A method for catalyzing industrial production of deuterated pharmaceutical intermediates by using immobilized nickel

Abstract

The present application relates to a kind of industrial production of deuterated pharmaceutical intermediate D using supported nickel catalysis method, reaction line condition is mild, conversion, selectivity is high, reaction yield, reaction efficiency is high, deuterium abundance is high, energy consumption is low, post-processing is convenient, reaction operation is simple, more suitable for industrial production.The present application can be prepared with high yield to obtain intermediate D, yield can reach about 90%, and product purity and deuterium abundance reach more than 99%, reach pharmaceutical grade.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a method for industrialized production of deuterated pharmaceutical intermediate D by using a solid-supported nickel catalyst. BACKGROUND

[0002] The novel coronavirus SARS-CoV-2 is a new strain of coronavirus that has never been found in humans before, and was first discovered and reported in 2019 and has not been well controlled in many countries and regions.

[0003] Common signs of human coronavirus infection include respiratory symptoms, fever, cough, shortness of breath, and difficulty breathing. In more severe cases, infection can lead to pneumonia, severe acute respiratory syndrome, kidney failure, and even death, and there is currently no specific treatment for the disease caused by the novel coronavirus.

[0004] The novel deuterated cyan compound is a small molecule 3CL protease inhibitor independently developed by Shanghai Gushen Pharmaceutical Co., Ltd., which can prevent the virus from cutting long protein chains into parts needed for self-replication by inhibiting the main protease, and has the structure: Experiments in vitro have shown that it has amazing anti-SARS-CoV-2 activity and can effectively inhibit viral replication. More surprisingly, on the basis of comparable viral inhibition activity, the compound achieved better pharmacokinetic properties than the oral anti-COVID-19 drugs developed by Pfizer and Merck. Currently, Shanghai Gushen Pharmaceutical Co., Ltd. has prepared for clinical trials for the treatment of COVID-19 patients. Once successful, the market prospects are very huge. Moreover, Shanghai Gushen Pharmaceutical Co., Ltd. has applied for an invention patent for the novel deuterated cyan compound (application number CN202111234708X).

[0005] Deuterated pharmaceutical intermediate D is a key intermediate for synthesizing the novel deuterated cyan compound, and the quality and cost of the final product will be greatly affected by the preparation process of the deuterated pharmaceutical intermediate D. The chemical formula of the deuterated pharmaceutical intermediate D is:

[0006] Although the applicant's prior patent CN202111234708X reports the deuterated pharmaceutical intermediate D and its synthesis route, i.e., using compound B as the starting material, in the presence of sodium borodeuteride and cobalt chloride, first through intermediate state C, and then cyclization to obtain D. The route is shown below:

[0007]

[0008] But the above route failed to provide quality description of intermediates, and after repeated found that the intermediate deuterium abundance was low, the cost was high, and it was not suitable for large-scale production. In order to meet the needs of production, the subsequent applicant patent CN2022100574053 optimized this route. The route is as follows:

[0009]

[0010] The above route uses Pd / C, PtO2, Raney nickel to catalyze the reaction, which has high activity, is flammable and explosive, and is usually stored in water. Direct use will bring in hydrogen source and affect product quality. Even if it is used after deuterated solvent treatment, there are still safety hazards and quality risks. Especially in production, it cannot be scaled up or needs to be modified, which greatly increases the cost. Therefore, in order to meet the needs of production, the route is optimized. SUMMARY

[0011] Based on this, the application provides a method for industrial production of deuterated pharmaceutical intermediate D using solid-supported nickel catalyst. The preparation process route of the application is simple, the catalyst is safe and easy to obtain, the cost is low, the yield and purity are high, and it is suitable for industrial production.

[0012] The specific technical solutions are as follows:

[0013] In the solvent, compound B undergoes deuterium reduction reaction in the presence of catalyst / deuterium gas to obtain intermediate D. The reaction route is as follows:

[0014]

[0015] The catalyst is selected from solid-supported nickel.

[0016] The solid-supported nickel main catalyst is nickel.

[0017] The content of nickel is 55-70%.

[0018] The solid-supported nickel carrier is at least one of diatomite, alumina, silicon oxide, and titanium oxide.

[0019] Preferably, the carrier is selected from alumina.

[0020] The preparation method of the solid-supported nickel is: by precipitation and other technologies, the active ingredient nickel is highly dispersed on the carrier, and then after filtration, washing, drying, calcination, reduction, and passivation, the finished product is formed. The brief process is as follows:

[0021]

[0022] The solvent is selected from deuterated solvent, non-deuterated solvent, or a combination of deuterated solvent and non-deuterated solvent.

[0023] Preferably, the solvent is selected from deuterated solvent.

[0024] Preferably, the deuterated solvent is selected from at least one of heavy water, deuterated alcohols, deuterated esters, deuterated hydrocarbons, deuterated ethers.

