Continuous synthesis method of perdeuterated carbazole

Abstract

The invention relates to the field of organic synthesis, and discloses a continuous deuteration preparation method of perdeuterated carbazole. The method comprises the following steps: taking carbazole and a deuterium source as raw materials, reacting under the catalysis conditions of a solvent and a catalyst, collecting an effluent reaction solution, cooling, filtering, concentrating and recrystallizing to obtain the perdeuterated carbazole. According to the present invention, the heavy metal chloride is adopted to catalyze the continuous reaction, the carbazole is adopted as the raw material, the hydrogen-deuterium exchange with the deuterium source is performed to synthesize the perdeuterated carbazole, the reaction condition is mild, the deuterium source is supplemented for multiple times during the reaction process so as to achieve the continuous deuteration, and the conversion rate and the yield are substantially improved. The whole reaction system is carried out in an isolated environment, no other impurities enter the reaction system, the product is free of pollution in the production process, the yield reaches 91% or above, the purity reaches 99.8% or above, and the deuteration degree reaches 99% or above. The whole process does not need high-temperature and high-pressure conditions, is relatively simple and convenient to operate, and facilitates industrial large-scale production.

Description

Technical Field

[0001] The present invention relates to the field of chemical synthesis, and more specifically, to a continuous synthesis method of perdeuterated carbazole. Background Art

[0002] Deuterium is a stable isotope of hydrogen (H), also known as heavy hydrogen. The deuterium nucleus consists of a proton and a deuterium. Its relative atomic weight is twice that of ordinary hydrogen, and its shape and volume are basically the same as hydrogen. In the field of pharmaceutical design, studies have found that replacing some hydrogen atoms in drug molecules with deuterium atoms can keep the activity of drug molecules basically unchanged. At the same time, replacing hydrogen with deuterium can reduce the drug metabolism rate, thereby reducing the dosage and frequency of taking drugs and reducing drug toxicity. Today, with the low success rate of new drugs, deuterium substitution is a good strategy for the redevelopment of old drugs. Deuterium-substituted drugs are becoming a hot area in the development of new drugs, and more than a dozen deuterium-substituted drugs have entered clinical trials. In 2009, the multi-million dollar research and development contract between a small biopharmaceutical company Concert and a large pharmaceutical company GlaxoSmithKline was regarded as a milestone in the development of deuterium-substituted drugs. After that, Concert further cooperated with several pharmaceutical companies (such as Jazz, Avanir and Celgene) to develop deuterium-substituted drugs. Like Concert, Auspex is a small biopharmaceutical company that started out by developing deuterated drugs. It was acquired by Teva in 2015. The deuterated drug they jointly developed, deuterated tetrabenazine (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, and the demand for deuterated raw materials is extremely high. my country has always relied on imports for reagents for the research and development of deuterated drugs. Therefore, developing a fully automatic synthesis process for deuterated drug synthesis intermediates to reverse the situation of dependence on imports has become a core issue that needs to be solved urgently in order for my country's pharmaceutical industry to improve its research and development capabilities, increase industrial benefits and comprehensive competitiveness, and gain the initiative in development.

[0004] As common materials in organic chemistry, carbazole compounds have been widely used in medicine, pesticides, dyes, and optoelectronic materials. In medicine, carbazole mycin and the non-steroidal drug carprofen are used as antibacterial drugs; carbazole amide compounds have an inhibitory effect on tumor cells.

