A kind of deuterated bupropion and preparation method thereof

Abstract

The present invention discloses a deuterated bupropion and a preparation method thereof, the method comprising: reacting bupropion and a deuterium source under the action of a photocatalyst and a co-catalyst under a light source in an inert gas atmosphere to obtain deuterated bupropion; wherein the deuterium source is d4-deuterated methanol or deuterated water; the reaction is as follows:

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to deuterated bupropion and a preparation method thereof. Background Art

[0002] Deuterated drugs refer to drugs in which the hydrogen atoms in one or some CH bonds in a compound molecule are replaced with deuterium atoms. Deuterium (2H) atoms and hydrogen (1H) atoms are isotopes with the same number of protons, but because the CD bond has a larger bond energy, breaking the CD bond requires more energy than breaking the CH bond, and the breaking of the carbon-hydrogen bond is an important step in the metabolism of the compound, so replacing the CH bond with a CD bond that is more difficult to break can reduce the drug metabolism rate. Compared with drug molecules before modification with deuterium atoms, deuterated drugs have the following advantages: 1) prolonging the half-life and / or blood drug concentration of the drug; 2) reducing the dose or frequency of drug administration to achieve the same drug exposure, improving patient compliance; 3) possibly blocking certain metabolic sites, reducing the generation of toxic metabolites, and reducing drug toxicity; 4) preventing certain drugs from isomerizing in the body and losing drug activity or even becoming toxic.

[0003] Therefore, deuterium substitution technology can be used to improve suboptimal drugs that are in clinical trials or already on the market. Deuterium tetrabenazine, jointly developed by Teva and Deuterium Drug Development, was approved for marketing by the FDA in 2017, becoming the first deuterium-substituted drug in history to be marketed, and was approved for marketing in China in May 2020. Its prototype drug tetrabenazine has previously been the mainstream drug for the treatment of Huntington's disease, but it has defects such as short half-life and low patient dependence. Deuterium tetrabenazine replaces the hydrogen atoms in the two methoxy groups on the benzene ring of tetrabenazine with deuterium atoms, significantly reducing the rate of drug metabolism and increasing the half-life of the drug, thereby reducing the amount of drug administered, while also inhibiting the withdrawal reaction caused by the decrease in drug blood concentration.

[0004] Since the research on the efficacy, toxicity and other properties of the prototype drugs on the market has been relatively thorough, the research and development cost and risk of failure of the new drug development model of deuterated modification of the drugs on the market are lower than that of the development of new drug compounds. Since 2000, the deuterated strategy has been widely used in drug research and has become one of the ways to break through compound patents and avoid the risks of new drug development. To date, more than ten deuterated drugs have entered the clinical trial stage worldwide, and hundreds of patent applications for deuterated drugs have been authorized by national intellectual property offices including the United States and China. Traditional methods mainly rely on flammable and explosive D2 or highly toxic CD3I or harsh LiAlD4 reduction methods. The above three types of deuterated reagents are expensive, highly dangerous in transportation and storage, and the number of deuterium labels cannot be controlled during use. Therefore, it is urgent to develop a green, mild and controllable deuterium labeling strategy to prepare deuterated drugs.

[0005] Bupropion hydrochloride, chemical name: (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride, is an aminoketone antidepressant. Recent studies have shown that bupropion hydrochloride also has a good therapeutic effect on smoking cessation and can improve the success rate of smoking cessation in patients. Bupropion is a moderate norepinephrine and relatively weak dopamine reuptake inhibitor. It does not act on serotonin. It has two main indications, one is depressive disorder and the other is smoking cessation. It can also be used for generalized anxiety, attention deficit hyperactivity disorder, obesity, dysthymia, social anxiety disorder, post-traumatic stress disorder, chronic fatigue syndrome, neuropathic pain and Parkinson's syndrome. Studies have shown that bupropion can also treat akathisia caused by antipsychotic drugs and sexual dysfunction caused by selective serotonin reuptake inhibitor antidepressants. The generally recommended starting dose of bupropion is 150 mg per day, taken once a day. If it is safe, the dose can be increased to 150 mg within four days, twice a day, with at least eight hours between consecutive doses. Common adverse reactions in clinical practice include headache, insomnia, restlessness, nausea and sweating. Surgical patients may experience hallucinations and delusions. One of its advantages is that it has no anticholinergic adverse reactions, few cardiovascular adverse reactions, no sedative effect, no weight gain, no changes in sexual function, and a relatively low possibility of turning manic, but it may cause psychotic symptoms or epileptic seizures. Therefore, it is necessary to carry out structural modification to reduce drug dosage, improve efficacy, and reduce side effects. Deuterium modification is the most efficient method.