[0025] Preferably, the deuterated solvent is selected from at least one of heavy water, deuterated methanol-d1, deuterated methanol-d4, deuterated ethanol-d1, deuterated ethanol-d6, deuterated isopropyl alcohol-d1 and deuterated isopropyl alcohol-d8, including but not limited to any mixed form of mixed solvents in the above-mentioned solvents.

[0026] In some embodiments, the solvent is selected from at least one of water, alcohols, esters, hydrocarbons, ethers, preferably methanol, ethanol, tetrahydrofuran, ethyl acetate, methyl tetrahydrofuran, including but not limited to any mixed form of mixed solvents in the above-mentioned solvents.

[0027] Preferably, the compound B needs to be pretreated before the reaction.

[0028] Preferably, the treatment method is a non-deuterated and deuterated combined solvent washing.

[0029] Preferably, the deuterated solvent of the above-mentioned treatment method is selected from at least one of heavy water, deuterated alcohols, deuterated esters, deuterated hydrocarbons, deuterated ethers, preferably heavy water; the non-deuterated solvent is selected from at least one of water, alcohols, esters, hydrocarbons, ethers, preferably at least one of tetrahydrofuran, ethyl acetate, methyl tetrahydrofuran.

[0030] Preferably, the weight ratio of the deuterated solvent to B in the above-mentioned treatment method is at least 5%.

[0031] Preferably, the reaction temperature is 25-100°C, preferably the reaction temperature is 30-60°C.

[0032] The preparation route of the deuterated pharmaceutical intermediate D of the present application has the following advantages and beneficial effects:

[0033] (1) The reaction conversion rate and selectivity in the present application are high, which greatly improves the reaction yield and deuterium abundance, reduces the cost, and the yield can reach about 90%, and the product purity and deuterium abundance both reach more than 99%;

[0034] (2) The reaction efficiency in the present application is high, the reaction temperature is low, multiple steps are carried out at room temperature, the energy consumption is low, and the reaction operation is simple;

[0035] (3) The synthesis route of the present application has mild conditions and convenient post-treatment, which is more suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1 The figure is the nuclear magnetic hydrogen spectrum of the deuterated pharmaceutical intermediate D.

[0037] Figure 2 Mass spectrum of deuterated pharmaceutical intermediate D. DETAILED DESCRIPTION

[0038] The method for catalyzing the industrial production of deuterated pharmaceutical intermediate D using solid nickel is further described in detail below in combination with specific examples.

[0039] The following detailed description is only exemplary and explanatory, and is not restrictive.

[0040] In the following examples, all solvents and reagents used are commercially available and used as received, unless otherwise specified.

[0041] The following abbreviations are used herein:

[0042] D2: deuterium gas

[0043] Synthesis of intermediate D

[0044]

[0045] Chemical formula: C 13 H 20 D2N2O5

[0046] Molecular weight: 288.34

[0047] Example 1

[0048] Compound B was pretreated with a mixture of tetrahydrofuran / deuterium oxide and then dried for standby.

[0049] The pretreated B (1.0 kg, 3.24 mol) was added to a 20 L hydrogenation reactor, deuterated methanol-d4 (5.0 L, 5V) was added, and aluminum oxide supported nickel (nickel content 63.5%, 300 g, 30 wt% of compound B) was added; nitrogen and deuterium gas were used to replace twice in turn, and finally the deuterium gas was pressurized to 0.5 Mpa; the temperature of the system was raised to 55°C, and the reaction was kept for 18 hours. After the reaction reached the end point, diatomite was padded for filtration, and the filter cake was rinsed with methanol. The solvent was removed by concentration under reduced pressure, and the obtained crude product was dissolved in 10 L dichloromethane. The organic phase was collected after washing with 5 L water once. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was removed by concentration under reduced pressure. The crude product was purified by crystallization with a mixed solution of methyl tert-butyl ether, petroleum ether and ethyl acetate, and white solid was obtained by filtration, with a purity of 99%, a yield of 90%, and a deuterium abundance of 99%.

[0050] LC-MS (ESI, m / z, C 13 H 20 D2N2O5, 189.17, [M+1] = M-100+1)

[0051] 1 H NMR (500 MHz, CDC13) δ: 6.16 (s, 1H), 5.51 (d, 1H), 4.30-4.32 (m, 1H), 3.73 (s, 3H), 2.42-2.48 (m, 2H), 2.10-2.15 (m, 1H), 1.83-1.81 (m, 2H), 1.27 (s, 9H).

[0052] Example 2

[0053] Compound B was pretreated with ethyl acetate / deuterated methanol-d1 mixed solvent and dried for standby.

[0054] The pretreated B (1.0 kg, 3.24 mol) was added to a 20 L hydrogenation reactor, deuterated methanol-d1 (5.0 L, 5V) was added, and silica gel supported nickel (nickel content 59.5%, 300 g, 30 wt% of compound B) was added; nitrogen and deuterium were replaced twice in turn, and finally deuterium was pressurized to 0.5 MPa; the system temperature was raised to 55°C, and the reaction was kept for 18 hours. After the reaction reached the end point, diatomite was padded for filtration, and the filter cake was rinsed with methanol. The solvent was removed by concentration under reduced pressure, and the obtained crude product was dissolved in 10 L dichloromethane. It was washed once with 5 L water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was removed by concentration under reduced pressure. The crude product was purified by crystallization with a mixed solution of methyl tert-butyl ether, petroleum ether and ethyl acetate, and white solid D was obtained by filtration, with a purity of 97%, a yield of 88%, and a deuterium abundance of 97%.

