A continuous synthesis of perdeuterated carbazole
By using fully automated synthesis control equipment and continuous fluid pipeline reaction, the problems of cumbersome synthesis steps and high cost in the existing technology of deuterated carbazole have been solved, and the production of deuterated carbazole with high yield and high purity has been achieved, which is suitable for industrial application.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANGHAI ABOTCHEM CO LTD
- Filing Date
- 2025-02-21
- Publication Date
- 2026-07-14
AI Technical Summary
Existing methods for synthesizing deuterated carbazole require multiple steps, use precious metal catalysts, and involve high temperatures and pressures, resulting in high costs and low deuterium isotope abundance, making industrial-scale production difficult.
The process employs fully automated synthesis control equipment, using a continuous fluid pipeline reaction and heavy metal catalysts to carry out deuteration under mild conditions. Combined with an automatic detection system and multiple deuterium source replenishments, it achieves high yield and high purity production of fully deuterated carbazole.
It achieves high yield (over 91%) and high purity (over 99.8%) of fully deuterated carbazole, with a deuteration degree of over 99%, avoiding the use of high temperature, high pressure and precious metal catalysts, making it suitable for industrial production.
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Figure CN119798140B_ABST
Abstract
Description
Technical Field
[0001] This application relates to the field of chemical synthesis, and more specifically, to a continuous synthesis method for per-deuterated carbazole. Background Technology
[0002] Deuterium is a stable isotope of hydrogen (H), also known as heavy hydrogen. The deuterium atom consists of one proton and one neutron, and its relative atomic mass is twice that of ordinary hydrogen. Its shape and volume are essentially the same as hydrogen. In the field of pharmaceutical design, research has found that replacing some hydrogen atoms in a drug molecule with deuterium atoms does not significantly alter the drug's activity. Furthermore, replacing hydrogen with deuterium can reduce the drug's metabolic rate, thereby reducing dosage and frequency, and decreasing drug toxicity. Given the low success rate of new drug development, deuteration is a promising strategy for redeveloping existing drugs. Deuterated drugs are becoming a hot area in new drug development, with more than ten deuterated drugs already in clinical trials. A multi-million dollar research contract between a small biopharmaceutical company, Concert, and a large pharmaceutical company, GlaxoSmithKline, in 2009 is considered a milestone in deuterated drug development. Subsequently, Concert has further collaborated with several pharmaceutical companies (such as Jazz, Avanir, and Celgene) to develop deuterated drugs. Like Concert, Auspex is a small biopharmaceutical company that started by developing deuterated drugs. It was acquired by Teva in 2015. The deuterated drug they jointly developed, deuterated benzodiazepine (trade name: Austedo), was approved by the FDA in April 2017, becoming the world's first deuterated drug.
[0003] Many Chinese companies have invested heavily in the research and development of deuterated drugs, resulting in an extremely high demand for deuterated raw materials. Historically, my country has relied on imports for reagents used in deuterated drug development. Therefore, developing fully automated synthesis processes for deuterated drug intermediates to reverse this import dependence has become a core issue that urgently needs to be addressed to improve the research and development capabilities of my country's pharmaceutical industry, increase industrial efficiency and overall competitiveness, and gain the initiative in development.
[0004] Carbazole compounds, as common materials in organic chemistry, have been widely used in medicine, pesticides, dyes, and optoelectronic materials. In medicine, carbazolemycin and the nonsteroidal anti-inflammatory drug carbofen are used as antibacterial agents; carbazole amide compounds have inhibitory effects on tumor cells.
