Preparation method of deuterated tert-butyl alcohol
By using anhydrous butyl ether as a solvent, the preparation process of deuterated tert-butyl alcohol is simplified, the problems of safety hazards, separation difficulties and high costs in the existing technology are solved, and the preparation of deuterated tert-butyl alcohol with high purity and high yield is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202510470488.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-15
- Publication Date
- 2025-09-19
Smart Images
Figure CN120664947A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of fine chemicals, and particularly relates to a method for preparing deuterated tert-butyl alcohol. Background Art
[0002] Deuterated compounds are widely used in fields such as nuclear magnetic resonance (NMR), pharmaceuticals, and OLEDs. In the pharmaceutical industry, replacing one or more carbon-hydrogen (CH) bonds in specific locations on drug molecules with carbon-deuterium (CD) bonds can prolong drug metabolism and reduce the production of toxic metabolites, thereby lowering drug dosage, improving safety, and achieving better therapeutic outcomes. Tert-Butyl Alcohol-d10 is primarily used in scientific research and as a laboratory reagent. It is an important chemical raw material and deuterated drug intermediate, serving as a key starting material for the synthesis of deuterated drugs such as deuterated atazanavir.
[0003] Among the existing methods for preparing tert-butanol-d10, some methods use diethyl ether as a reaction solvent. However, due to the low flash point of diethyl ether, it poses a serious safety hazard and is therefore not suitable for large-scale preparation of fully deuterated tert-butanol. Some methods use tetrahydrofuran instead of diethyl ether as a reaction solvent, but due to its boiling point being close to that of the product, separation is difficult. Another method first uses organic synthesis to prepare tert-butanol-d9, and then performs hydrogen-deuterium exchange with the deuterated product to obtain tert-butanol-d10. However, this process has the disadvantages of complex and tedious steps and high production costs. Summary of the Invention
[0004] In view of the shortcomings of the existing technology, the present invention provides a method for preparing deuterated tert-butanol, which has the advantages of high yield and simple operation and is suitable for large-scale production.
[0005] Specifically, the present invention provides the following technical solutions:
[0006] A method for preparing deuterated tert-butyl alcohol comprises the following steps:
[0007] A. Using anhydrous butyl ether as a reaction solvent, deuterated iodomethane and magnesium are reacted under the protection of an inert gas to generate deuterated methylmagnesium iodide;
[0008] B. reacting deuterated methylmagnesium iodide with deuterated acetone to generate an intermediate product;
[0009] C. The intermediate product is reacted with deuterated sulfuric acid and further purified to obtain deuterated tert-butyl alcohol.
[0010]
[0011] Preferably, the molar ratio of deuterated iodomethane to magnesium is 1:0.9-1.1; if the magnesium content exceeds the above range, the amount of deuterated sulfuric acid used will increase, which will increase the cost of producing and recovering the deuterium source;
[0012] The molar ratio of deuterated iodomethane to anhydrous butyl ether is 1:1.5-2.5;
[0013] The molar ratio of deuterated iodomethane to deuterated acetone is 1:0.8-1.1. If the deuterated acetone content exceeds the above range, unreacted deuterated acetone will remain in the reaction system after the reaction, increasing the difficulty and cost of subsequent purification, thereby reducing the yield of deuterated tert-butanol.
[0014] More preferably, the molar ratio of deuterated iodomethane, magnesium and deuterated acetone is 1:1:0.8.
[0015] Preferably, in step A, the reaction temperature of the deuterated iodomethane and magnesium is room temperature and the reaction time is 2 to 8 hours.
[0016] Preferably, in step B, reacting deuterated methylmagnesium iodide with deuterated acetone comprises the following steps: adding deuterated acetone dropwise to the reaction solution containing deuterated methylmagnesium iodide obtained in step A at 0-5° C., and reacting for more than 5 hours after the addition is complete.
[0017] Preferably, in step C, reacting the intermediate product with deuterated sulfuric acid comprises the following steps: adding deuterated sulfuric acid to the reaction solution containing the intermediate product obtained in step B at 0-5° C., and stirring at this temperature for at least 4 hours.
[0018] Preferably, in step C, the deuterated sulfuric acid is a D2SO4 D2O solution, wherein the mass fraction of D2SO4 is 5-15%.