[0006] At the same time, bupropion is a racemic mixture of R- and S-stereoisomers (enantiomers), which convert to each other in solution at room temperature. More importantly, they also convert in vivo after administration, which reduces the efficacy of the drug. If the chiral carbon can be hydrogen-deuterated, the R- and S-enantiomers can be "locked", avoiding the mutual conversion of stereoisomers, and it is also beneficial for the deuterium-stabilized enantiomers to be separated and used, thereby improving the performance of the drug. However, hydrogen-deuterated at this position is very difficult, and the synthesis involves the use of toxic or carcinogenic reagents, the reaction requires multiple steps, and causes waste of resources and environmental pollution. Therefore, it is urgent to develop an efficient and highly selective synthesis method to solve the problems of using toxic or carcinogenic reagents, the reaction process requires multiple steps, harsh conditions, and the waste of resources and environmental pollution in the synthesis of deuterated bupropion drugs. Summary of the invention

[0007] The purpose of the present invention is to provide a method for preparing deuterated bupropion, which avoids the use of expensive highly toxic reagents and highly dangerous reagents, reduces pollution and waste, reduces costs, and is suitable for large-scale industrial production. The present invention has mild reaction conditions, high deuteration rate and high yield.

[0008] In order to achieve the above object, the present invention adopts the following technical solution:

[0009] The present invention provides a method for preparing deuterated bupropion, the method comprising:

[0010] In an inert gas atmosphere, bupropion and a deuterium source are reacted under the action of a photocatalyst and a co-catalyst under a light source to obtain deuterated bupropion; wherein the deuterium source is d4-deuterated methanol or deuterated water; the reaction is as follows:

[0011]

[0012] Furthermore, the photocatalyst is composed of 1% to 5% of a metal catalyst and 95% to 99% of an organic complex by mass fraction, wherein the metal catalyst is selected from Pd, Pt, Au or Ag; the organic complex is a complex composed of a nitrogen-containing heterocycle and a closed borane, wherein the nitrogen-containing heterocycle in the organic complex is selected from copper phthalocyanine, iron phthalocyanine, cobalt phthalocyanine, nickel phthalocyanine or zinc phthalocyanine, and the closed borane in the organic complex is selected from Na2B 12 H 12 , Na2B 10 H 10 , NaB6H7 or Na2B 12 (OH) 12 ; The molar ratio of the nitrogen-containing heterocycle to the closed borane is 2:1, 1:1 or 1:2.

[0013] Furthermore, the co-catalyst is tetrabutylammonium bromide or tetraethylammonium bromide.

[0014] Furthermore, the light source is light in the wavelength range of 200 to 800 nm.

[0015] Furthermore, the photocatalytic reaction time is 24 to 72 hours, and the reaction temperature is 25 to 60°C.

[0016] Furthermore, the molar volume ratio of bupropion to the deuterium source is 1 mmol: (2-5) ml.

[0017] The embodiment of the present invention also provides deuterated bupropion prepared by the method described above.

[0018] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

[0019] The present invention provides a method for preparing deuterated bupropion, which uses the drug bupropion as a raw material, uses more environmentally friendly, low-cost, and easily available deuterated water and deuterated methanol as deuterium sources, and the above-mentioned deuterium source, under the action of photocatalyst, realizes a selective deuteration reaction of hydrogen on the carbon adjacent to the carbonyl group in bupropion at room temperature and pressure, as shown in the reaction formula, thereby preparing a deuterated bupropion drug molecule. The method of the present invention avoids the use of expensive highly toxic reagents and highly dangerous reagents, reduces pollution and waste, reduces costs, and is suitable for large-scale industrial production. The present invention has mild reaction conditions, high deuteration rate, and high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following briefly introduces the drawings required for use in the description of the embodiments. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0021] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of deuterated bupropion in Example 1 of the present invention.