[0055] Example 3

[0056] Compound B was pretreated with methyl tetrahydrofuran / deuterated water mixed solvent and dried for standby.

[0057] The pretreated B (1.0 kg, 3.24 mol) was added to a 20 L hydrogenation reactor, deuterated methanol-d1 (5.0 L, 5V) was added, and silica gel supported nickel (nickel content 59.5%, 300 g, 30 wt% of compound B) was added; nitrogen and deuterium were replaced twice in turn, and finally deuterium was pressurized to 0.5 MPa; the system temperature was raised to 55°C, and the reaction was kept for 18 hours. After the reaction reached the end point, diatomite was padded for filtration, and the filter cake was rinsed with methanol. The solvent was removed by concentration under reduced pressure, and the obtained crude product was dissolved in 10 L dichloromethane. It was washed once with 5 L water, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was removed by concentration under reduced pressure. The crude product was purified by crystallization with a mixed solution of methyl tert-butyl ether, petroleum ether and ethyl acetate, and white solid D was obtained by filtration, with a purity of 97%, a yield of 88%, and a deuterium abundance of 97%.

[0058] Example 4

[0059] Compound B was pretreated with ethyl acetate / deuterated ethanol-d1 mixed solvent and dried for standby.

[0060] The pretreated B (1.0 kg, 3.24 mol) was added to a 20 L hydrogenation reactor, deuterated ethanol-d1 (5.0 L, 5V) was added, titanium oxide supported nickel (nickel content 69.2%, 300 g, 30 wt% of compound B) was added; nitrogen and deuterium were used to replace twice in turn, and finally deuterium was pressurized to 0.5 Mpa; the temperature of the system was raised to 55°C, and the reaction was kept for 18 hours. After the reaction reached the end point, diatomite was padded for filtration, and the filter cake was rinsed with methanol. The solvent was removed by concentration under reduced pressure, and the obtained crude product was dissolved in 10 L dichloromethane. 5 L of water was used for washing once, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was removed by concentration under reduced pressure. The crude product was purified by crystallization with a mixed solution of methyl tert-butyl ether, petroleum ether and ethyl acetate, and white solid D was obtained by filtration, with a purity of 95%, a yield of 83%, and a deuterium abundance of 96%.

[0061] The above embodiments only express several embodiments of the present application, and the description is more specific and detailed, but it cannot be understood as a limitation on the scope of the patent. It should be noted that for ordinary skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, which belong to the protection scope of the present application. Therefore, the protection scope of the present application patent should be subject to the appended claims.

Claims

1. A method for the industrial production of deuterated pharmaceutical intermediate D using supported nickel catalysis, characterized in that, Includes the following steps: Compound B is pretreated by washing with a combination of non-deuterated and deuterated solvents; In a solvent, compound B undergoes a deuteration reduction reaction in the presence of a catalyst / deuterium gas to give intermediate D. The reaction route is as follows: , The catalyst is selected from solid-supported nickel, the main catalyst of the solid-supported nickel is nickel, the nickel content is 55-70%, and the support of the solid-supported nickel is alumina.

2. The method for industrial production of deuterated pharmaceutical intermediate D using supported nickel catalysis according to claim 1, characterized in that: The reaction solvent is selected from deuterated solvents, non-deuterated solvents, or a combination of deuterated and non-deuterated solvents.

3. The method for industrial production of deuterated pharmaceutical intermediate D using supported nickel catalysis according to claim 2, characterized in that: The deuterated solvent is at least one of heavy water, deuterated methanol-d1, deuterated methanol-d4, deuterated ethanol-d1, deuterated ethanol-d6, deuterated isopropanol-d1, and deuterated isopropanol-d8.

4. The method for industrial production of deuterated pharmaceutical intermediate D using supported nickel catalysis according to claim 2, characterized in that: The non-deuterated solvent is at least one of methanol, ethanol, tetrahydrofuran, ethyl acetate, and methyltetrahydrofuran.

5. The method for industrial production of deuterated pharmaceutical intermediate D using supported nickel catalysis according to claim 1, characterized in that: In the pretreatment washing solvent, the deuterated solvent is heavy water; the non-deuterated solvent is at least one of tetrahydrofuran, ethyl acetate, and methyltetrahydrofuran.

6. The method for industrial production of deuterated pharmaceutical intermediate D using supported nickel catalysis according to claim 5, characterized in that: The weight ratio of the deuterated solvent to B is at least 5%.

7. A method for the industrial production of deuterated pharmaceutical intermediate D using supported nickel catalysis according to any one of claims 1-6, characterized in that: The reaction temperature is 25–100 °C.

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