[0005] In 2015, Chiharu Suzuki et al. used deuterated o-aminobiphenyl as a raw material, used an iridium catalyst, and 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 raw material to synthesize deuterated carbazole. These synthesis methods all require multiple steps of synthesis to obtain the final product, and deuteration does not occur in the last step, which greatly increases the cost of synthesizing deuterated carbazole. In order to simplify the synthesis steps, the existing technology is to directly prepare deuterated carbazole by hydrogen-deuterium exchange on carbazole compounds to reduce the synthesis steps of deuterated carbazole compounds. In 2019, Kim Seo Ra used heavy water as a deuterium source, under Pd / C catalysis, microwave, 160 degrees, and 13 atmospheres (B. Korean. Chem. Soc. 2019, 40, 186-188), to achieve the synthesis of carbazole directly converted to perdeuterated carbazole. In 2021, Anhui Xiulang New Materials Technology Co., Ltd. published a patent (CN112876406), which used heavy water as a deuterium source, hydrofluoric acid catalysis, and 120 degrees to deuterate carbazole to perdeuterated carbazole, with a deuteration rate of 95%. In 2022, Ningbo Cuiying Chemical Technology Co., Ltd. published a patent (CN114853557), which used carbazole as a raw material, heavy water as a deuterium source, and polyfluoric anhydride catalysis, 240°C high temperature conditions, deuterated 5 times, and achieved the preparation of perdeuterated carbazole. Deuteration reactions such as these require expensive noble metal catalysts, high temperatures and high pressures. Although acid catalysis avoids noble metal catalysts, the acidic hydrogen in the acid catalyst itself reduces the isotopic abundance of deuterium, which is not conducive to the preparation of highly deuterated products. Therefore, the development of a new synthesis method for perdeuterated carbazole is of great significance for the industrial production of perdeuterated carbazole. Summary of the invention

[0006] The invention overcomes the shortcomings of the prior art, independently develops, designs and manufactures a set of fully automated synthesis control equipment, and provides a continuous deuterated preparation method of perdeuterated carbazole, which has relatively mild reaction conditions, good deuterated effect, high deuterium isotope abundance, high product purity and yield, and low pollution.

[0007] To realize the present invention, the perdeuterated carbazole synthesis route is:

[0008]

[0009] The product obtained by the present invention is a compound in which all hydrogen atoms on carbazole are deuterated. The perdeuterated carbazole obtained by the present invention is a white solid with a yield of more than 91%, a purity of more than 99.8%, and a deuteration degree of more than 99%.

[0010] The present application provides a fully automated synthesis control device, which specifically adopts the following scheme:

[0011] A fully automatic synthesis control device, comprising:

[0012] Injector;

[0013] A pipeline reactor, connected to the sample injector, comprising a plurality of pipeline reaction units connected in series;

[0014] A circulating heating device, connected to the pipeline reactor, comprising a heater and a circulating pump, for heating the reaction;

[0015] The automatic detection system is connected to the pipeline reactor and is used to detect the purity and deuteration degree of the product. When it is detected that the product content does not meet the requirements, the cyclic reaction continues.

[0016] The present application provides a method for preparing a perdeuterated carbazole by continuous deuteration, comprising the following steps:

[0017] Carbazole and a deuterium source are used as raw materials, and a reaction occurs under the catalytic conditions of a solvent and a catalyst. The reaction liquid flowing out is collected, cooled, filtered, concentrated, and recrystallized to obtain fully deuterated carbazole. The reaction route is as follows:

[0018]

[0019] Further optionally, the method specifically comprises the following steps:

[0020] Step (1): Fill the catalyst unit with a molecular sieve loaded with a metal catalyst, start circulating heating in an inert gas atmosphere, and preheat the pipeline to the reaction temperature;

[0021] Step (2): uniformly mixing carbazole, a deuterium source and a solvent, and pumping them into a preheated continuous pipeline reactor at a certain flow rate, and at the same time slowly pumping the deuterium source into each pipeline reaction unit;

[0022] Step (3): Add an automatic detection system to detect the purity and deuterium degree of the product. If the product does not meet the requirements, it will automatically enter the circulation system;

[0023] Step (4): collecting the reaction solution, filtering, concentrating and recrystallizing to obtain a fully deuterated carbazole product, and recovering a low-purity deuterium source.

[0024] Optionally, in step (1), the metal catalyst is selected from halides of heavy metals such as Fe, Ni, Co, Pt, Pd, Ir, Mo and Cu.

[0025] Further optionally, in step (1), the metal catalyst is MoCl 5 .

[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 having 5 to 10 carbon atoms, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide.

[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 deuterium supplement source is pumped in at a flow rate of 0.1-5 mL / min.

[0036] Further optionally, in step (2), the deuterium supplement source is pumped in at a flow rate of 1-2 mL / min.