[0022] Figure 2 This is the carbon nuclear magnetic resonance spectrum of deuterated bupropion in Example 1 of the present invention. DETAILED DESCRIPTION

[0023] The present invention will be described in detail below in conjunction with specific implementations and examples, and the advantages and various effects of the present invention will be more clearly presented. It should be understood by those skilled in the art that these specific implementations and examples are used to illustrate the present invention, rather than to limit the present invention.

[0024] Throughout the specification, unless otherwise specifically stated, the terms used herein should be understood as meanings commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. In the event of a conflict, the present specification takes precedence.

[0025] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or obtained by existing methods.

[0026] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0027] According to a typical embodiment of the present invention, a method for preparing deuterated bupropion is provided, the method comprising:

[0028] In an inert gas atmosphere, bupropion and a deuterium source are reacted under the action of a photocatalyst and a co-catalyst under a light source to obtain deuterated bupropion; wherein the deuterium source is d4-deuterated methanol or deuterated water; the reaction is as follows:

[0029]

[0030] In an optional embodiment, the photocatalyst is composed of 1% to 5% of a metal catalyst and 95% to 99% of an organic complex by mass fraction, wherein the metal catalyst is selected from Pd, Pt, Au or Ag; the organic complex is a complex composed of a nitrogen-containing heterocycle and a closed borane, wherein the nitrogen-containing heterocycle in the organic complex is selected from copper phthalocyanine, iron phthalocyanine, cobalt phthalocyanine, nickel phthalocyanine or zinc phthalocyanine, and the closed borane in the organic complex is selected from Na2B 12 H 12 , Na2B 10 H 10 , NaB6H7 or Na2B 12 (OH) 12 ; The molar ratio of the nitrogen-containing heterocycle to the closed borane is 2:1, 1:1 or 1:2.

[0031] If the mass fraction ratio of the metal catalyst and the organic complex is not 1% to 5%: 95% to 99%, by-products may be generated, resulting in a reduced deuteration conversion rate, complicated post-processing and other adverse effects. If the molar ratio of the nitrogen-containing heterocycle to the closed borane is not within the range, there may be adverse effects such as reduced catalyst activity, reduced reaction activity, and reduced deuteration conversion rate.

[0032] In this embodiment, the bupropion raw material, deuterium source, photocatalyst and co-catalyst are mixed and placed in a photoreaction tube, a stirring magnet is added, and the mixture is placed under a light source under an inert gas atmosphere for stirring reaction to obtain deuterated bupropion. During the reaction, the closed borane and phthalocyanine compound complex in the catalyst generates a free radical state under light irradiation, and then generates an intermediate with the deuterium source; then, under the activation of the noble metal atom, a hydrogen-deuterium exchange reaction is achieved through HD exchange, and the α-position proton hydrogen of the bupropion carbonyl group is deuterated to obtain deuterated bupropion. In this embodiment, the bupropion raw material is used, and under the joint catalytic action of ultraviolet light, photocatalyst and co-catalyst, a one-pot reaction is carried out with a deuterium source to obtain deuterated bupropion.

[0033] In an optional embodiment, the co-catalyst is tetrabutylammonium bromide or tetraethylammonium bromide. The addition of the co-catalyst can improve the dispersibility of the catalyst, improve the catalyst activity, and promote the photocatalytic decomposition of deuterated water. More preferably, the co-catalyst is tetrabutylammonium bromide. The addition of tetrabutylammonium bromide can improve the dispersibility of the catalyst, improve the catalyst activity, promote the photocatalytic decomposition of deuterated water and increase the yield of the reaction.

[0034] The light source is light in the wavelength range of 200 to 800 nm. Further, the light source is light in the wavelength range of 360 nm.

[0035] The photocatalytic reaction time is 24 to 72 hours, and the reaction temperature is 25 to 60°C.