[0019] Preferably, in step C, the purification comprises the following steps: standing and separating the layers to obtain an upper organic phase and a lower aqueous phase, and distilling the upper organic phase under normal pressure at 110° C. to obtain a first deuterated tert-butanol product;
[0020] The lower aqueous phase is subjected to atmospheric distillation at 100° C. to distill out a mixture containing deuterated tert-butanol and heavy water, which is further separated to obtain a second deuterated tert-butanol product;
[0021] The residual liquid after the first atmospheric distillation is subjected to a second atmospheric distillation at 130°C to distill out the heavy water for recycling.
[0022] The beneficial effects of the present invention are at least:
[0023] (1) The present invention provides a method for preparing deuterated tert-butanol, which directly synthesizes deuterated tert-butanol in one step. Compared with the traditional method of first synthesizing tert-butanol-D9 and then preparing deuterated tert-butanol by hydrogen-deuterium exchange, the process is simple, the operation is simple, and it is conducive to industrial scale-up and production.
[0024] (2) The present invention provides a method for preparing deuterated tert-butyl alcohol. The reaction solvent uses anhydrous butyl ether with a high boiling point. The subsequent separation difficulty is low. Only a simple distillation operation is required to obtain deuterated tert-butyl alcohol with a deuteration rate of >98% and a purity of >99%, which is convenient for industrial production.
[0025] (3) The present invention provides a method for preparing deuterated tert-butanol, which reduces the difficulty and cost of subsequent purification and improves the yield of deuterated tert-butanol by optimizing the dosage ratio of raw materials.
[0026] (4) The present invention provides a method for preparing deuterated tert-butyl alcohol, wherein the deuterated water after the reaction can be recycled and reused, thereby reducing production costs. BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Figure 1 This is the gas phase spectrum of deuterated tert-butyl alcohol prepared in Example 1.
[0028] Figure 2 This is the NMR spectrum of deuterated tert-butyl alcohol prepared in Example 1. DETAILED DESCRIPTION
[0029] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. The following embodiments are used to illustrate the present invention but are not intended to limit the scope of the present invention. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in the field or the product instructions shall be followed.
[0030] Example 1
[0031] A. Add 34 g of magnesium rod and 500 ml of anhydrous butyl ether into a flask. Add 210 g of deuterated iodomethane dropwise under a nitrogen atmosphere and react at room temperature for 4 hours.
[0032] B. Cool to 0°C, add 92 g of deuterated acetone dropwise, and continue the reaction overnight;
[0033] C. Cool to 0°C, add 120 g of 10% mass fraction of deuterated sulfuric acid, keep warm and stir for 4 hours, let stand to separate, take the organic phase and distill at 110°C for 2-3 hours to separate butyl ether and deuterated tert-butanol with a boiling point difference of 60°C to obtain the first deuterated tert-butanol product;
[0034] The aqueous phase was subjected to atmospheric distillation at 100° C. to distill out an azeotrope of deuterated tert-butanol and heavy water. The azeotrope was subjected to a water absorbent to remove water to obtain a second deuterated tert-butanol product. The first deuterated tert-butanol product and the second deuterated tert-butanol product were combined to obtain a deuterated tert-butanol product with a deuteration rate of 98.8% and a purity of 99.38%.
[0035] The residual liquid after the first distillation was subjected to a second atmospheric distillation at 130° C. to recover heavy water. The deuteration rate of the heavy water did not decrease, and the recovered heavy water could be used to prepare the next 10% mass fraction of deuterated sulfuric acid.
[0036] The purity of deuterated tert-butyl alcohol is obtained from gas chromatography. Figure 1 This is the gas phase spectrum of the deuterated tert-butanol product prepared in Example 1. From the peak position at 2.286 min in the figure, the purity of the deuterated tert-butanol is 99.38%.
[0037] The deuterium substitution rate of deuterated tert-butanol was obtained by nuclear magnetic resonance, and the deuterium substitution rate was calculated by comparing the homemade sample with the standard sample. Figure 2 This is the NMR spectrum of the deuterated tert-butyl alcohol product prepared in Example 1. The 1.069 ppm vibration peak in the figure is the hydrogen spectrum of the methyl group in the deuterated tert-butyl alcohol. The 4.696 ppm vibration peak in the figure is the hydrogen spectrum of the hydroxyl group in the deuterated tert-butyl alcohol.
[0038] Comparative Example 1
[0039] A. Add 34 g of magnesium rod and 500 ml of anhydrous tetrahydrofuran into a flask. Add 210 g of deuterated iodomethane dropwise under a nitrogen atmosphere and react at room temperature for 4 hours.