[0037] In summary, this application has the following beneficial effects:

[0038] The invention uses a continuous fluid pipeline reaction catalyzed by heavy metal chloride, takes carbazole as a raw material, and synthesizes fully deuterated carbazole by hydrogen-deuterium exchange with a deuterium source. The reaction conditions are mild, and the deuterium source is supplemented multiple times during the reaction process to achieve continuous deuteration, thereby greatly improving the conversion rate and yield. The entire reaction system is carried out in an isolated environment, and no other impurities enter the reaction system. The product is pollution-free during the production process, and the yield reaches more than 91%, the purity is greater than 99.8%, and the deuteration degree reaches more than 99%. The entire process does not require high temperature and high pressure conditions, the operation is relatively simple, and it is conducive to realizing industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 : Schematic diagram of the reaction process and device of the embodiment of the present application. DETAILED DESCRIPTION

[0040] The structure and effect of the present application are further described in detail below in conjunction with the embodiments. It is to be understood that the specific embodiments described herein are only used to explain the invention, rather than to limit the invention. It is also necessary to explain that, for ease of description, only the parts related to the invention rather than the entire structure are shown in the accompanying drawings.

[0041] Example 1

[0042] This embodiment discloses a fully automated synthesis control device, referring to Figure 1 , the fully automated synthesis control equipment comprises:

[0043] Injector;

[0044] A pipeline reactor, connected to the sample injector, comprising a plurality of pipeline reaction units connected in series;

[0045] A circulating heating device, connected to the pipeline reactor, comprising a heater and a circulating pump, for heating the reaction;

[0046] The automatic detection system is connected to the pipeline reactor and is used to detect the purity and deuteration degree of the product. When it is detected that the product content does not meet the requirements, the cyclic reaction continues.

[0047] Example 2

[0048] This embodiment discloses a method for preparing a perdeuterated carbazole by continuous deuteration, comprising the following steps:

[0049] Carbazole and a deuterium source are used as raw materials, and a reaction occurs under the catalytic conditions of a solvent and a catalyst. The reaction liquid flowing out is collected, cooled, filtered, concentrated, and recrystallized to obtain fully deuterated carbazole. The reaction route is as follows:

[0050]

[0051] The method specifically comprises the following steps:

[0052] 1) Molybdenum pentachloride is loaded on a molecular sieve and filled into a catalyst unit of a pipeline reactor, and a circulating heating device is started to preheat the pipeline to 80°C.

[0053] 2) Carbazole (100.0 g, 0.60 mol, 1 equivalent), heavy water (120 g, 6.0 mol, 10 equivalents) and dioxane (423 g, 4.8 mol, 8 equivalents) were stirred and mixed uniformly, and after the pipeline temperature reached 80° C., the reaction materials were pumped into the continuous pipeline reactor through an injector at a flow rate of 10 mL / min.

[0054] 3) After the reaction materials 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 samples. Qualified products flow out from the outlet at the end of the reactor, and unqualified products enter the circulation system for further deuteration.

[0056] 5) Collect the outflowing reaction solution, cool it down, filter, concentrate and recrystallize to obtain 97.2g of deuterated carbazole, and recover low-purity deuterium water. The final yield of deuterated carbazole is 92.8%, the purity is 99.9% and the deuteration degree is 99.6%.

[0057] Example 3

[0058] This embodiment discloses a method for preparing a perdeuterated carbazole by continuous deuteration, comprising the following steps:

[0059] Carbazole and a deuterium source are used as raw materials, and a reaction occurs under the catalytic conditions of a solvent and a catalyst. The reaction liquid flowing out is collected, cooled, filtered, concentrated, and recrystallized to obtain fully deuterated carbazole. The reaction route is as follows:

[0060]

[0061] The method specifically comprises the following steps:

[0062] 1) Molybdenum pentachloride is loaded on a molecular sieve and filled into a catalyst unit of a pipeline reactor, and a circulating heating device is started to preheat the pipeline to 90°C.

[0063] 2) Carbazole (100.0 g, 0.60 mol, 1 equivalent), heavy water (180 g, 9.0 mol, 15 equivalents) and dioxane (528 g, 6.0 mol, 10 equivalents) were stirred and mixed uniformly, and after the pipeline temperature reached 90° C., the reaction materials were pumped into the continuous pipeline reactor through an injector at a flow rate of 15 mL / min.

[0064] 3) After the reaction materials 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 samples. Qualified products flow out from the outlet at the end of the reactor, and unqualified products enter the circulation system for further deuteration.