[0036] The material ratio of bupropion and deuterium source is: bupropion (mmol) to deuterium source (mL) is 1:2 to 1:5. If too much deuterium source is added, the probability of contact between the catalyst and the bupropion substrate is reduced, which has adverse effects such as slowing down the reaction rate and prolonging the reaction time; if too little deuterium source is added, deuteration is incomplete, the deuteration rate is reduced, and separation is difficult.

[0037] This embodiment uses the raw material drug compound (bupropion) as the raw material, uses safer, more environmentally friendly, and inexpensive deuterated water and deuterated methanol as the deuterium source, and uses a photocatalyst to achieve a selective hydrogen-deuterium exchange reaction of the α-position proton hydrogen of the carbonyl group in bupropion at room temperature and pressure under the action of photocatalysis, thereby preparing a deuterated bupropion drug molecule. The method of this embodiment has higher selectivity, milder reaction conditions, and more economic applicability than the traditional synthesis of deuterated drugs by hydrogen-deuterium exchange, and is suitable for large-scale production of deuterated bupropion drug molecules. The method of this embodiment solves the problems of using deuterium gas, toxic deuterium sources, harsh reaction conditions, low selectivity, and high costs in the existing method for synthesizing deuterated drugs. The deuterated bupropion drug obtained in this embodiment can show excellent pharmacokinetic properties, and the half-life is more than twice that of undeuterated bupropion, which is conducive to reducing the frequency of administration and reducing the side effects of the drug.

[0038] In this embodiment, deuterated water and deuterated methanol are used as the source of deuterated methyl, and the position and number of deuterium in the deuterated reaction are precisely controlled with high selectivity. Since it is a photocatalytic reaction, the reaction conditions are milder. The new method of the present invention can be applied to the synthesis of other deuterated chemicals, and has the advantages of controllable number of deuterium and selectable position, which can reduce the preparation cost of deuterated chemicals and make it widely used in drug synthesis, reaction mechanism research, kinetic research, drug metabolism calibration, biomolecule labeling, etc.

[0039] The following is a detailed description of the preparation method of deuterated bupropion of the present application in combination with examples, comparative examples and experimental data.

[0040] Embodiment 1:

[0041] Weigh 0.5mmol bupropion and 30.0mg Pt@PcCu@Na2B 12 H 12 Photocatalyst (Pt content is 1% of the total mass of photocatalyst, PcCu and Na2B 12 H12 The molar ratio is 2:1) and 35 mg of tetrabutylammonium bromide are added to a 5 mL photoreaction tube, 2 mL of deuterated water is added, a stirring magnet is added, the reaction system is replaced with a nitrogen protection state, and then the photoreaction is placed under a 360 nm light source for illumination reaction for 48 hours. After the reaction is completed, the light source is removed, the reaction mixture is filtered to separate the solid catalyst, and then extracted with 5.0 mL of CH2Cl2, the extract is dried over anhydrous sodium sulfate, and the dichloromethane solvent is removed by rotary evaporation, and then a white solid is obtained by column chromatography (developing solvent: dichloromethane / ethyl acetate), which is the pure target product, such as Figure 1 , Figure 2 As shown, 1 HNMR, 13 The structure was confirmed by C-NMR and infrared spectroscopy. The peak of the α-proton hydrogen of the carbonyl group in the nuclear magnetic hydrogen spectrum near 5.3ppm disappeared. The yield was 95% and the deuteration rate was 98%.

[0042] Figure 1 NMR of deuterated bupropion 1 H spectrum: 1 HNMR (ppm, 400MHz, DMSO-d6): 9.76 (d, J=12.6Hz, 1H), 8.61 (dd, J=12.8, 6.9Hz, 1H), 8.24 (t, J=1.9Hz, 1H), 8.14 (ddd, J=7.8,1.7,1.0Hz,1H), 7.83(ddd,J=8.0,2.1,1.0Hz,1H), 7.63(t,J=7.9Hz,1H), 1.50(d,J=7.0Hz,3H), 1.29(s,9H);

[0043] Figure 2 NMR of deuterated bupropion 13 C spectrum: 13 C-NMR (ppm, 100MHz for carbon, DMSO-d6): 195.51, 134.80, 134.71, 134.13, 131.36, 128.65, 127.81, 127.78, 58.14, 52.99, 52.87, 26.10, 26.03, 25.98, 25.93, 18.09.