[0005] In 2015, Chiharu Suzuki et al. used deuterated o-aminobiphenyl as a starting material and employed an iridium catalyst with NC coupling to obtain deuterated carbazole. In 2016, Wen Lixian et al. used Pd(OAc)₂ and Cu(OAc)₂ as catalysts and deuterated diphenylamine as a starting material to synthesize deuterated carbazole. These synthetic methods all require multiple steps to obtain the final product, and deuteration does not occur in the final step, which significantly increases the cost of synthesizing deuterated carbazole. To simplify the synthetic process, existing techniques involve directly preparing deuterated carbazole through hydrogen-deuterium exchange on carbazole compounds, thereby reducing the number of synthetic steps for deuterated carbazole compounds. In 2019, Kim Seo Ra synthesized carbazole directly to all-deuterated carbazole using heavy water as the deuterium source under Pd / C catalysis, microwave conditions, 160°C, and 13 atmospheres of pressure (B.Korean.Chem.Soc.2019,40,186-188). In 2021, Anhui Xiulang New Material Technology Co., Ltd. published a patent (CN112876406) that used heavy water as the deuterium source, hydrofluoric acid catalysis, and 120°C to deuterate carbazole to all-deuterated carbazole, achieving a deuteration rate of 95%. In 2022, Ningbo Cuiying Chemical Technology Co., Ltd. published a patent (CN114853557) that used carbazole as a raw material and heavy water as the deuterium source, under polyfluoro anhydride catalysis and 240°C high temperature conditions, achieving the preparation of all-deuterated carbazole through five deuteration cycles. Such deuteration reactions require expensive precious metal catalysts and involve high temperatures and pressures. While acid catalysis avoids the need for precious metal catalysts, the acidic hydrogen atoms inherent in the catalyst reduce the isotopic abundance of deuterium, which is detrimental to the preparation of highly deuterated products. Therefore, developing new synthetic methods for per-deuterated carbazole is of great significance for the industrial production of per-deuterated carbazole. Summary of the Invention
[0006] This invention overcomes the shortcomings of existing technologies by independently developing, designing, and manufacturing a fully automated synthesis control device, providing a continuous deuteration preparation method for fully deuterated carbazole. The method features mild reaction conditions, good deuteration effect, high deuterium isotope abundance, high product purity and yield, and low pollution.
[0007] To achieve the present invention, the synthetic route for the per-deuterium carbazole is as follows:
[0008]
[0009] The product obtained by this invention is a compound in which all hydrogen atoms on the carbazole are deuterated. The per-deuterated carbazole obtained by this invention is a white solid with a yield of over 91%, a purity greater than 99.8%, and a degree of deuteration greater than 99%.
[0010] This application provides a fully automated synthesis control device, which specifically adopts the following solution:
[0011] A fully automated synthesis control device, comprising:
[0012] Injector;
[0013] A tubular reactor, connected to the injector, comprises multiple tubular reaction units connected in series.
[0014] A circulating heating device, connected to the pipeline reactor, includes a heater and a circulating pump for heating the reaction;
[0015] An automatic detection system, connected to the pipeline reactor, is used to detect the purity and deuteration of the product. When the product content is found to be non-compliant, the cycle reaction continues.
[0016] This application provides a method for the continuous deuteration preparation of fully deuterated carbazole, comprising the following steps:
[0017] Using carbazole and deuterium as raw materials, a reaction occurs under solvent and catalyst conditions. The effluent reaction solution is collected, cooled, filtered, concentrated, and recrystallized to obtain per-deuterated carbazole. The reaction route is as follows:
[0018]
[0019] Further, optionally, the method specifically includes the following steps:
[0020] Step (1): Fill the catalyst unit with molecular sieve loaded with metal catalyst, and in an inert gas atmosphere, turn on the circulating heating to preheat the pipeline to the reaction temperature;
[0021] Step (2): Mix carbazole, deuterium source and solvent evenly, and pump into the preheated continuous pipeline reactor at a certain flow rate, while slowly pumping deuterium source into each pipeline reaction unit.
[0022] Step (3): Add an automatic detection system to detect the purity and deuteration of the product. Products that do not meet the requirements will automatically enter the circulation system.
[0023] Step (4): Collect the reaction solution, filter, concentrate and recrystallize to obtain the fully deuterated carbazole product, and recover the low-purity deuterium source.
[0024] Optionally, in step (1), the metal catalyst is selected from the halide salts of heavy metals such as Fe, Ni, Co, Pt, Pd, Ir, Mo, and Cu.
[0025] Further optionally, in step (1), the metal catalyst is MoCl5.
[0026] Optionally, in step (1), the reaction temperature is 50-120°C.
[0027] Further optionally, in step (1), the reaction temperature is 80-90°C.
[0028] Optionally, in step (1), the inert gas is nitrogen or argon.
[0029] Optionally, in step (2), the molar ratio of carbazole:deuterium source:solvent is 1:(8-30):(5-10).
[0030] Further optionally, in step (2), the molar ratio of carbazole:deuterium source:solvent is 1:10:8.
[0031] Optionally, in step (2), the deuterium source reagent is selected from one or two of heavy water, deuterated methanol, deuterated ethanol, deuterated isopropanol, and deuterated benzene.