[0040] B. Cool to 0°C, add 92 g of deuterated acetone dropwise, and continue the reaction overnight;
[0041] C. Cool to 0°C, add 120 g of 10% by mass deuterated sulfuric acid, keep warm and stir for 4 hours, let stand to separate, and take the organic phase. The boiling point of tetrahydrofuran in the organic phase is 66°C, and the boiling point of tert-butanol is 82°C, with a boiling point difference of 16°C. Ordinary distillation cannot purify deuterated tert-butanol, and a distillation column with a high theoretical plate number is required for separation and purification. According to the material ratio of deuterated tert-butanol to tetrahydrofuran, the distillation column section temperature and reflux ratio are adjusted to first distill out the tetrahydrofuran and deuterated tert-butanol mixture, and then distill out deuterated tert-butanol with a purity of more than 99%. This process takes 24-48 hours. At the same time, since the tetrahydrofuran and deuterated tert-butanol mixture cannot be further purified, 10-15% of the deuterated tert-butanol is lost, thereby reducing the yield. Therefore, compared with Example 1, Comparative Example 1 uses tetrahydrofuran as the reaction solvent, which has the disadvantages of high production equipment cost, long time consumption and low yield.
[0042] Example 2
[0043] A. Add 40 g of magnesium rod and 500 ml of anhydrous butyl ether into a flask. Add 210 g of deuterated iodomethane dropwise under a nitrogen atmosphere and react at room temperature for 4 hours.
[0044] B. Cool to 0°C, add 92 g of deuterated acetone dropwise, and continue the reaction overnight;
[0045] C. Cool to 0°C, add 240 g of 10% mass fraction of deuterated sulfuric acid, keep warm and stir for 4 hours, let stand to separate, take the organic phase and distill at 110°C for 2-3 hours to separate the butyl ether and deuterated tert-butyl alcohol with a large boiling point difference, and obtain the first deuterated tert-butyl alcohol product;
[0046] The aqueous phase was subjected to atmospheric distillation at 100° C. to distill out an azeotrope of deuterated tert-butanol and water. The azeotrope was subjected to a water absorbent to remove water to obtain a second deuterated tert-butanol product. The first deuterated tert-butanol product and the second deuterated tert-butanol product were combined to obtain a deuterated tert-butanol product with a deuteration rate of 98.73% and a purity of 99.14%.
[0047] The residual liquid after the first distillation is subjected to a second atmospheric distillation at 130° C. to recover heavy water, and the recovered heavy water can be used to prepare the next 10% mass fraction of deuterated sulfuric acid.
[0048] Compared with Example 1, the increased magnesium content in Example 2 will increase the amount of deuterated sulfuric acid used, increasing the cost of producing and recovering the deuterium source.
[0049] Example 3
[0050] A. Add 34 g of magnesium rod and 500 ml of anhydrous butyl ether into a flask. Add 210 g of deuterated iodomethane dropwise under a nitrogen atmosphere and react at room temperature for 4 hours.
[0051] B. Cool to 0°C, add 115 g of deuterated acetone dropwise, and continue the reaction overnight;
[0052] C. Cool to 0°C, add 120 g of 10% mass fraction deuterated sulfuric acid, keep warm and stir for 4 hours, let stand to separate, take the organic phase for distillation, separate butyl ether, deuterated tert-butyl alcohol and deuterated acetone, first distill the deuterated acetone and then distill to obtain the first deuterated tert-butyl alcohol product;
[0053] The aqueous phase is subjected to atmospheric distillation at 100° C. to distill out a mixture of deuterated tert-butanol, deuterated acetone, and water. The deuterated acetone must first be removed by rectification, and the remaining deuterated tert-butanol and water azeotrope is subjected to a water absorbent to remove water to obtain a second deuterated tert-butanol product. The first deuterated tert-butanol product and the second deuterated tert-butanol product are combined to obtain a deuterated tert-butanol product with a deuteration rate of 98.50% and a purity of 99.02%.
[0054] The residual liquid after the first distillation is subjected to a second atmospheric distillation at 130° C. to recover heavy water, and the recovered heavy water can be used to prepare the next 10% mass fraction of deuterated sulfuric acid.
