distillation vessel is controlled below 30℃. The organic phase is filtered to obtain the filtrate. (7) Add the filtrate to another distillation vessel, and control the internal temperature of the distillation vessel to be 55℃~65℃ and the vacuum degree to be 500~700mmbar until no liquid flows out; (8) Adjust the internal temperature of the distillation vessel to 70℃~80℃ and the vacuum degree to less than 100mmbar to obtain purified deuterated 1,2-dibromoethane.

2. The preparation method according to claim 1, characterized in that: The ratio of tetradeuterium glycol, N-bromosuccinimide, triphenylphosphine, and solvent is 1 mol: 2.0–3 mol: 2.0–3 mol: 0.8–1.5 L.

3. The preparation method according to claim 1, characterized in that: The solvent is selected from one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, and chloroform.

4. The preparation method according to claim 1, characterized in that: In step (5), the solvent evaporated in one step accounts for 40% to 60% of the total volume of the solvent used in the reaction.

5. The preparation method according to claim 1, characterized in that: In step (5), the amount of n-hexane added accounts for 40% to 60% of the total volume of the solvent used in the reaction.

6. The preparation method according to claim 1, characterized in that: In step (8), the purity of the deuterated 1,2-dibromoethane obtained is above 98 wt%.

7. The preparation method according to claim 1, characterized in that: Step (4) is as follows: a) The product containing deuterated 1,2-dibromoethane obtained in step (3) is first washed with sodium sulfite aqueous solution, then washed with sodium bicarbonate aqueous solution. After the pH is measured to 7-8, the product is allowed to stand and separated, and the lower organic phase is retained. b) Wash the organic phase obtained in step a) with water again, check the pH to 7-8, let it stand and separate the liquid, retaining the lower organic phase; c) Wash the organic phase obtained in step b) with an aqueous sodium chloride solution, let it stand and separate the layers, retaining the lower organic phase.

8. The preparation method according to claim 7, characterized in that: The amounts of sodium sulfite aqueous solution, sodium bicarbonate aqueous solution, water, and sodium chloride aqueous solution used are based on N-bromosuccinimide, and the ratio of N-bromosuccinimide:sodium sulfite aqueous solution:sodium bicarbonate aqueous solution:water:sodium chloride aqueous solution = 1 mol:0.08~0.2L:0.08~0.2L:0.08~0.2L:0.08~0.2L. The concentration of the sodium sulfite aqueous solution is 10wt%~25wt%, the concentration of the sodium bicarbonate aqueous solution is 5wt%~8wt%, and the concentration of the sodium chloride aqueous solution is 5wt%~30wt%.

Images