[0032] Optionally, in step (2), the organic solvent is selected from any one or more of cycloalkanes, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide with 5-10 carbon atoms.
[0033] Optionally, in step (2), the reaction flow rate is 5-20 mL / min.
[0034] Further optionally, in step (2), the reaction flow rate is 10-15 mL / min.
[0035] Optionally, in step (2), the flow rate of the supplementary deuterium source pumped in is 0.1-5 mL / min.
[0036] Further optionally, in step (2), the flow rate of the supplementary deuterium source pumped in is 1-2 mL / min.
[0037] In summary, this application has the following beneficial effects:
[0038] This invention utilizes a continuous fluid pipeline reaction catalyzed by heavy metal chlorides to synthesize fully deuterated carbazole from carbazole via hydrogen-deuterium exchange with a deuterium source. The reaction conditions are mild, and continuous deuteration is achieved through multiple replenishments of the deuterium source during the reaction, significantly improving both conversion and yield. The entire reaction system is conducted in an isolated environment, preventing the introduction of other impurities. The product is produced without contamination, achieving a yield exceeding 91%, a purity greater than 99.8%, and a deuteration degree exceeding 99%. The entire process does not require high temperature or high pressure conditions, making it relatively simple to operate and conducive to large-scale industrial production. Attached Figure Description
[0039] Figure 1 : A schematic diagram of the reaction process and apparatus in the embodiments of this application. Detailed Implementation
[0040] The structure and effects of this application will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and not intended to limit it. Furthermore, it should be noted that, for ease of description, the accompanying drawings show only the parts relevant to the invention, not the entire structure.
[0041] Example 1
[0042] This embodiment discloses a fully automated synthesis control device, referring to... Figure 1 The fully automated synthesis control equipment includes:
[0043] Injector;
[0044] A tubular reactor, connected to the injector, comprises multiple tubular reaction units connected in series.
[0045] A circulating heating device, connected to the pipeline reactor, includes a heater and a circulating pump for heating the reaction;
[0046] An automatic detection system, connected to the pipeline reactor, is used to detect the purity and deuteration of the product. When the product content is found to be non-compliant, the cycle reaction continues.
[0047] Example 2
[0048] This embodiment discloses a continuous deuteration preparation method for fully deuterated carbazole, comprising the following steps:
[0049] Using carbazole and deuterium as raw materials, a reaction occurs under solvent and catalyst conditions. The effluent reaction solution is collected, cooled, filtered, concentrated, and recrystallized to obtain per-deuterated carbazole. The reaction route is as follows:
[0050]
[0051] The method specifically includes the following steps:
[0052] 1) Load molybdenum pentachloride onto a molecular sieve and fill it into the catalyst unit of the pipeline reactor. Start the circulating heating device to preheat the pipeline to 80°C.
[0053] 2) Mix carbazole (100.0g, 0.60mol, 1 equivalent), heavy water (120g, 6.0mol, 10 equivalent) and dioxane (423g, 4.8mol, 8 equivalent) thoroughly. After the pipeline temperature reaches 80℃, pump the reactants into the continuous pipeline reactor through the injector at a flow rate of 10mL / min.
[0054] 3) After the reactants come out of the catalyst packing pipe, heavy water is added at a flow rate of 1 mL / min.
[0055] 4) The automatic detection system detects the purity and deuterated products of the sample. Qualified products flow out from the end outlet of the reactor, while unqualified products enter the circulation system for further deuteration.
[0056] 5) Collect the effluent reaction solution, cool it, filter, concentrate, and recrystallize to obtain 97.2 g of fully deuterated carbazole, and recover low-purity deuterated water. The final yield of fully deuterated carbazole was 92.8%, the purity was 99.9%, and the deuteration degree was 99.6%.
[0057] Example 3
[0058] This embodiment discloses a continuous deuteration preparation method for fully deuterated carbazole, comprising the following steps:
[0059] Using carbazole and deuterium as raw materials, a reaction occurs under solvent and catalyst conditions. The effluent reaction solution is collected, cooled, filtered, concentrated, and recrystallized to obtain per-deuterated carbazole. The reaction route is as follows:
[0060]
[0061] The method specifically includes the following steps:
[0062] 1) Load molybdenum pentachloride onto a molecular sieve and fill it into the catalyst unit of the pipeline reactor. Start the circulating heating device to preheat the pipeline to 90°C.