[0044] Embodiment 2:

[0045] Weigh 0.5mmol bupropion and 20.0mg Pd@PcCo@Na2B 10 H 10 Photocatalyst (Pd content is 2% of the total mass of photocatalyst, PcCo and Na2B 10 H 10The molar ratio is 1:1) and 30 mg of tetrabutylammonium bromide are added to a 5 mL photoreaction tube, 2 mL of deuterated methanol is added, a stirring magnet is added, the reaction system is replaced with an argon protection state, and then the photoreaction is placed under a 250 nm light source for illumination reaction for 72 hours. After the reaction is completed, the light source is removed, the reaction mixture is filtered to separate the solid catalyst, and then extracted with 5.0 mL of dichloromethane, the extract is dried over anhydrous sodium sulfate, and the dichloromethane solvent is removed by rotary evaporation, and then a white solid is obtained by column chromatography (developing solvent: dichloromethane / ethyl acetate), which is the pure target product. 1 HNMR, 13 The structure was confirmed by C-NMR and infrared spectroscopy. The peak of the α-position proton hydrogen of the carbonyl group in the nuclear magnetic hydrogen spectrum near 5.3ppm disappeared. The yield was 90% and the deuteration rate was 95%.

[0046] Embodiment 3:

[0047] 0.5mmol bupropion, 25.0mg Au@PcFe@NaB6H7 photocatalyst (Au content is 3% of the total mass of the photocatalyst, and the molar ratio of PcFe and NaB6H7 is 1:2) and 30mg tetrabutylammonium bromide are weighed and added to a 5mL photoreaction tube, 1mL of deuterated water is added, a stirring magnet is added, the reaction system is replaced with a nitrogen protection state, and then the photoreaction is placed under a 400nm light source for 56 hours. After the reaction is completed, the light source is removed, the reaction mixture is filtered to separate the solid catalyst, and then extracted with 5.0mL of dichloromethane, the extract is dried with anhydrous sodium sulfate, and the dichloromethane solvent is removed by rotary evaporation, and then a white solid is obtained by column chromatography (developing solvent: dichloromethane / ethyl acetate), which is the pure target product. 1 HNMR, 13 The structure was confirmed by C-NMR and infrared spectroscopy. The peak of the α-position proton hydrogen of the carbonyl group in the nuclear magnetic hydrogen spectrum near 5.3ppm disappeared. The yield was 85% and the deuteration rate was 92%.

[0048] Embodiment 4:

[0049] Weigh 0.5mmol bupropion and 25.0mg Ag@PcNi@Na2B 12 (OH) 12 Photocatalyst (Au content is 4% of the total mass of photocatalyst, PcFe and Na2B 12 (OH) 12The molar ratio is 1:1) and 45 mg of tetrabutylammonium bromide are added to a 5 mL photoreaction tube, 2.5 mL of deuterated methanol is added, a stirring magnet is added, the reaction system is replaced with a nitrogen protection state, and then the photoreaction is placed under a 660 nm light source for illumination reaction for 72 hours. After the reaction is completed, the light source is removed, the reaction mixture is filtered to separate the solid catalyst, and then extracted with 5.0 mL of dichloromethane, the extract is dried over anhydrous sodium sulfate, and the dichloromethane solvent is removed by rotary evaporation, and then a white solid is obtained by column chromatography (developing solvent: dichloromethane / ethyl acetate), which is the pure target product. 1 HNMR, 13 The structure was confirmed by C-NMR and infrared spectroscopy. The peak of the α-position proton hydrogen of the carbonyl group in the nuclear magnetic hydrogen spectrum near 5.3ppm disappeared. The yield was 90% and the deuteration rate was 93%.