[0055] In Example 3, the amount of deuterated acetone is increased, and unreacted deuterated acetone will remain in the reaction system after the reaction, which increases the difficulty and cost of subsequent distillation and purification, thereby reducing the yield of deuterated tert-butanol.
[0056] Example 4
[0057] A. Add 34 g of magnesium rod and 500 ml of anhydrous butyl ether into a flask. Add 210 g of deuterated iodomethane dropwise under a nitrogen atmosphere and react at room temperature for 4 hours.
[0058] B. Cool to 0°C, add 92 g of deuterated acetone dropwise, and continue the reaction overnight;
[0059] C. Cool to 0°C, add 120 g of 10% mass fraction deuterated sulfuric acid, keep warm and stir for 4 hours, let stand to separate, take the organic phase and distill at 110°C for 2-3 hours to separate the butyl ether and deuterated tert-butyl alcohol with a large boiling point difference, and obtain the first deuterated tert-butyl alcohol product;
[0060] The aqueous phase was subjected to atmospheric distillation at 100° C. to distill out an azeotrope of deuterated tert-butanol and water. The azeotrope was subjected to a water absorbent dehydration operation to obtain a second deuterated tert-butanol product. The first deuterated tert-butanol product and the second deuterated tert-butanol product were combined to obtain a deuterated tert-butanol product with a deuteration rate of 98.56% and a purity of 99.36%.
[0061] Example 4: If the heavy water in the residual liquid remaining after the first vacuum distillation is not recovered, 100 grams of salt-containing heavy water will be lost, wasting the deuterium source and increasing the production cost.
[0062] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.
Claims
1. A method for preparing deuterated tert-butyl alcohol, characterized in that: The following steps are involved: A. Using anhydrous butyl ether as a reaction solvent, deuterated iodomethane and magnesium are reacted under the protection of an inert gas to generate deuterated methylmagnesium iodide; B. reacting deuterated methylmagnesium iodide with deuterated acetone to generate an intermediate product; C. The intermediate product is reacted with deuterated sulfuric acid and further purified to obtain deuterated tert-butyl alcohol.
2. The method for preparing deuterated tert-butyl alcohol according to claim 1, wherein The molar ratio of deuterated iodomethane to magnesium is 1:0.9-1.1; The molar ratio of deuterated iodomethane to anhydrous butyl ether is 1:1.5-2.5; The molar ratio of deuterated iodomethane to deuterated acetone is 1:0.8-1.
1.
3. The method for preparing deuterated tert-butyl alcohol according to claim 2, wherein: The molar ratio of deuterated iodomethane, magnesium and deuterated acetone is 1:1:0.
8.
4. The method for preparing deuterated tert-butyl alcohol according to any one of claims 1 to 3, wherein: In step A, the reaction temperature of the deuterated iodomethane and magnesium is room temperature and the reaction time is 2 to 8 hours.
5. The method for preparing deuterated tert-butyl alcohol according to any one of claims 1 to 3, characterized in that: In step B, the reaction of deuterated methylmagnesium iodide with deuterated acetone comprises the following steps: adding deuterated acetone dropwise to the reaction solution containing deuterated methylmagnesium iodide obtained in step A at 0-5° C., and reacting for more than 5 hours after the addition is complete.
6. The method for preparing deuterated tert-butyl alcohol according to any one of claims 1 to 3, characterized in that: In step C, reacting the intermediate product with deuterated sulfuric acid comprises the following steps: adding deuterated sulfuric acid to the reaction solution containing the intermediate product obtained in step B at 0-5° C., and stirring at this temperature for at least 4 hours.
7. The method for preparing deuterated tert-butyl alcohol according to any one of claims 1 to 3, characterized in that: In step C, the deuterated sulfuric acid is a D2SO4 D2O solution, wherein the mass fraction of D2SO4 is 5-15%.
8. The method for preparing deuterated tert-butyl alcohol according to any one of claims 1 to 3, characterized in that: In step C, the purification comprises the following steps: standing for separation to obtain an upper organic phase and a lower aqueous phase, and distilling the upper organic phase at 110° C. under normal pressure to obtain a first deuterated tert-butyl alcohol product; The lower aqueous phase is subjected to atmospheric distillation at 100° C. to distill out a mixture containing deuterated tert-butanol and heavy water, which is further separated to obtain a second deuterated tert-butanol product; The residual liquid after the first atmospheric distillation is subjected to a second atmospheric distillation at 130°C to distill out the heavy water for recycling.