[0063] 2) Mix carbazole (100.0g, 0.60mol, 1 equivalent), heavy water (180g, 9.0mol, 15 equivalent) and dioxane (528g, 6.0mol, 10 equivalent) evenly. After the pipeline temperature reaches 90℃, pump the reactants into the continuous pipeline reactor through the injector at a flow rate of 15mL / min.
[0064] 3) After the reactants come out of the catalyst packing pipe, heavy water is added at a flow rate of 2 mL / min.
[0065] 4) The automatic detection system detects the purity and deuterated products of the sample. Qualified products flow out from the end outlet of the reactor, while unqualified products enter the circulation system for further deuteration.
[0066] 5) Collect the effluent reaction solution, cool it, filter, concentrate, and recrystallize to obtain 96.4 g of fully deuterated carbazole, and recover low-purity deuterated water. The final yield of fully deuterated carbazole was 92%, the purity was 99.8%, and the deuteration degree was 99.3%.
[0067] Example 4
[0068] This embodiment discloses a continuous deuteration preparation method for fully deuterated carbazole, comprising the following steps:
[0069] Using carbazole and deuterium as raw materials, a reaction occurs under solvent and catalyst conditions. The effluent reaction solution is collected, cooled, filtered, concentrated, and recrystallized to obtain per-deuterated carbazole. The reaction route is as follows:
[0070]
[0071] The method specifically includes the following steps:
[0072] 1) Load molybdenum pentachloride onto a molecular sieve and fill it into the catalyst unit of the pipeline reactor. Start the circulating heating device to preheat the pipeline to 80°C.
[0073] 2) Mix carbazole (100.0g, 0.60mol, 1 equivalent), heavy water (240g, 12.0mol, 20 equivalent) and dioxane (264g, 3.0mol, 5 equivalent) thoroughly. After the pipeline temperature reaches 80℃, pump the reactants into the continuous pipeline reactor through the injector at a flow rate of 10mL / min.
[0074] 3) After the reactants come out of the catalyst packing pipe, heavy water is added at a flow rate of 1 mL / min.
[0075] 4) The automatic detection system detects the purity and deuterated products of the sample. Qualified products flow out from the end outlet of the reactor, while unqualified products enter the circulation system for further deuteration.
[0076] 5) Collect the effluent reaction solution, cool it, filter, concentrate, and recrystallize to obtain 96.0 g of fully deuterated carbazole, and recover low-purity deuterated water. The final yield of fully deuterated carbazole was 91.6%, the purity was 99.8%, and the deuteration degree was 99.0%.
[0077] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.
Claims
1. A method for the continuous deuteration preparation of fully deuterated carbazole, characterized in that, Includes the following steps: Using carbazole and deuterium as raw materials, a reaction occurs under solvent and catalyst conditions. The effluent reaction solution is collected, cooled, filtered, concentrated, and recrystallized to obtain per-deuterated carbazole. The reaction route is as follows: The method specifically includes the following steps: The catalyst unit is filled with molecular sieves loaded with metal catalysts. Under an inert gas atmosphere, the circulating heating is turned on to preheat the pipeline to the reaction temperature. Carbazole, deuterium source and solvent are mixed evenly and pumped into the preheated continuous pipeline reactor at a certain flow rate. At the same time, deuterium source is slowly pumped into each pipeline reaction unit. An automatic detection system is added to detect the purity and deuteration degree of the product. Products that do not meet the requirements are automatically sent to the circulation system. The reaction solution is collected, filtered, concentrated, and recrystallized to obtain fully deuterated carbazole. The reaction flow rate is 5-20 mL / min. The deuterium source replenishment pump flow rate is 0.1-5 mL / min. The metal catalyst is MoCl. 5； The replenishment of the deuterium source is controlled by an automatic detection system during the reaction process; The deuterium source reagent is heavy water; The solvent is selected as 1,4-dioxane; The reaction temperature is 80-90℃.
2. The continuous deuteration preparation method of fully deuterated carbazole according to claim 1, characterized in that, The molar ratio of carbazole:deuterium source:solvent is 1:(8-30):(5-10).
3. The continuous deuteration preparation method of fully deuterated carbazole according to claim 2, characterized in that, The molar ratio of carbazole:deuterium source:solvent is 1:10:8.