[0050] Embodiment 5:

[0051] Weigh 0.5mmol bupropion, 25.0mg Ag@PcZn@Na2B 12 H 12 Photocatalyst (Pt content is 5% of the total mass of photocatalyst, PcFe and Na2B 12 H 12 The molar ratio is 1:2) and 30 mg of tetrabutylammonium bromide are added to a 5 mL photoreaction tube, 2 mL of deuterated methanol is added, a stirring magnet is added, the reaction system is replaced with a nitrogen protection state, and then the photoreaction is placed under an 800 nm light source for illumination reaction for 24 hours. After the reaction is completed, the light source is removed, the reaction mixture is filtered to separate the solid catalyst, and then extracted with 5.0 mL of dichloromethane, the extract is dried over anhydrous sodium sulfate, and the dichloromethane solvent is removed by rotary evaporation, and then a white solid is obtained by column chromatography (developing solvent: dichloromethane / ethyl acetate), which is the pure target product. 1 HNMR, 13 The structure was confirmed by C-NMR and infrared spectroscopy. The peak of the α-proton hydrogen of the carbonyl group in the nuclear magnetic hydrogen spectrum near 5.3ppm disappeared. The yield was 75% and the deuteration rate was 90%.

[0052] Comparative Example 1:

[0053] Weigh 0.5mmol bupropion, 25.0mg Ag@PcZn@Na2B 12 H 12 Photocatalyst (Pt content is 0.5% of the total mass of photocatalyst, PcFe and Na2B 12 H 12The molar ratio is 1:2) and 30 mg of tetrabutylammonium bromide are added to a 5 mL photoreaction tube, 0.5 mL of deuterated methanol is added, a stirring magnet is added, the reaction system is replaced with a nitrogen protection state, and then the photoreaction is placed under an 800 nm light source for illumination reaction for 48 hours. After the reaction is completed, the light source is removed, the reaction mixture is filtered to separate the solid catalyst, and then extracted with 5.0 mL of dichloromethane, the extract is dried over anhydrous sodium sulfate, and the dichloromethane solvent is removed by rotary evaporation, and then a white solid is obtained by column chromatography (developing solvent: dichloromethane / ethyl acetate), which is the pure target product. 1 HNMR, 13 The structure was confirmed by C-NMR and infrared spectroscopy. The peak of the α-position proton hydrogen of the carbonyl group in the nuclear magnetic hydrogen spectrum near 5.3ppm disappeared. The yield was 45% and the deuteration rate was 75%.

[0054] In this comparative example, the content of the metal catalyst Pd in ​​the photocatalyst is 0.5%, which is less than the range of 1% to 5% in the embodiment of the present invention. The ratio of bupropion (mmol) to deuterium source (mL) is 1:1, which is less than the range of 1:2 to 1:5 in the embodiment of the present invention. The yield of preparing deuterated bupropion is low.

[0055] Comparative Example 2:

[0056] Weigh 0.5mmol bupropion, 25.0mg Ag@PcZn@Na2B 12 H 12 Photocatalyst (Pt content is 8% of the total mass of photocatalyst, PcFe and Na2B 12 H 12 The molar ratio is 1:2) and 30 mg of tetrabutylammonium bromide are added to a 5 mL photoreaction tube, 5 mL of deuterated methanol is added, a stirring magnet is added, the reaction system is replaced with a nitrogen protection state, and then the photoreaction is placed under an 800 nm light source for illumination reaction for 48 hours. After the reaction is completed, the light source is removed, the reaction mixture is filtered to separate the solid catalyst, and then extracted with 5.0 mL of dichloromethane, the extract is dried over anhydrous sodium sulfate, and the dichloromethane solvent is removed by rotary evaporation, and then a white solid is obtained by column chromatography (developing solvent: dichloromethane / ethyl acetate), which is the pure target product. 1 HNMR, 13 The structure was confirmed by C-NMR and infrared spectroscopy. The peak of the α-position proton hydrogen of the carbonyl group in the nuclear magnetic hydrogen spectrum near 5.3ppm disappeared. The yield was 25% and the deuteration rate was 50%.

[0057] In this comparative example, the content of the metal catalyst Pd in ​​the photocatalyst is 8%, which is greater than the range of 1% to 5% in the embodiment of the present invention; the ratio of bupropion (mmol) to deuterium source (mL) is 1:10, which is greater than the range of 1:2 to 1:5 in the embodiment of the present invention, and the yield of preparing deuterated bupropion is low.