[0066] 5) Collect the outflowing reaction solution, cool it, filter, concentrate and recrystallize to obtain 96.4g of deuterated carbazole, and recover low-purity deuterium water. The final yield of deuterated carbazole is 92%, the purity is 99.8%, and the deuteration degree is 99.3%.

[0067] Example 4

[0068] This embodiment discloses a method for preparing a perdeuterated carbazole by continuous deuteration, comprising the following steps:

[0069] Carbazole and a deuterium source are used as raw materials, and a reaction occurs under the catalytic conditions of a solvent and a catalyst. The reaction liquid flowing out is collected, cooled, filtered, concentrated, and recrystallized to obtain fully deuterated carbazole. The reaction route is as follows:

[0070]

[0071] The method specifically comprises the following steps:

[0072] 1) Molybdenum pentachloride is loaded on a molecular sieve and filled into a catalyst unit of a pipeline reactor, and a circulating heating device is started to preheat the pipeline to 80°C.

[0073] 2) Carbazole (100.0 g, 0.60 mol, 1 equivalent), heavy water (240 g, 12.0 mol, 20 equivalents) and dioxane (264 g, 3.0 mol, 5 equivalents) were stirred and mixed uniformly, and after the pipeline temperature reached 80° C., the reaction materials were pumped into the continuous pipeline reactor through an injector at a flow rate of 10 mL / min.

[0074] 3) After the reaction materials 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 samples. Qualified products flow out from the outlet at the end of the reactor, and unqualified products enter the circulation system for further deuteration.

[0076] 5) Collect the outflowing reaction solution, cool it, filter, concentrate and recrystallize to obtain 96.0 g of deuterated carbazole, and recover low-purity deuterium water. The final yield of deuterated carbazole is 91.6%, the purity is 99.8%, and the deuteration degree is 99.0%.

[0077] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A method for preparing a perdeuterated carbazole by continuous deuteration, characterized in that: The following steps are involved: Carbazole and a deuterium source are used as raw materials, and a reaction occurs under the catalytic conditions of a solvent and a catalyst. The reaction liquid flowing out is collected, cooled, filtered, concentrated, and recrystallized to obtain fully deuterated carbazole. The reaction route is as follows:

2. The method for preparing perdeuterated carbazole by continuous deuteration according to claim 1, characterized in that: The method specifically comprises the following steps: The metal catalyst is loaded into the reactor, and the reactor is preheated to the reaction temperature under an inert gas atmosphere; Mix carbazole, deuterium source and solvent evenly, and pump them into the preheated reactor at a certain flow rate for reaction, while slowly pumping the deuterium source into the reaction system; The reaction solution is collected, filtered, concentrated and recrystallized to obtain perdeuterated carbazole.

3. The method for preparing perdeuterated carbazole by continuous deuteration according to claim 1, characterized in that: The metal catalyst is selected from the halide salts of heavy metals such as Fe, Ni, Co, Pt, Pd, Ir, Mo and Cu.

4. The method for preparing perdeuterated carbazole by continuous deuteration according to claim 3, characterized in that: The metal catalyst is MoCl5.

5. The method for preparing perdeuterated carbazole by continuous deuteration according to claim 1, characterized in that: The reaction temperature is 50-120°C.

6. The method for preparing perdeuterated carbazole by continuous deuteration according to claim 1, characterized in that: The molar ratio of carbazole:deuterium source:solvent is 1:(8-30):(5-10).

7. The method for preparing perdeuterated carbazole by continuous deuteration according to claim 6, characterized in that: The molar ratio of carbazole:deuterium source:solvent is 1:10:

8.

8. The method for preparing perdeuterated carbazole by continuous deuteration according to claim 1, characterized in that: The deuterium source reagent is selected from one or two of heavy water, deuterated methanol, deuterated ethanol, deuterated isopropanol, and deuterated benzene.

9. The method for preparing perdeuterated carbazole by continuous deuteration according to claim 1, characterized in that: The solvent is selected from any one or more of cycloalkanes with carbon atoms of 5 to 10, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide.

10. The method for preparing perdeuterated carbazole by continuous deuteration according to claim 2, characterized in that: The reaction flow rate is 5-20 mL / min; the deuterium supplement source pump flow rate is 0.1-5 mL / min.

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