[0058] Comparative Example 3:

[0059] Weigh 0.5mmol bupropion, 25.0mg Ag@PcZn@Na2B 12 H 12 Photocatalyst (Au content is 8% of the total mass of photocatalyst, PcFe and Na2B 12 H 12 The molar ratio is 1:2) and 30 mg of tetrabutylammonium bromide are added to a 5 mL photoreaction tube, 10 mL of deuterated water is added, a stirring magnet is added, the reaction system is replaced with a nitrogen protection state, and then the photoreaction is placed under a 600 nm light source for illumination reaction for 24 hours. After the reaction is completed, the light source is removed, the reaction mixture is filtered to separate the solid catalyst, and then extracted with 5.0 mL of dichloromethane, the extract is dried over anhydrous sodium sulfate, and the dichloromethane solvent is removed by rotary evaporation, and then a white solid is obtained by column chromatography (developing solvent: dichloromethane / ethyl acetate), which is the pure target product. 1 HNMR, 13 The structure was confirmed by C-NMR and infrared spectroscopy. The peak of the α-position proton hydrogen of the carbonyl group in the nuclear magnetic hydrogen spectrum near 5.3ppm disappeared. The yield was 18% and the deuteration rate was 45%.

[0060] In this comparative example, the content of the metal catalyst Au in the photocatalyst is 8%, which is greater than the range of 1% to 5% in the embodiment of the present invention. The ratio of bupropion (mmol) to deuterium source (mL) is 1:20, which is greater than the range of 1:2 to 1:5 in the embodiment of the present invention. The yield of preparing deuterated bupropion is low.

[0061] In summary, the present invention provides a method for preparing deuterated bupropion. The present invention uses bupropion API as a raw material, uses more environmentally friendly and inexpensive deuterated water and deuterated methanol as deuterium sources, and uses a photocatalyst to achieve a selective deuteration reaction of the α-position proton of the carbonyl group of the bupropion molecule at room temperature and pressure under the action of photocatalysis, thereby preparing deuterated bupropion drug molecules. The method of the present invention has higher selectivity, milder reaction conditions and more economical applicability than the traditional synthesis of deuterated drugs by hydrogen-deuterium exchange, and is more suitable for large-scale production of deuterated bupropion drug molecules.

[0062] Finally, it should be noted that the terms "comprises," "includes," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements that are inherent to such process, method, article, or apparatus.

[0063] Although the preferred embodiments of the present invention have been described, those skilled in the art may make other changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0064] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A method for preparing deuterated bupropion, characterized in that: The method comprises: In an inert gas atmosphere, bupropion and a deuterium source are reacted under the action of a photocatalyst and a co-catalyst under a light source to obtain deuterated bupropion; wherein the deuterium source is d4-deuterated methanol or deuterated water; the reaction is as follows: The photocatalyst is composed of 1% to 5% of a metal catalyst and 95% to 99% of an organic complex by mass fraction, wherein the metal catalyst is selected from Pd, Pt, Au or Ag; the organic complex is a complex composed of a nitrogen-containing heterocycle and a closed borane, wherein the nitrogen-containing heterocycle in the organic complex is selected from copper phthalocyanine, iron phthalocyanine, cobalt phthalocyanine, nickel phthalocyanine or zinc phthalocyanine, and the closed borane in the organic complex is selected from Na2B 12 H 12 , Na2B 10 H 10 , NaB6H7 or Na2B 12 (OH) 12 ; The molar ratio of the nitrogen-containing heterocycle to the closed borane is 2:1, 1:1 or 1:2; The co-catalyst is tetrabutylammonium bromide or tetraethylammonium bromide; The light source is light in the wavelength range of 200 to 800 nm.

2. The method according to claim 1, characterized in that The photocatalytic reaction time is 24 to 72 hours, and the reaction temperature is 25 to 60°C.

3. The method according to claim 1, characterized in that The molar volume ratio of bupropion to the deuterium source is 1 mmol: (2-5) ml.

4. The method according to claim 1, characterized in that The inert atmosphere is nitrogen or argon.

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